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1.
J Agric Food Chem ; 67(45): 12419-12427, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31610126

RESUMO

The liver X receptors (LXRs) are major regulators of lipogenesis, and their reduced activation by an inhibitor could be a treatment strategy for fatty liver disease. Small molecules originating from dietary food are considered suitable and attractive drug candidates for humans in terms of safety. In this study, an edible plant, Lysimachia vulgaris (LV), used as a traditional and medicinal food in East Asia was evaluated for lipogenesis decreasing effects. Activity-guided fractionation was performed, and the isolated compounds were identified using spectroscopic methods. We conducted in vitro real-time polymerase chain reaction (PCR) and Western blotting as well as histological and biochemical analyses following in vivo treatments. Using a high-fat diet animal model, we confirmed that LV extracts (LVE) decreased lipogenic metabolism and restored liver function to control levels. To identify active components, we conducted activity-guided fractionation and then isolated compounds. Two compounds, loliolide and pinoresinol, were identified in the dichloromethane fraction, and they significantly attenuated the expression levels of lipogenic factors including sterol regulatory element-binding protein (SREBP)-1, stearoyl-CoA desaturase 1 (SCD1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Importantly, loliolide and pinoresinol significantly accelerated the protein degradation of LXRs by enhanced ubiquitination, which inhibited lipogenesis. These results suggest that loliolide and pinoresinol might be potential candidate supplementary treatments for nonalcoholic fatty liver disease (NAFLD) by reducing lipogenesis through increased ubiquitination of LXRs.


Assuntos
Benzofuranos/administração & dosagem , Furanos/administração & dosagem , Lignanas/administração & dosagem , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Primulaceae/química , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Humanos , Fígado/metabolismo , Receptores X do Fígado/genética , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
2.
Chemosphere ; 235: 1030-1040, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31561292

RESUMO

Organic pesticides are one of the main environmental pollutants, and how to reduce their environmental risks is an important issue. In this contribution, we disclose the molecular basis for the resistance of American sloughgrass to aryloxyphenoxypropionic acid pesticides using site-directed mutagenesis and molecular modeling and then construct an effective screening model. The results indicated that the target-site mutation (Trp-1999-Leu) in acetyl-coenzyme A carboxylase (ACCase) can affect the effectiveness of the pesticides (clodinafop, fenoxaprop, cyhalofop, and metamifop), and the plant resistance to fenoxaprop, clodinafop, cyhalofop, and metamifop was found to be 564, 19.5, 10, and 0.19 times, respectively. The established computational models (i.e. wild-type/mutant ACCase models) could be used for rational screening and evaluation of the resistance to pesticides. The resistance induced by target gene mutation can markedly reduce the bioreactivity of the ACCase-clodinafop/fenoxaprop adducts, and the magnitudes are 10 and 102, respectively. Such event will seriously aggravate environmental pollution. However, the biological issue has no distinct effect on cyhalofop (RI=10), and meanwhile it may markedly increase the bioefficacy of metamifop (RI=0.19). We could selectively adopt the two chemicals so as to decrease the residual pesticides in the environment. Significantly, research findings from the computational screening models were found to be negatively correlated with the resistance level derived from the bioassay testing, suggesting that the screening models can be used to guide the usage of pesticides. Obviously, this story may shed novel insight on the reduction of environmental risks of pesticides and other organic pollutants.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Biologia Computacional/métodos , Resistência a Herbicidas/genética , Praguicidas/toxicidade , Proteínas de Plantas/antagonistas & inibidores , Poaceae/crescimento & desenvolvimento , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Anilidas/toxicidade , Benzoxazóis/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Mutação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Poaceae/efeitos dos fármacos , Poaceae/enzimologia , Propionatos/toxicidade , Conformação Proteica , Piridinas/toxicidade , Estados Unidos
3.
Expert Opin Investig Drugs ; 28(10): 917-930, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31430206

RESUMO

Introduction: Acetyl-CoA Carboxylase (ACC) is an essential rate-limiting enzyme in fatty acid metabolism. For many years, ACC inhibitors have gained great attention for developing therapeutics for various human diseases including microbial infections, metabolic syndrome, obesity, diabetes, and cancer. Areas covered: We present a comprehensive review and update of ACC inhibitors. We look at the current advance of ACC inhibitors in clinical studies and the implications in drug discovery. We searched ScienceDirect ( https://www.sciencedirect.com/ ), ACS ( https://pubs.acs.org/ ), Wiley ( https://onlinelibrary.wiley.com/ ), NCBI ( https://www.ncbi.nlm.nih.gov/ ) and World Health Organization ( https://www.who.int/ ). The keywords used were Acetyl-CoA Carboxylase, lipid, inhibitors and metabolic syndrome. All documents were published before June 2019. Expert opinion: The key regulatory role of ACC in fatty acid synthesis and oxidation pathways makes it an attractive target for various metabolic diseases. In particular, the combination of ACC inhibitors with other drugs is a new strategy for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expanding the clinical indications for ACC inhibitors will be one of the hot directions in the future. It is also worth looking forward to exploring safe and efficient inhibitors that act on the BC domain of ACC.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Acetil-CoA Carboxilase/metabolismo , Animais , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Inibidores Enzimáticos/efeitos adversos , Ácidos Graxos/metabolismo , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/fisiopatologia , Síndrome Metabólica/fisiopatologia
4.
Pestic Biochem Physiol ; 158: 143-148, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378350

RESUMO

Chinese sprangletop (Leptochloa chinensis (L.) Nees) is one of the most troublesome grass weeds in rice in China. Seven suspected cyhalofop-butyl-resistant L. chinensis populations were collected from different rice fields with a history of cyhalofop-butyl use. The level of resistance and resistance mechanisms in seven populations were studied. Dose-response tests indicated that five populations (JS3, JS4, JS6, JS7 and JS8) had evolved high-level resistance (26.9 to 123.0-fold) to cyhalofop-butyl compared with the susceptible (S) population, and other two populations (JS2 and JS5) were still sensitive to the herbicide. Two acetyl-coenzyme A carboxylase (ACCase) genes were cloned from each population, and three different ACCase mutations (Ile-1781-Leu, Trp-1999-Cys, and Trp-2027-Cys) in ACCase2 gene were determined in different resistant (R) populations. In addition, no resistance-conferring mutations was detected in the R population (JS7), and ACCase gene expression was similar between the S and R populations. Thus, non-target-site resistance mechanisms may be involved in the JS7 population. Moreover, the patterns of cross-resistance of JS6 (Ile-1781-Leu), JS4 (Trp-1999-Cys), JS8 (Trp-2027-Cys), and JS7 (unknown resistance mechanisms) populations to other ACCase-inhibiting herbicides were determined. The JS6 and JS8 populations showed resistance to fenoxaprop-P-ethyl, metamifop, clethodim and pinoxaden, the JS4 population was resistant to fenoxaprop-P-ethyl, metamifop and pinoxaden, and the JS7 population had resistance only to fenoxaprop-P-ethyl and metamifop. These results indicated the diversity of the target-site mutations in ACCase gene of L. chinensis, and provide a better understanding of cross-resistance in L. chinensis, which would be helpful for the management of cyhalofop-butyl-resistant L. chinensis.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Butanos/farmacologia , Herbicidas/farmacologia , Nitrilos/farmacologia , Poaceae/metabolismo , Acetil-CoA Carboxilase/genética , China , Resistência a Herbicidas/genética , Poaceae/efeitos dos fármacos
5.
Chem Biol Interact ; 311: 108755, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31319077

RESUMO

Effective control of white adipose tissue accumulation would provide a therapeutic strategy for obesity, which poses a growing global problem. The plant chemical mangiferin stimulates adenosine monophosphate-activated protein kinase (AMPK), which inhibits adipogenesis and has therefore been considered a therapeutic target for obesity and related diseases. We previously reported the anti-inflammatory properties of 6'-O-acetyl mangiferin (OAM). In this study, we evaluated the potential of OAM as an AMPK activator in vitro in 3T3-L1 preadipocytes. OAM inhibited adipogenesis as indicated by lower intracellular lipid and triglyceride accumulation as well as reduced adipogenic gene and protein expression upon treatment. OAM-treated 3T3-L1 cells excreted more glycerol, indicating increased lipolysis, which was supported by increased expression of lipolysis-related genes, including adipose triglyceride lipase and hormone-sensitive lipase. We determined that OAM upregulates lipolysis via phosphorylation-dependent activation of AMPK. Further, OAM upregulated the ß-oxidation pathway as indicated by enhanced expression of phosphorylated acetyl-CoA-carboxylase and long-chain acyl-CoA synthetase 1. In conclusion, OAM markedly decreased intracellular lipid accumulation by enhancing lipolysis via AMPK activation and by upregulating ß-oxidation. Thus, OAM has potential as a drug for the prevention and/or improvement of obesity and related diseases and deserves further study.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Iris (Planta)/química , Lipólise/efeitos dos fármacos , Xantonas/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Iris (Planta)/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
6.
J Food Sci ; 84(7): 1900-1908, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31183867

RESUMO

The quality of canola oil is affected by different extraction methods. The effect of cold-pressed canola oil (CPCO) diet and traditional refined bleached deodorized canola oil (RBDCO) diet on lipid accumulation and hepatic steatosis in mice were investigated. The body weight, peroxisome proliferator-activated receptor-α concentration, serum lipid profile, insulin sensitivity, and oxidative stress were increased in mice fed with CPCO diet, which had higher unsaturated fatty acid, tocopherols, phytosterols, and phospholipids but lower saturated fatty acid than RBDCO, after 12 weeks,. Moreover, CPCO significantly increased tocopherols and phytosterols content in liver and reduced liver cholesterol contents and lipid vacuoles accumulation than RBDCO. Also, serum proinflammatory cytokines, 3-hydroxy-3-methylglutary coenzyme A reductase expression level, lipogenic enzymes, and transcriptional factors such as sterol regulatory element-binding proteins 1c, acetyl-CoA carboxylase, and fatty acid synthase in the liver were also markedly downregulated from CPCO diet mice. Overall, CPCO can reduce lipid accumulation and hepatic steatosis by regulating oxidative stress and lipid metabolism in Kun Ming mice compared with RBDCO. PRACTICAL APPLICATION: The results suggested that more bioactive components were contained in cold-pressed canola oil (CPCO) rather than refined bleached deodorized canola oil (RBDCO). CPCO could lower the risk of obesity and hyperlipidemia, reduce lipid accumulation, and prevent hepatic steatosis. It could be considered as a kind of better edible oil than RBDCO.


Assuntos
Fígado Gorduroso/dietoterapia , Metabolismo dos Lipídeos , Estresse Oxidativo , Óleo de Brassica napus/química , Óleo de Brassica napus/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Colesterol/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/análise , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Humanos , Resistência à Insulina , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , PPAR alfa/genética , PPAR alfa/metabolismo , Fosfolipídeos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
7.
J Agric Food Chem ; 67(26): 7336-7347, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31184119

RESUMO

The current research aimed to explore the impact of (-)-hydroxycitric acid (HCA) on fat metabolism and investigate whether this action of (-)-HCA was associated with modulation of glucose-6-phosphote isomerase (GPI) expression in chicken embryos. We constructed a recombinant plasmid (sh2-GPI) to inhibit GPI expression, and then embryos were treated with (-)-HCA. Results showed that (-)-HCA reduced lipid droplet accumulation, triglyceride content, and lipogenesis factors mRNA level and increased lipolysis factors mRNA expression, while this effect caused by (-)-HCA was markedly reversed when the chicken embryos were pretreated with sh2-GPI. (-)-HCA increased phospho (p)-acetyl-CoA carboxylase, enoyl-CoA hydratase short chain-1, carnitine palmitoyl transferase 1A, p-AMP-activated protein kinase, and peroxisome proliferators-activated receptor α protein expression, and this action of (-)-HCA also dispelled when the chicken embryos were pretreated with sh2-GPI. These data demonstrated that (-)-HCA decreased fat deposition via activation of the AMPK pathway, and the fat-reduction action of (-)-HCA was due to the increasing of GPI expression in chicken embryos.


Assuntos
Embrião de Galinha/efeitos dos fármacos , Embrião de Galinha/enzimologia , Citratos/farmacologia , Gorduras/metabolismo , Glucose-6-Fosfato Isomerase/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Embrião de Galinha/metabolismo , Galinhas , Citratos/química , Suplementos Nutricionais/análise , Glucose-6-Fosfato Isomerase/metabolismo , Triglicerídeos/metabolismo
8.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142011

RESUMO

Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride levels. Various physiological activities of omega-3 fatty acids are due to their agonistic actions on G-protein-coupled receptor 40 (GPR40) and GPR120. Lipid droplets (LD) accumulation in hepatocytes confirmed that DHA treatment reduced the number of larger ( >10 µm2) LDs, as well as the total area of LDs. Moreover, DHA lowered protein and mRNA expression levels of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase and stearoyl-CoA desaturase-1 (SCD-1) in primary hepatocytes incubated with liver X receptor (LXR) agonist T0901317 or high glucose and insulin. DHA also decreased protein expression of nuclear and precursor sterol response-element binding protein (SREBP)-1, a key lipogenesis transcription factor. We further found that exposure of murine primary hepatocytes to DHA for 12 h increased GPR40 and GPR120 mRNA levels. Specific agonists (Compound A for GPR120 and AMG-1638 for GPR40), hepatocytes from GPR120 knock-out mice and GPR40 selective antagonist (GW1100) were used to assess whether DHA's antilipogenic effects are mediated through GPR120 or GPR40. Compound A did not decrease SREBP-1 and FAS protein expression in hepatocytes exposed to T0901317 or high glucose with insulin. Moreover, DHA downregulated lipogenesis enzyme expression in GPR120-null hepatocytes. In contrast, AMG-1638 lowered SREBP-1 and SCD-1 protein levels. Additionally, GW1100, a GPR40 antagonist, reversed the antilipogenic effects of DHA. Collectively, our data demonstrate that DHA downregulates the expression SREBP-1-mediated lipogenic enzymes via GPR40 in primary hepatocytes.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Hepatócitos/metabolismo , Lipogênese , Receptores Acoplados a Proteínas-G/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Células Cultivadas , Ácidos Graxos Ômega-3/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
9.
J Nat Med ; 73(4): 707-716, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31104252

RESUMO

Diabetes is a chronic disease associated with triglyceride metabolism disorder, being an etiological factor in fatty liver disease, hypertension, and cardiovascular diseases. Diet-based therapy including energy balance and herbal supplements is a suitable approach to ameliorate progression of the disease. Leaves of Lippia triphylla (lemon verbena) from the family Verbenaceae are a foodstuff used as a tea drink or cooking seasoning, with confirmed safety during long-term use. We report herein the regulatory effect of L. triphylla extract (LTE) and its major compound acteoside (ACT) on abnormal liver lipid metabolism. Both LTE and ACT administration significantly decreased serum and hepatic lipid content, increased the phosphorylation level of the energy metabolism moderator adenosine 5'-monophosphate-activated protein kinase (AMPK), and reduced two major markers of lipid synthesis, viz. acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), with an obvious enhancement in ACC phosphorylation. Furthermore, ACT promoted lipolysis and fatty acid oxidation by increasing messenger RNA (mRNA) expression of adipose triglyceride lipase (ATGL) and carnitine palmitoyltransferase (CPT)-1. These results provide scientific evidence for the development of functional foods containing L. triphylla extract and acteoside for treatment of diabetes-associated lipid metabolism disorder.


Assuntos
Diabetes Mellitus/dietoterapia , Glucosídeos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lippia/química , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Ácido Graxo Sintase Tipo I/metabolismo , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
10.
Nat Plants ; 5(5): 480-485, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988404

RESUMO

Developing herbicide-tolerant varieties by genome editing holds great promise for addressing the worsening weed problems in wheat cultivation1. Here, we generated transgene-free wheat germplasms harbouring herbicide tolerance mutations that confer tolerance to sulfonylurea-, imidazolinone- and aryloxyphenoxy propionate-type herbicides by base editing the acetolactate synthase (ALS) and acetyl-coenzyme A carboxylase genes. These stackable herbicide tolerance traits provide a potentially powerful tool for weed management. In addition, we found that base editing at the wheat ALS Pro-174 codon (TaALS-P174) endowed wheat with sufficient resistance to nicosulfuron herbicide in MS growth medium to allow selection. When the TaALS-P174 editor was coupled with editors for other targets of interest, co-editing occurred in the nicosulfuron-resistant plants, and selection for resistance in growth medium enriched the frequency of coupled targets by several-fold. This selectable co-editing system has the potential to greatly bolster adoption of base editing for crop improvement applications.


Assuntos
Edição de Genes/métodos , Resistência a Herbicidas/genética , Triticum/genética , Acetolactato Sintase/genética , Acetolactato Sintase/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Alelos , Códon/genética , Marcadores Genéticos/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Característica Quantitativa Herdável , Alinhamento de Sequência , Triticum/efeitos dos fármacos , Triticum/enzimologia , Controle de Plantas Daninhas/métodos
11.
Phytomedicine ; 59: 152782, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005808

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Swertia bimaculata (Sieb. et Zucc.) Hook. Thoms.ex Clarke, a glabrous or procumbent perennial herb, is a traditional herb medicine. Swertiamarin, a secoiridoid glycoside, is a representative ingredient in this medical plant crude extract and shows antidiabetic and antihyperlipidaemic activities and protective effect against hepatic injury. PURPOSE: The present study aimed to determine whether swertiamarin can attenuate NAFLD in fructose-fed mice. METHODS: Healthy male mice freely drank water containing 10% fructose for 12 consecutive weeks, whereas animals in those swertiamarin tested groups received different doses of swertiamarin (25, 50 and 100 mg/kg) by intragastric administration once a day from the ninth week to the twelfth week. RESULTS: At the end of the experiment, fructose-fed mice administrated with swertiamarin showed low levels of serum glucose, triglycerides, uric acid, alanine aminotransferase and aspartate transaminase. Histological examinations suggested the alleviation of hepatic ballooning degeneration and steatosis by swertiamarin treatment. Moreover, swertiamarin administration mitigated hepatic oxidative stress along with decreases of hepatic pro-inflammation cytokines, which was associated with decrease of hepatic xanthine oxidase (XO) activity and enhancements of anti-oxidant defense system enzymes, as well as activation of nuclear factor E2-related factor 2 (Nrf2) in fructose-fed mice. In addition, swertiamarin down-regulated expression of sterol-regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1) in liver of fructose-fed mice. CONCLUSION: The present study demonstrates that swertiamarin alleviates NAFLD and metabolic alterations in fructose-fed mice.


Assuntos
Frutose/efeitos adversos , Glucosídeos Iridoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pironas/farmacologia , Acetil-CoA Carboxilase/metabolismo , Alanina Transaminase/metabolismo , Animais , Citocinas/metabolismo , Ácido Graxo Sintases/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Xantina Oxidase/metabolismo
12.
Microb Cell Fact ; 18(1): 71, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975146

RESUMO

BACKGROUND: In the last years, different biotechnologically relevant microorganisms have been engineered for the synthesis of plant polyphenols such as flavonoids and stilbenes. However, low intracellular availability of malonyl-CoA as essential precursor for most plant polyphenols of interest is regarded as the decisive bottleneck preventing high product titers. RESULTS: In this study, Corynebacterium glutamicum, which emerged as promising cell factory for plant polyphenol production, was tailored by rational metabolic engineering towards providing significantly more malonyl-CoA for product synthesis. This was achieved by improving carbon source uptake, transcriptional deregulation of accBC and accD1 encoding the two subunits of the acetyl-CoA carboxylase (ACC), reduced flux into the tricarboxylic acid (TCA) cycle, and elimination of anaplerotic carboxylation of pyruvate. The constructed strains were used for the synthesis of the pharmacologically interesting plant pentaketide noreugenin, which is produced by plants such as Aloe arborescens from five molecules of malonyl-CoA. In this context, accumulation of the C1/C6 cyclized intermediate 1-(2,4,6-trihydroxyphenyl)butane-1,3-dione (TPBD) was observed, which could be fully cyclized to the bicyclic product noreugenin by acidification. CONCLUSION: The best strain C. glutamicum Nor2 C5 mufasOBCD1 PO6-iolT1 ∆pyc allowed for synthesis of 53.32 mg/L (0.278 mM) noreugenin in CGXII medium supplemented with casamino acids within 24 h.


Assuntos
Corynebacterium glutamicum/metabolismo , Glicosídeos/biossíntese , Malonil Coenzima A/metabolismo , Engenharia Metabólica , Plantas/química , Acetil-CoA Carboxilase/metabolismo , Ciclo do Ácido Cítrico , Polifenóis/biossíntese , Ácido Pirúvico/metabolismo
13.
Emerg Microbes Infect ; 8(1): 624-636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30999821

RESUMO

Flaviviruses are (re)-emerging RNA viruses strictly dependent on lipid metabolism for infection. In the search for host targeting antivirals, we explored the effect of pharmacological modulation of fatty acid metabolism during flavivirus infection. Considering the central role of acetyl-Coenzyme A carboxylase (ACC) on fatty acid metabolism, we analyzed the effect of three small-molecule ACC inhibitors (PF-05175157, PF-05206574, and PF-06256254) on the infection of medically relevant flaviviruses, namely West Nile virus (WNV), dengue virus, and Zika virus. Treatment with these compounds inhibited the multiplication of the three viruses in cultured cells. PF-05175157 induced a reduction of the viral load in serum and kidney in WNV-infected mice, unveiling its therapeutic potential for the treatment of chronic kidney disease associated with persistent WNV infection. This study constitutes a proof of concept of the reliability of ACC inhibitors to become viable antiviral candidates. These results support the repositioning of metabolic inhibitors as broad-spectrum antivirals.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Vírus da Dengue/fisiologia , Dengue/enzimologia , Inibidores Enzimáticos/administração & dosagem , Febre do Nilo Ocidental/enzimologia , Vírus do Nilo Ocidental/fisiologia , Infecção por Zika virus/enzimologia , Zika virus/fisiologia , Acetil-CoA Carboxilase/metabolismo , Animais , Antivirais/administração & dosagem , Dengue/tratamento farmacológico , Dengue/virologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Replicação Viral/efeitos dos fármacos , Febre do Nilo Ocidental/tratamento farmacológico , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/genética , Zika virus/efeitos dos fármacos , Zika virus/genética , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/virologia
14.
Nutrients ; 11(4)2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30935037

RESUMO

The aim of this study was to investigate the effect of melatonin on hepatic lipid metabolism in hamsters with high-fat diet (HFD)-induced dyslipidemia. Male Syrian hamsters were kept on either a chow control (C) or HFD for four weeks. After four weeks, animals fed the HFD were further randomly assigned to four groups: high-fat only (P), melatonin low-dosage (L), medium-dosage (M), and high-dosage (H) groups. The L, M, and H groups, respectively, received 10, 20, and 50 mg/kg/day of a melatonin solution, while the P and C groups received the ethanol vehicle. After eight weeks of the intervention, results showed that a low dose of melatonin significantly reduced HFD-induced hepatic cholesterol and triglycerides; decreased plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol; and increased plasma high-density lipoprotein cholesterol (p < 0.05). In addition, melatonin markedly decreased activities of the hepatic lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (p < 0.05), and elevated the relative hepatic carnitine palmitoyltransferase-1α expression in hamsters with HFD-induced hyperlipidemia. Consequently, melatonin reduced activities of the hepatic lipogenic enzymes, ACC and FAS. In summary, chronic melatonin administration improved HFD-induced dyslipidemia and hepatic lipid accumulation in Syrian hamsters with HFD-induced dyslipidemia, which might have occurred through inhibiting the lipogenesis pathway.


Assuntos
Antioxidantes/farmacologia , Hiperlipidemias/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Melatonina/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Acetil-CoA Carboxilase/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácido Graxo Sintases/metabolismo , Humanos , Hiperlipidemias/etiologia , Fígado/metabolismo , Masculino , Mesocricetus , Hepatopatia Gordurosa não Alcoólica/etiologia , Triglicerídeos/metabolismo
15.
Cell Mol Life Sci ; 76(17): 3407-3432, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30944974

RESUMO

Nucleocytoplasmic transport is dysregulated in sporadic and familial amyotrophic lateral sclerosis (ALS) and retinal ganglion neurons (RGNs) are purportedly involved in ALS. The Ran-binding protein 2 (Ranbp2) controls rate-limiting steps of nucleocytoplasmic transport. Mice with Ranbp2 loss in Thy1+-motoneurons develop cardinal ALS-like motor traits, but the impairments in RGNs and the degree of dysfunctional consonance between RGNs and motoneurons caused by Ranbp2 loss are unknown. This will help to understand the role of nucleocytoplasmic transport in the differential vulnerability of neuronal cell types to ALS and to uncover non-motor endophenotypes with pathognomonic signs of ALS. Here, we ascertain Ranbp2's function and endophenotypes in RGNs of an ALS-like mouse model lacking Ranbp2 in motoneurons and RGNs. Thy1+-RGNs lacking Ranbp2 shared with motoneurons the dysregulation of nucleocytoplasmic transport. RGN abnormalities were comprised morphologically by soma hypertrophy and optic nerve axonopathy and physiologically by a delay of the visual pathway's evoked potentials. Whole-transcriptome analysis showed restricted transcriptional changes in optic nerves that were distinct from those found in sciatic nerves. Specifically, the level and nucleocytoplasmic partition of the anti-apoptotic and novel substrate of Ranbp2, Pttg1/securin, were dysregulated. Further, acetyl-CoA carboxylase 1, which modulates de novo synthesis of fatty acids and T-cell immunity, showed the highest up-regulation (35-fold). This effect was reflected by the activation of ramified CD11b+ and CD45+-microglia, increase of F4\80+-microglia and a shift from pseudopodial/lamellipodial to amoeboidal F4\80+-microglia intermingled between RGNs of naive mice. Further, there was the intracellular sequestration in RGNs of metalloproteinase-28, which regulates macrophage recruitment and polarization in inflammation. Hence, Ranbp2 genetic insults in RGNs and motoneurons trigger distinct paracrine signaling likely by the dysregulation of nucleocytoplasmic transport of neuronal-type selective substrates. Immune-modulators underpinning RGN-to-microglial signaling are regulated by Ranbp2, and this neuronal-glial system manifests endophenotypes that are likely useful in the prognosis and diagnosis of motoneuron diseases, such as ALS.


Assuntos
Microglia/metabolismo , Chaperonas Moleculares/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Células Ganglionares da Retina/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Transporte Ativo do Núcleo Celular , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Modelos Animais de Doenças , Potenciais Evocados/efeitos dos fármacos , Regulação da Expressão Gênica , Metabolismo dos Lipídeos , Metaloproteinases da Matriz Secretadas/genética , Metaloproteinases da Matriz Secretadas/metabolismo , Camundongos , Camundongos Knockout , Chaperonas Moleculares/genética , Neurônios Motores/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/deficiência , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Nervo Óptico/anormalidades , Nervo Óptico/patologia , Comunicação Parácrina , Tamoxifeno/farmacologia , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo , Transcriptoma
16.
Curr Med Sci ; 39(1): 37-43, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30868489

RESUMO

This study aimed to verify the effects of berberine (BBR) on the fat metabolism proteins involved in the sirtuin 3 (SIRT3)/adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway in the liver tissues of rats with high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD). Forty-eight rats were randomly divided into the normal control (NC) group, HFD group or BBR group, with 16 rats in each group. After 8 and 16 weeks of treatment, serum and liver samples were collected. Subsequently, body parameters, biochemical parameters and liver pathology were examined. The expression levels of proteins involved in the SIRT3/AMPK/ACC pathway in the liver were detected by Western blotting. After 8 and 16 weeks of a HFD, the successful establishment of rat models with different degrees of NAFLD was confirmed by hematoxylin and eosin (H&E) and Oil Red O staining. NAFLD rat models exhibited obesity and hyperlipidemia, and the protein expression levels of SIRT3, p-AMPK, p-ACC, and CPT-1A in the liver were significantly decreased compared to those in the NC group. The concurrent administration of BBR with the HFD effectively improved serum and liver lipid profiles and ameliorated liver injury. Furthermore, the protein expression levels of SIRT3, p-AMPK, p-ACC, and CPT-1A in the liver were significantly increased in the BBR group as compared with those in the HFD group. In conclusion, our data suggest that the mechanism by which BBR ameliorates HFD-induced hepatic steatosis may be related to the activation of the SIRT3/AMPK/ACC pathway in the liver.


Assuntos
Berberina/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Acetil-CoA Carboxilase/metabolismo , Adenilato Quinase/metabolismo , Animais , Berberina/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , Modelos Animais de Doenças , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Fosforilação/efeitos dos fármacos , Distribuição Aleatória , Ratos , Sirtuínas/metabolismo
17.
Gen Comp Endocrinol ; 277: 82-89, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902611

RESUMO

In this experiment, Genetically improved farmed Nile tilapia Oreochromis niloticus were intraperitoneally injected with 1 g glucose/kg of body weight or saline. Red and white muscle tissues were collected at 0, 1, 2, 4, 6 and 12 h after the glucose tolerance test (GTT) or saline injection, and the time course of changes in molecular and metabolic adaption of glucose metabolism of these two tissues were evaluated. The results showed that the expression of insulin-responsive glucose transporter 4 (glut4) was up-regulated at 4 h after the GTT in the red muscle, implying an increase of glucose uptake. However, the expression of glut4 in the white muscle did not change with glucose load. The glycolysis of red muscle in tilapia was stimulated during 2-4 h after the GTT, as the expression of hexokinase 1b (hk1b), hk2, phosphofructokinase muscle type a (pfkma) and pfkmb and the activity of HK and PFK increased. By contrast, only the expression of hk1b was up-regulated at 6 h after the GTT in the white muscle. The mRNA level of glycogen synthase 1 (gys1) and glycogen content increased at 2 and 6 h, respectively after the GTT in the red muscle, suggesting that glucose storage was provoked. However, glycogen content in the white muscle was not impacted by GTT. Lipogenesis was stimulated in the red muscle as reflected by up-regulated expression of acetyl-CoA carboxylase α (accα) (during 2-4 h) and accß (during 4-12 h) with GTT. In the white muscle, however, the expression of accα was not changed, and mRNA level of accß was not up-regulated until 6 h after the GTT. Taken together, it was concluded that the glycolytic and glycogen synthesis mechanisms in the red muscle were highly regulated by an acute glucose load while those in the white muscle were less responsive to this stimulus.


Assuntos
Adaptação Fisiológica , Ciclídeos/metabolismo , Glucose/metabolismo , Músculos/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Animais Geneticamente Modificados , Ciclídeos/genética , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Glicogênio Sintase/metabolismo , Hexoquinase/genética , Hexoquinase/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Fosfofrutoquinases/metabolismo
18.
PLoS One ; 14(3): e0209392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30875375

RESUMO

PURPOSE: Triple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC. MATERIALS AND METHODS: (i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. Immunoblot analysis assessed AMPK, acetyl-CoA carboxylase (ACC), ribosomal protein S6, cyclin D1, and cleaved PARP. (ii) Sulforhodamine B growth assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. Proliferation was also assessed by counting cells after 72h of FND-4b treatment. (iii) Cell death ELISA assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. RESULTS: (i) FND-4b increased AMPK activation with concomitant decreases in ACC activity, phosphorylated S6, and cyclin D1 in all subtypes. (ii) FND-4b decreased proliferation in all cells, while dose-dependent growth decreases were found in ER+BC and TNBC. (iii) Increases in apoptosis were observed in ER+BC and the MDA-MB-231 cell line with FND-4b treatment. CONCLUSIONS: Our findings indicate that FND-4b decreases proliferation for a variety of breast cancers by activating AMPK and has notable effects on TNBC. The growth reductions were mediated through decreases in fatty acid synthesis (ACC), mTOR signaling (S6), and cell cycle flux (cyclin D1). ER+BC cells were more susceptible to FND-4b-induced apoptosis, but MDA-MB-231 cells still underwent apoptosis with higher dose treatment. Further development of FND compounds could result in a novel therapeutic for TNBC.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ativação Enzimática/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Acetil-CoA Carboxilase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Poli(ADP-Ribose) Polimerases/metabolismo , Receptores Estrogênicos/metabolismo , Proteína S6 Ribossômica/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
19.
Biomed Pharmacother ; 111: 1353-1358, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841449

RESUMO

Better understanding of the molecular mechanism involved in hepatocellular carcinoma (HCC) progression is essential for the development of therapeutic strategies to overcome chemoresistance in HCC patients. In this work, we show that 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative pentose phosphate pathway, is important for HCC growth and survival. Compared to normal liver tissues, we demonstrate that 6PGD expression is upregulated in HCC tissues. 6PGD overexpression increases 6PGD activity and promotes growth in normal liver cells. In contrast, targeting 6PGD using both genetic and pharmacological approaches inhibits HCC growth and survival. Combination of chemotherapeutic agents with 6PGD inhibition achieves greater efficacy in inhibiting HCC growth and survival than chemotherapeutic agent alone. We further show that inhibition of 6PGD activates AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase 1 (ACC1), and decreases level of NADPH/NAD + and NADH in HCC, leading to SIRT1 activity reduction and oxidative stress. Conversely, AMPK depletion significantly abolishes the effects of physcion (a selective small-molecule 6PGD inhibitor) in decreasing NADPH/NAD + ratio, growth and survival, confirming the role of AMPK as the relevant upstream activator with 6PGD inhibition in HCC cells. Our work is the first to demonstrate the upregulation of 6PGD and its critical involvement in growth and survival in HCC. Our findings suggest 6PGD as a promising therapeutic target to overcome chemoresistance in HCC.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Fosfogluconato Desidrogenase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , NADP/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Sirtuína 1/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Pestic Biochem Physiol ; 154: 78-87, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30765060

RESUMO

A series of novel aryloxyphenoxypropionate (APP) herbicides containing benzofuran moiety were designed, synthesized and tested for herbicidal activity. The bioassay results indicated that most of target compounds possessed moderate to good herbicidal activity against monocotyledonous weeds. Compounds 5a-5d and 6a-6d showed 100% control efficiency against crabgrass (Digitaria sanguinalis) and barnyard grass (Echinochloa crus-galli) in both pre-emergence and post-emergence treatments at the dosage of 1500 g a.i. ha-1. Compound 6c was the most promising, with herbicidal activity better than clodinafop-propargyl. Molecular docking for compound 6c and its hydrolysis acid 1c were performed. ACCase activities of some compounds were also tested. Theoretical calculations for corresponding hydrolysis products 1a-1ewere carried out. Based on the results of molecular docking, enzyme activity test and theoretical calculation, the potential mechanism for herbicidal activity of these compounds was evaluated.


Assuntos
Benzofuranos/farmacologia , Herbicidas/farmacologia , Propionatos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Benzofuranos/química , Digitaria/efeitos dos fármacos , Digitaria/fisiologia , Desenho de Drogas , Echinochloa/efeitos dos fármacos , Echinochloa/fisiologia , Herbicidas/química , Modelos Teóricos , Simulação de Acoplamento Molecular , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Propionatos/química
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