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1.
Food Chem ; 329: 127168, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512395

RESUMO

A polyphenols-rich extract was obtained from polyvinylpolypyrrolidone (PVPP) winery residue, and its neuroprotective effects and ability to modulate the kinetics of type 2 diabetes-relevant enzymes were characterized. The PVPP-white wine extract is a mixture of polyphenols (840.08 ± 161.25 µg/mg, dry weight) dominated by proanthocyanidins and hydroxycinnamic acids, affording strong antioxidant activity, as detected by the protection of membrane lipids against oxidation and superoxide radical anion scavenging activity. Regarding type 2 diabetes framework, the extract inhibits α-glucosidase (Ki = 166.9 µg/mL) and aldose reductase (Ki = 127.5 µg/mL) through non-competitive mechanisms. Despite the modest ability to inhibit rat brain acetylcholinesterase, it protects neuronal SH-SY5Y cells against oxidative damage promoted by glutamate, decreasing reactive oxygen species generation and preserving cell redox state. Thus, PVPP-white wine extract has potential to support the development of functional foods and/or nutraceuticals aiming neuroprotection and glucose homeostasis regulation, with high relevance in Alzheimers disease and type 2 diabetes interlink.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Povidona/análogos & derivados , Vinho , Acetilcolinesterase , Aldeído Redutase/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Proteínas Ligadas por GPI/antagonistas & inibidores , Ácido Glutâmico/toxicidade , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/prevenção & controle , Oxirredução , Extratos Vegetais/química , Polifenóis/análise , Polifenóis/farmacologia , Povidona/química , Proantocianidinas/química , Proantocianidinas/farmacologia , Ratos , Vinho/análise
2.
PLoS One ; 15(6): e0235061, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569334

RESUMO

Aflatoxin B1 aldehyde reductase (AFAR) enzyme activity has been associated to a higher resistance to the aflatoxin B1 (AFB1) toxicity in ethoxyquin-fed rats. However, no studies about AFAR activity and its relationship with tolerance to AFB1 have been conducted in poultry. To determine the role of AFAR in poultry tolerance, the hepatic in vitro enzymatic activity of AFAR was investigated in liver cytosol from four commercial poultry species (chicken, quail, turkey and duck). Specifically, the kinetic parameters Vmax, Km and intrinsic clearance (CLint) were determined for AFB1 dialdehyde reductase (AFB1-monoalcohol production) and AFB1 monoalcohol reductase (AFB1-dialcohol production). In all cases, AFB1 monoalcohol reductase activity saturated at the highest aflatoxin B1 dialdehyde concentration tested (66.4 µM), whereas AFB1 dialdehyde reductase did not. Both activities were highly and significantly correlated and therefore are most likely catalyzed by the same AFAR enzyme. However, it appears that production of the AFB1 monoalcohol is favored over the AFB1 dialcohol. The production of alcohols from aflatoxin dialdehyde showed the highest enzymatic efficiency (highest CLint value) in chickens, a species resistant to AFB1; however, it was also high in the turkey, a species with intermediate sensitivity; further, CLint values were lowest in another tolerant species (quail) and in the most sensitive poultry species (the duck). These results suggest that AFAR activity is related to resistance to the acute toxic effects of AFB1 only in chickens and ducks. Genetic selection of ducks for high AFAR activity could be a means to control aflatoxin sensitivity in this poultry species.


Assuntos
Aflatoxina B1/análogos & derivados , Aldeído Redutase/metabolismo , Aves Domésticas/metabolismo , Aflatoxina B1/química , Aflatoxina B1/toxicidade , Animais , Feminino , Cinética , Masculino
3.
DNA Cell Biol ; 39(7): 1322-1327, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32412859

RESUMO

To study the expression of aldo-keto reductase 1 member B1 (AKR1B1) in gastric carcinoma (GC), the correlation between AKR1B1 and the clinicopathological characteristics of GC patients, and provide reference for the diagnosis and prognosis of GC patients. One hundred thirty-six patients with GC were collected, and the expression level of AKR1B1 in GC and adjacent tissues was detected by immunohistochemistry assays. The clinicopathological features and prognosis of GC patients were collected to analyze the relationship with AKR1B1 expression. The positive expression of AKR1B1 in GC tissues was significantly higher than that of adjacent nontumor tissues. The difference of AKR1B1 expression between GC tissues and paired adjacent nontumor tissues was statistically significant (p < 0.001). AKR1B1 was closely related to tumor size, regional lymph node (N), metastases (M), and tumor-node-metastasis (TNM) stage (p < 0.05). The overall survival of patients with low expression of AKR1B1 was significantly better than that of patients with high expression of AKR1B1 by Kaplan-Meier survival analysis (p < 0.001). AKR1B1 plays an important role in the occurrence and development of GC, and it has a certain reference value for the prognosis of GC patients.


Assuntos
Aldeído Redutase/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia
4.
Life Sci ; 249: 117501, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142766

RESUMO

AIMS: Aldehyde reductase (AKR1A) is involved in the synthesis of ascorbic acid (AsA) as well as the detoxification of aldehydes. AKR1A-/- (KO) mice produce about 10% of the normal amounts of AsA compared to AKR1A+/+ (WT) mice. We investigated physiologic roles of AKR1A in running using the KO mice. MAIN METHODS: The KO mice were subjected to a treadmill test under either restricted AsA production or a sufficiency by supplementation and compared the results with those of WT mice. Contents of glucose, aspartate aminotransferase, AsA and free fatty acids in blood were measured. Glycogen contents were measured in the liver and skeletal muscle, and hepatic proteins were examined by immunoblot analyses. KEY FINDINGS: Running performance was higher in the KO mice than the WT mice irrespective of the AsA status. After the exercise period, blood glucose levels were decreased in the WT mice but were preserved in the KO mice. Liver glycogen levels were also consistently preserved in the KO mice after exercise. Free fatty acid levels tended to be originally high in blood plasma compared to those of the WT mice and were increased to similar extent in them. A key regulator of energy metabolism, PGC-1α, and the products of downstream target genes that encode for glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphatase, were constitutively at high levels in the KO mice. SIGNIFICANCE: The genetic ablation of AKR1A activates the PGC-1α pathway and spare glucose, which would consequently confer exercise endurance.


Assuntos
Aldeído Redutase/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Condicionamento Físico Animal , Resistência Física , Aldeído Redutase/metabolismo , Animais , Glicemia/metabolismo , Metabolismo Energético , Ácidos Graxos não Esterificados/sangue , Metabolismo dos Lipídeos , Glicogênio Hepático/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética
5.
J Biosci Bioeng ; 130(1): 1-5, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32205048

RESUMO

High temperature fermentation can substantially reduce the contaminations and condensation costs. Candida glycerinogenes was more resistant to high temperature than Saccharomyces cerevisiae. Quantitative real-time PCR results showed that 7 of 33 candidates served as potential high temperature inducible promoters in C. glycerinogenes. Fluorescence analysis indicated that PCgcwp1 showed the highest activity at 42°C. PCgaac and PCgpot1 showed medium-high expression, while PCghsp12, PCgatp1, PCgino1 and PCgscl were modest or weaker expression. Above seven promoters were further used to control the expression of xylose reductase gene from Neurospora crassa in C. glycerinogenes. Compared with 30°C, the xylitol yields of the seven recombinant strains were all improved at 42°C, and PCgcwp1 showed the highest xylitol production which was increased by 204% and reached 15.4 g/L. These results showed a potential to high temperature fermentation on the stress tolerant C. glycerinogenes and some of novel high temperature inducible promoters.


Assuntos
Candida/genética , Regiões Promotoras Genéticas , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Candida/metabolismo , Fermentação , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Temperatura Alta , Xilitol/metabolismo , Xilose/metabolismo
6.
J Enzyme Inhib Med Chem ; 35(1): 511-523, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31939312

RESUMO

A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Aldeído Redutase/metabolismo , Animais , Anti-Helmínticos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Quinazolinas/síntese química , Schistosoma mansoni/enzimologia , Relação Estrutura-Atividade
7.
PLoS One ; 15(1): e0227666, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945099

RESUMO

Species-specific sex pheromones play key roles in moth sexual communication. Although the general pathway of Type-I sex pheromone biosynthesis is well established, only a handful of genes encoding enzymes involved in this pathway have been characterized. Streltzoviella insularis is a destructive wood-boring pest of many street trees in China, and the female sex pheromone of this species comprises a blend of (Z)-3-tetradecenyl acetate, (E)-3-tetradecenyl acetate, and (Z)-5-dodecenyl acetate. This organism therefore provides an excellent model for research on the diversity of genes and molecular mechanisms involved in pheromone production. Herein, we assembled the pheromone gland transcriptome of S. insularis by next-generation sequencing and identified 74 genes encoding candidate key enzymes involved in the fatty acid biosynthesis, ß-oxidation, and functional group modification. In addition, tissue expression patterns further showed that an acetyl-CoA carboxylase and two desaturases were highly expressed in the pheromone glands compared with the other tissues, indicating possible roles in S. insularis sex pheromone biosynthesis. Finally, we proposed putative S. insularis biosynthetic pathways for sex pheromone components and highlighted candidate genes. Our findings lay a solid foundation for understanding the molecular mechanisms underpinning S. insularis sex pheromone biosynthesis, and provide potential targets for disrupting chemical communication that could assist the development of novel pest control methods.


Assuntos
Genes de Insetos , Mariposas/genética , Mariposas/metabolismo , Atrativos Sexuais/biossíntese , Atrativos Sexuais/genética , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Acetiltransferases/genética , Acetiltransferases/metabolismo , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Animais , Vias Biossintéticas/genética , China , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Filogenia , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Glândulas Odoríferas/metabolismo , Análise de Sequência de RNA , Transcriptoma
8.
Enzyme Microb Technol ; 132: 109415, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31731965

RESUMO

Aldo-keto reductases (AKRs) are nicotinamide-dependent enzymes that catalyze the transformation of aldehydes and ketones into alcohols. They are spread across all phyla, and those from microbial origin have proved to be highly robust and versatile biocatalysts. In this work, we have discovered and characterized a microbial AKR from the yeast Rhodotorula mucilaginosa by combining genome-mining and expression assays. The new enzyme, named AKR3B4, was expressed by a simple protocol in very good amounts. It displays a selective substrate profile exclusively transforming aldehydes into alcohols. Also, AKR3B4 shows very good stability at medium temperatures, in a broad range of pH values and in the presence of green organic solvents. Conversion assays demonstrate it is an excellent biocatalyst to be used in the synthesis of aromatic alcohols, and also to produce furan-3-ylmethanol and the valuable sweetener xylitol. These results show that AKR3B4 displays attractive features so as to be used in chemoenzymatic processes.


Assuntos
Aldo-Ceto Redutases/genética , Aldo-Ceto Redutases/metabolismo , Rhodotorula/enzimologia , Rhodotorula/genética , Oxirredutases do Álcool/metabolismo , Álcoois/metabolismo , Aldeído Redutase/metabolismo , Aldeídos/metabolismo , Clonagem Molecular , Enzimas , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Especificidade por Substrato
9.
Dokl Biochem Biophys ; 488(1): 320-323, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31768851

RESUMO

It was shown for the first time that pentaamino acid derivative of fullerene C60 (potassium salt of fullerenylpenta-N-dihydroxytyrosine) affects three targets of type 2 diabetes mellitus. It competitively inhibits the enzymes aldose reductase and sorbitol dehydrogenase and also has an antiglycation effect on bovine serum albumin. The inhibition constants for these enzymes were calculated.


Assuntos
Aldeído Redutase/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , L-Iditol 2-Desidrogenase/química , Aldeído Redutase/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , L-Iditol 2-Desidrogenase/metabolismo , Camundongos
10.
Chem Biol Interact ; 314: 108839, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563593

RESUMO

Here, we show that incubation of three human gastrointestinal cancer cell lines (HCT15, LoVo and MKN45) with doxorubicin (DOX) provokes autophagy through facilitating production of reactive oxygen species (ROS). HCT15 cell treatment with DOX resulted in up-regulation of Beclin1, down-regulation of Bcl2, activation of AMPK and JNK, and Akt inactivation, all of which were restored by pretreating with an antioxidant N-acetyl-l-cysteine. These data suggest that all the autophagy-related alterations evoked by DOX result from the ROS production. In the DOX-resistant cancer cells, degree of autophagy elicited by DOX was milder than the parental cells, and DOX treatment hardly activated the ROS-dependent apoptotic signals [formation of 4-hydroxy-2-nonenal (HNE), cytochrome-c release into cytosol, and activation of JNK and caspase-3], inferring an inverse correlation between cellular antioxidant capacity and autophagy induction by DOX. Monitoring of expression levels of aldo-keto reductases (AKRs) in the parental and DOX-resistant cells revealed an up-regulation of AKR1B10 and/or AKR1C3 with acquiring the DOX resistance. Knockdown and inhibition of AKR1B10 or AKR1C3 in these cells enhanced DOX-elicited autophagy. Measurement of DOX-reductase activity and HNE-sensitivity assay also suggested that both AKR1B10 (via high HNE-reductase activity) and AKR1C3 (via low HNE-reductase and DOX-reductase activities) are involved in the development of DOX resistance. Combination of inhibitors of autophagy and the two AKRs overcame DOX resistance and cross-resistance of gastrointestinal cancer cells with resistance development to DOX or cis-diamminedichloroplatinum. Therefore, concomitant treatment with the inhibitors may be effective as an adjuvant therapy for elevating DOX sensitivity of gastrointestinal cancer cells.


Assuntos
Aldo-Ceto Redutases/metabolismo , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Aldeído Redutase/metabolismo , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Cell Host Microbe ; 26(2): 240-251.e8, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31350199

RESUMO

Interorgan immunological communication is critical to connect the local-systemic innate immune response and orchestrate a homeostatic host defense. However, the factors and their roles in this process remain unclear. We find Drosophila IMD response in guts can sequentially trigger a systemic IMD reaction in the fat body. Sugar alcohols of the polyol pathway are essential for the spatiotemporal regulation of gut-fat body immunological communication (GFIC). IMD activation in guts causes elevated levels of sorbitol and galactitol in hemolymph. Aldose reductase (AR) in hemocytes, the rate-limiting enzyme of the polyol pathway, is necessary and sufficient for the increase of plasma sugar alcohols. Sorbitol relays GFIC by subsequent activation of Metalloprotease 2, which cleaves PGRP-LC to activate IMD response in fat bodies. Thus, this work unveils how GFIC relies on the intermediate activation of the polyol pathway in hemolymph and demonstrates that AR provides a critical metabolic checkpoint in the global inflammatory response.


Assuntos
Alarminas/imunologia , Drosophila/imunologia , Imunidade Inata/fisiologia , Polímeros/metabolismo , Álcoois Açúcares/metabolismo , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Aldo-Ceto Redutases/genética , Animais , Animais Geneticamente Modificados , Proteínas de Transporte/metabolismo , Drosophila/genética , Corpo Adiposo/metabolismo , Galactitol/sangue , Galactitol/metabolismo , Hemolinfa/metabolismo , Humanos , Inflamação/imunologia , Masculino , Metaloproteases/metabolismo , Transdução de Sinais/imunologia , Sorbitol/sangue , Sorbitol/metabolismo , Álcoois Açúcares/sangue
12.
Environ Sci Pollut Res Int ; 26(26): 26664-26673, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292874

RESUMO

Cyclophosphamide (CYP) is a common anticancer drug used in the treatment of various malignancies. Naringin (NG) is a natural bioflavonoid that have been reported to have many medicinal and pharmacological properties. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase (CA), α-glycosidase (α-Gly), and aldose reductase (AR) enzymes are the essential biological molecules needed for metabolic processes in all living cells. In the present study, the aim was to investigate the effect of NG against CYP-induced liver, brain, kidney, heart, and testis toxicities on some metabolic enzyme activities such as AChE, BChE, CA, α-Gly, and AR. Thirty-five male Wistar rats were randomly divided into five groups with each group consisting of seven rats. The rats were subjected to oral treatment of NG (50 and 100 mg/kg body weight) for 7 days before administering a single dose of CYP (200 mg/kg body weight, i.p) on the seventh day. Treatment with NG in all tissues regulated these enzyme activities in CYP-induced rats. The results of this study showed that NG regulates abnormal increases and decreases in CYP-induced metabolic enzyme activities in all tissues.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/antagonistas & inibidores , Flavanonas/farmacologia , Acetilcolinesterase/metabolismo , Aldeído Redutase/metabolismo , Animais , Antineoplásicos Alquilantes/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Butirilcolinesterase/metabolismo , Anidrases Carbônicas/metabolismo , Ciclofosfamida/efeitos adversos , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Miocárdio , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Testículo/efeitos dos fármacos , Testículo/enzimologia
13.
Enzyme Microb Technol ; 129: 109359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31307575

RESUMO

Thermotolerant yeast Kluyveromyces marxianus can assimilate xylose but cannot produce ethanol from xylose under anaerobic conditions. Here, we constructed two recombinant K. marxianus strains, DMB5 and DMB13, that express xylose reductase (XR), NAD+- or protein-engineered NADP+-dependent xylitol dehydrogenase (XDH), and xylulokinase (XK) from K. marxianus. These strains, together with previously reported strain DMB3-7, which expresses Scheffersomyces stipitis XR and NAD+-dependent XDH and Saccharomyces cerevisiae XK, were compared to evaluate enzymatic activities and ethanol productivities at 30 °C and 40 °C. Unlike the activities of xylose metabolic enzymes in DMB3-7, enzymatic activities of XR, XDH, and XK in both DMB5 and DMB13 hardly decreased even at 40 °C, suggesting that these enzymes from K. marxianus are highly thermostable. The most efficient glucose/xylose co-fermentation at 40 °C was found in DMB13; namely, DMB13 rapidly converted xylose to ethanol, especially after glucose depletion, and showed the highest ethanol yield (0.402 g/g). These findings support the view that alteration of coenzyme specificity of XDH expressed in K. marxianus will be efficacious for high-temperature ethanol production from mixed sugars containing xylose.


Assuntos
Etanol/metabolismo , Kluyveromyces/metabolismo , Xilose/metabolismo , Aldeído Redutase/química , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , D-Xilulose Redutase/química , D-Xilulose Redutase/genética , D-Xilulose Redutase/metabolismo , Fermentação , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Temperatura Alta , Kluyveromyces/química , Kluyveromyces/enzimologia , Kluyveromyces/genética , Temperatura , Xilitol/metabolismo
14.
Nat Commun ; 10(1): 2698, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221959

RESUMO

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10High-enhanced metastatic colonisation with no impact on AKR1B10Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.


Assuntos
Aldeído Redutase/metabolismo , Neoplasias da Mama/patologia , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Aldo-Ceto Redutases , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Feminino , Glicólise , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Recidiva Local de Neoplasia/metabolismo , Oxirredução , Estresse Oxidativo , Esferoides Celulares , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Chem Pharm Bull (Tokyo) ; 67(6): 556-565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155561

RESUMO

Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).


Assuntos
Aldeído Redutase/metabolismo , Inibidores Enzimáticos/síntese química , Pirazinas/química , Aldeído Redutase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Pirazinas/síntese química , Pirazinas/metabolismo
16.
Biotechnol Appl Biochem ; 66(5): 781-786, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31135076

RESUMO

Aldose reductase (AR), α-amylase, and α-glycosidase are vital enzymes to prevent diabetic complications. Here, AR was purified from sheep kidney using elementary methods with 111.11-purification fold and with 0.85% purification yield. The interactions between some phenolic compounds and the AR, α-glycosidase, and α-amylase enzyme were determined. It was found that phenolic compounds exhibit potential inhibitor properties for these enzymes. For α-amylase, studied phenolic compounds showed IC50 values in the range of 601.56-2,067.78 nM. For α-glycosidase, Ki values were found in the range of 169.25 ± 27.22-572.88 ± 106.76 nM. For AR, Ki values in the range of 8.48 ± 0.56-43.26 ± 7.63 µM. However, genistein showed the best inhibition effect toward AR and α-glycosidase, but delphinidin chloride exhibited the best inhibition effect against α-amylase enzyme. We determined that all compounds showed noncompetitive inhibition effect against AR and α-glycosidase. Also, studied phenolic compounds may be useful in the prevention or treatment of diabetic complications.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Fenóis/farmacologia , alfa-Amilases/antagonistas & inibidores , Aldeído Redutase/isolamento & purificação , Aldeído Redutase/metabolismo , Animais , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/isolamento & purificação , Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Rim/efeitos dos fármacos , Rim/enzimologia , Estrutura Molecular , Fenóis/administração & dosagem , Fenóis/química , Ovinos , alfa-Amilases/isolamento & purificação , alfa-Amilases/metabolismo
17.
Molecules ; 24(10)2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31130646

RESUMO

Diabetes complications, including peripheral neuropathy, cataracts, impaired wound healing, vascular damage, arterial wall stiffening and retinopathy diseases, are among the most predominant health problems facing the world's population today. The 22 Peruvian plant extracts were screened for their potential inhibitory activity against rat lens aldose reductase (RLAR) and DPPH radical scavenging. Among them, we have found that Tanacetum parthenium L. (TP) has the RLAR, AGEs and DPPH radical scavenging activities. We used for screening of active components in TP against RLAR and DPPH for the first time by ultrafiltration (UF) and DPPH. Compounds in TP were isolated by Sephadex column chromatography and their structures were established by MS and NMR spectroscopic analyses. Among the isolated compounds, ferulic acid, apigenin, luteolin-7-O-glucoside, luteolin, chrysosplenol, and kaempferol showed potent inhibition with IC50 values of 1.11-3.20 and 6.44-16.23 µM for RLAR and DPPH radical scavenging. Furthermore, these compounds suppressed sorbitol accumulation in rat lenses and ferulic acid, luteolin-7-O-glucoside, and luteolin have AGEs inhibitory activities with IC50 values of 3.43-6.73 µM. In summary, our study provides interesting plants for further study with respect to the treatment and prevention of diabetic complication of Peruvian plant and can provide the scientific base of the traditional uses.


Assuntos
Aldeído Redutase/metabolismo , Plantas Medicinais/química , Tanacetum parthenium/química , Animais , Apigenina/química , Compostos de Bifenilo/química , Cromatografia Líquida de Alta Pressão , Ácidos Cumáricos/química , Flavonas/química , Glucosídeos/química , Quempferóis/química , Luteolina/química , Picratos/química , Ratos , Sorbitol/química
18.
Appl Microbiol Biotechnol ; 103(14): 5699-5713, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115629

RESUMO

The aldehyde reductases from the short-chain dehydrogenase/reductase (SDR) family were identified as a series of critical enzymes for the improved tolerance of Saccharomyces cerevisiae to the aldehydes by catalyzing the detoxification reactions of aldehydes. Herein, we report that a novel aldehyde reductase Ykl107wp deduced from YKL107W from S. cerevisiae belongs to the classical SDR group and can catalyze the reduction reactions of acetaldehyde (AA), glycolaldehyde (GA), furfural (FF), formaldehyde (FA), and propionaldehyde (PA) but cannot reduce the six representative ketones. Ykl107wp displayed the best maximum velocity (Vmax), catalytic rate constant (Kcat), catalytic efficiency (Kcat/Km), and highest affinity (Km) to acetaldehyde. The optimum pH of Ykl107wp was 6.0 for the reduction of AA and 7.0 for the reduction of GA and FF, and the optimum temperatures were 40, 35, and 30 °C for the reduction of AA, GA, and FF, respectively. Ykl107wp for the reduction of AA was greatly affected by metal ions, chemical additives, and salts and showed poor thermal and pH stability, but its stability was slightly affected by a substrate. Ykl107wp was localized in endoplasmic reticulum and prevented the yeast cells from damage caused by furfural via the detoxification of furfural to furfural alcohol. This research provides guidelines for the study of uncharacterized classical SDR aldehyde reductases and exploration of their protective mechanisms on the corresponding organelles.


Assuntos
Acetaldeído/análogos & derivados , Acetaldeído/metabolismo , Aldeído Redutase/metabolismo , Furaldeído/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Aldeído Redutase/genética , Catálise , Inativação Metabólica , Cinética , Proteínas de Saccharomyces cerevisiae/genética
19.
J Nutr ; 149(5): 776-787, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050753

RESUMO

BACKGROUND: Methylglyoxal (MGO), an important precursor of advanced glycation end products (AGEs), circulates at high concentrations in diabetic patients' blood and plays an important role in the pathogenesis of diabetes and other chronic diseases. OBJECTIVES: The aim of this study was to determine whether dietary genistein can prevent indicators of metabolic syndrome (MetS) induced by a very-high-fat (VHF) diet or a high-fat (HF) diet plus exogenous MGO, and the accumulation of MGO and AGEs in mice. METHODS: Male, 6-wk-old C57BL/6J mice (n = 15) were fed a low-fat (LF) diet (10% fat energy) or a VHF diet (60% fat energy) alone or including 0.25% genistein (VHF-G) for 16 wk in study 1. In study 2, 75 similar mice were fed the LF diet (LF) or the HF diet alone (HF) or in combination with up to 0.2% MGO in water (HFM) and 0.067% (HFM-GL) or 0.2% (HFM-GH) dietary genistein for 18 wk. Anthropometric and metabolic data were obtained in both studies to determine the effects of MGO and genistein on variables indicative of MetS. RESULTS: Body weight gain, fat deposits, dyslipidemia, hyperglycemia, and fatty liver were ameliorated by dietary genistein in both studies. The plasma MGO concentration in VHF-G mice was 52% lower than that in VHF mice. Moreover, the AGE concentrations in plasma, liver, and kidney of VHF-G mice were 73%, 52%, and 49%, respectively, lower than in the VHF group (study 1). Similarly, the concentrations of plasma MGO and AGE in plasma, liver, and kidney of HFM-GH mice were 33.5%, 49%, 69%, and 54% lower than in HFM mice (study 2). Genistein inhibited AGE formation by trapping MGO to form adducts and upregulating the expressions of glyoxalase I and II and aldose reductase in liver and kidney to detoxify MGO in both studies. CONCLUSIONS: Our data demonstrate for the first time that genistein significantly lowers MGO and AGE concentrations in 2 mouse MetS models via multiple pathways.


Assuntos
Dieta Hiperlipídica , Genisteína/farmacologia , Produtos Finais de Glicação Avançada/metabolismo , Síndrome Metabólica , Extratos Vegetais/farmacologia , Aldeído Pirúvico/sangue , Tecido Adiposo/metabolismo , Aldeído Redutase/metabolismo , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/prevenção & controle , Gorduras na Dieta/efeitos adversos , Dislipidemias/etiologia , Dislipidemias/prevenção & controle , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Genisteína/uso terapêutico , Hiperglicemia/etiologia , Hiperglicemia/prevenção & controle , Rim/efeitos dos fármacos , Rim/metabolismo , Lactoilglutationa Liase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/prevenção & controle , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/prevenção & controle , Extratos Vegetais/uso terapêutico , Soja/química , Tioléster Hidrolases/metabolismo , Ganho de Peso/efeitos dos fármacos
20.
Microb Cell Fact ; 18(1): 83, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31103047

RESUMO

BACKGROUND: As renewable biomass, lignocellulose remains one of the major choices for most countries in tackling global energy shortage and environment pollution. Efficient utilization of xylose, an important monosaccharide in lignocellulose, is essential for the production of high-value compounds, such as ethanol, lipids, and isoprenoids. Protopanaxadiol (PPD), a kind of isoprenoids, has important medical values and great market potential. RESULTS: The engineered protopanaxadiol-producing Yarrowia lipolytica strain, which can use xylose as the sole carbon source, was constructed by introducing xylose reductase (XR) and xylitol dehydrogenase (XDH) from Scheffersomyces stipitis, overexpressing endogenous xylulose kinase (ylXKS) and heterologous PPD synthetic modules, and then 18.18 mg/L of PPD was obtained. Metabolic engineering strategies such as regulating cofactor balance, enhancing precursor flux, and improving xylose metabolism rate via XR (K270R/N272D) mutation, the overexpression of tHMG1/ERG9/ERG20 and transaldolase (TAL)/transketolase (TKL)/xylose transporter (TX), were implemented to enhance PPD production. The final Y14 strain exhibited the greatest PPD titer from xylose by fed-batch fermentation in a 5-L fermenter, reaching 300.63 mg/L [yield, 2.505 mg/g (sugar); productivity, 2.505 mg/L/h], which was significantly higher than the titer of glucose fermentation [titer, 167.17 mg/L; yield, 1.194 mg/g (sugar); productivity, 1.548 mg/L/h]. CONCLUSION: The results showed that xylose was more suitable for PPD synthesis than glucose due to the enhanced carbon flux towards acetyl-CoA, the precursor for PPD biosynthetic pathway. This is the first report to produce PPD in Y. lipolytica with xylose as the sole carbon source, which developed a promising strategy for the efficient production of high-value triterpenoid compounds.


Assuntos
Sapogeninas/metabolismo , Xilose/metabolismo , Yarrowia/genética , Yarrowia/metabolismo , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Biomassa , Vias Biossintéticas , D-Xilulose Redutase/genética , D-Xilulose Redutase/metabolismo , Fermentação , Engenharia Metabólica/métodos , Redes e Vias Metabólicas , Organismos Geneticamente Modificados
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