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1.
Med Chem ; 16(1): 119-127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30963981

RESUMO

BACKGROUND: Topiroxostat is an excellent xanthine oxidase (XO) inhibitor, possessing a specific 3,5-diaryl-1,2,4-triazole framework. OBJECTIVE: The present work was aimed to investigate the preliminary structure-activity relationship (SAR) of 2-cyanopyridine-4-yl-like fragments of topiroxostat analogues. METHODS: A series of 5-benzyl-3-pyridyl-1H-1,2,4-triazole derivatives (1a-j and 2a-j) were designed and synthesized by replacement of the 2-cyanopyridine-4-yl moiety with substituted benzyl groups. XO inhibitory activity in vitro was evaluated. Furthermore, molecular modeling simulations were performed to predict the possible interactions between the synthesized compounds and XO binding pocket. RESULTS: The SARs analysis demonstrated that 3,5-diaryl-1,2,4-triazole framework is not essential; in spite of its lower potency, 5-benzyl-3-pyridyl-1H-1,2,4-triazole is an acceptable scaffold for XO inhibitory activity to some extent. A 3'-nitro and a 4'-sec-butoxy group link to the benzyl moiety will be welcome. Furthermore, the most promising compound, 1h, was identified with an IC50 value of 0.16 µM, and the basis of XO inhibition by 1h was rationalized through the aid of molecular modelling studies. CONCLUSION: Compound 1h could be a lead compound for further investigation and the present work may provide some insight into the search for more structurally diverse XO inhibitors with topiroxostat as a prototype.


Assuntos
Inibidores Enzimáticos/farmacologia , Triazóis/farmacologia , Xantina Oxidase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Xantina Oxidase/metabolismo
2.
Phytochemistry ; 169: 112162, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31627115

RESUMO

Twelve undescribed triterpenoid pentacyclic glycosides, medicagenic acid (3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 3-O-ß-D-glucuronopyranosyl-28-O-{[α-L-rhamnopyranosyl-(1 → 2)]-[ß-D-apiofuranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 3-O-ß-D-glucuronopyranosyl-28-O-{[α-L-rhamnopyranosyl-(1 → 2)]-3,4-O-diacetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[2-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[3-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[4-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[ß-D-glucopyranosyl-(1 → 2)]-[ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid), zanhic acid (3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}2ß,3ß,16α-trihydroxyolean-12-ene-23,28-dioic acid, 3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-ß-D-fucopyranosyl-(1→)}-2ß,3ß,16α-trihydroxyolean-12-ene-23,28-dioic acid), 29-hydroxy-medicagenic acid (3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß,29ß-trihydroxyolean-12-ene-23,28-dioic acid) and herniaric acid (28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-18-ene-23,28-dioic acid) were isolated from the whole plant extract of Herniaria glabra L. (Caryophyllaceae), wild growing in the Ukraine. In addition, five known triterpenoid saponins; i.e. herniariasaponins 1, 4, 5, 6, and 7 were also isolated. Their structures were elucidated by HRESIMS, 1D and 2D NMR spectroscopy, as well as by comparison with the literature data. Twelve herniariasaponins, the purified crude extract, and the saponin fraction were evaluated in vitro for their xanthine oxidase, collagenase, elastase, and tyrosinase inhibitory activity. Moreover, herniariasaponins 4, 5, and 7 were screened for their cholinesterase inhibitory potential. As a result, no or low inhibition towards the mentioned enzymes was observed.


Assuntos
Caryophyllaceae/química , Inibidores Enzimáticos/farmacologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Animais , Colinesterases/metabolismo , Colagenases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Conformação Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Saponinas/química , Saponinas/isolamento & purificação , Estereoisomerismo , Ucrânia , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
3.
Chem Biol Interact ; 316: 108929, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31857090

RESUMO

Fatty liver is the hepatic consequence of chronic insulin resistance (IR) and related syndromes. It is mostly accompanied by inflammatory and oxidative molecules. Increased activity of xanthine oxidase (XO) exerts both inflammatory and oxidative effects and has been implicated in metabolic derangements including non-alcoholic fatty liver disease. Short chain fatty acids (SCFAs) elicit beneficial metabolic alterations in IR and related syndromes. In the present study, we evaluated the preventive effects of a SCFA, acetate, on nicotine-induced dysmetabolism and fatty liver. Twenty-four male Wistar rats (n = 6/group): vehicle-treatment (p.o.), nicotine-treated (1.0 mg/kg; p.o.), sodium acetate-treated (200 mg/kg; p.o.) and nicotine + sodium acetate-treated groups. The treatments lasted for 8 weeks. IR was estimated by oral glucose tolerance test and homeostatic model assessment of IR. Plasma and hepatic free fatty acid, triglyceride (TG), glutathione peroxidase, adenosine deaminase (ADA), XO and uric acid (UA) were measured. Nicotine exposure resulted in reduced body weight, liver weight, visceral adiposity, glycogen content and glycogen synthase activity. Conversely, exposure to nicotine increased fasting plasma glucose, lactate, IR, plasma and hepatic TG, free fatty acid, TG/HDL-cholesterol ratio, lipid peroxidation, liver function enzymes, plasma and hepatic UA, XO and ADA activities. However, plasma and hepatic glucose-6-phosphate dehydrogenase-dependent antioxidant defense was not affected by nicotine. Concomitant treatment with acetate ameliorated nicotine-induced effects. Taken together, these results indicate that nicotine exposure leads to excess deposition of lipid in the liver by enhancing XO activity. The results also imply that acetate confers hepatoprotection and is accompanied by decreased XO activity.


Assuntos
Lipídeos/análise , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Acetato de Sódio/farmacologia , Xantina Oxidase/metabolismo , Animais , Área Sob a Curva , Ácidos Graxos não Esterificados/sangue , Teste de Tolerância a Glucose , Resistência à Insulina , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Nicotina/farmacologia , Curva ROC , Ratos , Ratos Wistar , Triglicerídeos/sangue , Xantina Oxidase/sangue
4.
Nat Commun ; 10(1): 4904, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659168

RESUMO

Xanthine oxidoreductase has been implicated in cancer. Nonetheless, the role played by its two convertible forms, xanthine dehydrogenase (XDH) and oxidase (XO) during tumorigenesis is not understood. Here we produce XDH-stable and XO-locked knock-in (ki) mice to address this question. After tumor transfer, XO ki mice show strongly increased tumor growth compared to wild type (WT) and XDH ki mice. Hematopoietic XO expression is responsible for this effect. After macrophage depletion, tumor growth is reduced. Adoptive transfer of XO-ki macrophages in WT mice increases tumor growth. In vitro, XO ki macrophages produce higher levels of reactive oxygen species (ROS) responsible for the increased Tregs observed in the tumors. Blocking ROS in vivo slows down tumor growth. Collectively, these results indicate that the balance of XO/XDH plays an important role in immune surveillance of tumor development. Strategies that inhibit the XO form specifically may be valuable in controlling cancer growth.


Assuntos
Neoplasias/enzimologia , Xantina Desidrogenase/genética , Xantina Oxidase/genética , Animais , Proliferação de Células , Feminino , Técnicas de Introdução de Genes , Humanos , Macrófagos/enzimologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Xantina Desidrogenase/metabolismo , Xantina Oxidase/metabolismo
5.
Comput Biol Chem ; 83: 107137, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639647

RESUMO

Xanthine oxidase (XO) is a form of xanthine oxidoreductase, a type of enzyme that plays a key role in the induction of hyperuricemia and raising superoxide radical level in blood. The present study was performed to evaluate the inhibitory activity of isoflavonoids (1-3) isolated from the ethyl acetate fraction of Apios americana, on the catalytic reaction mediated by XO. The isoflavonoids exhibited potential inhibitory activity within microgram/mL along with quenching effect towards XO. A reduction in the respective IC50 values was observed in the presence of high concentration of substrate. Molecular docking study revealed Ser876 and Arg880 as the key amino acids involved in the interaction of the enzyme with inhibitor. Apparently, the results demonstrated isoflavonoids as one of the natural products with a potential inhibitory effect on XO.


Assuntos
Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fabaceae/química , Isoflavonas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Isoflavonas/química , Isoflavonas/isolamento & purificação , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
6.
Eur J Med Chem ; 183: 111717, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557611

RESUMO

In our previous study, we reported a series of N-phenylisonicotinamide derivatives as novel xanthine oxidase (XO) inhibitors and identified N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (compound 1) as the most potent one with an IC50 value of 0.312 µM. To further optimize the structure and improve the potency, a structure-based drug design (SBDD) strategy was performed to construct the missing H-bond between the small molecule and the Asn768 residue of XO. We introduced a tetrazole moiety at the 3'-position of the phenyl to serve as an H-bond acceptor and obtained a series of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives (2a-t and 6-8). Besides, to investigate the influence of the amide-reversal, some N-(pyridin-4-yl)-3-(1H-tetrazol-1-yl)benzamide derivatives (3c, 3e, 3i, 3k and 3u) were also synthesized and evaluated. Biological evaluation and structure-activity relationship analysis demonstrated that the 3'-(1H-tetrazol-1-yl) moiety was an excellent fragment for the N-phenylisonicotinamide scaffold; a substituted benzyloxy, especially, an m-cyanobenzyloxy (e.g., 2s), linking at the 4'-position was welcome for the potency; and the amide-reversal could damage the potency, so maintenance of the N-phenylisonicotinamide scaffold was essential. In summary, starting from compound 1, the SBDD effort successfully identified a promising XO inhibitor 2s (IC50 = 0.031 µM), with a 10-fold gain in potency. Its potency was very close to the positive control topiroxostat (IC50 = 0.021 µM). A Lineweaver-Burk plot indicated that compound 2s acted as a mixed-type XO inhibitor. Molecular docking and molecular dynamics simulations revealed that the tetrazole moiety could occupy the Asn768-sub-pocket with N-4 atom accepting an H-bond from the Asn768 residue, as expected.


Assuntos
Niacinamida/análogos & derivados , Niacinamida/síntese química , Xantina Oxidase/antagonistas & inibidores , Animais , Benzamidas/química , Bovinos , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Niacinamida/metabolismo , Nitrilos/metabolismo , Ligação Proteica , Piridinas/metabolismo , Relação Estrutura-Atividade , Tetrazóis/química , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismo
7.
Eur J Med Chem ; 181: 111558, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369933

RESUMO

In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5-carboxylic acid derivatives that presented excellent in vitro xanthine oxidase (XO) inhibitory potency. To further investigate the structure-activity relationships of these compounds, the imidazole ring was transformed to a pyrimidine ring to design 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (8a-8j), 2-(4-alkoxy-3-cyano)phenyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (9c, 9e, 9j, 9l) and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids (10c, 10e, 10j, 10l). These compounds exhibited remarkable in vitro XO inhibitory potency with IC50 values ranging from 0.0181 µM to 0.5677 µM. Specifically, compounds 10c and 10e, with IC50 values of 0.0240 µM and 0.0181 µM, respectively, emerged as the most potent XO inhibitors, and their potencies were comparable to that of febuxostat. Structure-activity relationship analysis revealed that the methyl group at 4-position of pyrimidine ring could damage the potency, and the XO inhibitory potency was maintained when carbonyl group was changed to an imino group. Lineweaver-Burk plot analysis revealed that the representative compound 10c acted as a mixed-type inhibitor. A potassium oxonate induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 10c, and the results showed that compound 10c (5 mg/kg) was able to significantly lower the serum uric acid level. Furthermore, in acute oral toxicity study, no sign of toxicity was observed when the mice were administered with a single 2000 mg/kg oral dose of compound 10c. These results suggested that compound 10c was a potent and promising uric acid-lowing agent for the treatment of hyperuricemia.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
8.
Eur J Med Chem ; 181: 111559, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376568

RESUMO

Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 µM to 0.629 µM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 µM, which was comparable to febuxostat (IC50 = 0.0236 µM). The structure-activity relationship results revealed that the hydrophobic group at the 4'-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Hiperuricemia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
9.
Nutrients ; 11(8)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430927

RESUMO

Caffeine is commonly taken via the daily dietary consumption of caffeine-containing foods. The absorbed caffeine is metabolized to yield various metabolites by drug-metabolizing enzymes, and measuring the levels of each caffeine metabolite can provide useful information for evaluating the phenotypes of those enzymes. In this study, the urinary concentrations of caffeine and its 13 metabolites were determined, and the phenotypes of drug metabolic enzymes were investigated based on the caffeine metabolite ratios. Human urine samples were pretreated using solid phase extraction, and caffeine and its metabolites were analyzed using liquid chromatography-tandem mass spectrometry. Based on the urinary caffeine metabolite concentrations, the caffeine metabolite ratios were calculated for six human subjects at specified time points after caffeine intake. Variations in urinary metabolite levels among individuals and time points were reported. In addition, the resultant enzyme activities showed different patterns, depending on the metabolite ratio equations applied. However, some data presented a constant metabolite ratio range, irrespective of time points, even at pre-dose. This suggests the possibility of urinary caffeine metabolite analysis for routine clinical examination. These findings show that urinary caffeine and the metabolite analysis would be useful in evaluating metabolic phenotypes for personalized medicine.


Assuntos
Arilamina N-Acetiltransferase/metabolismo , Cafeína/metabolismo , Cafeína/urina , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2A6/metabolismo , Xantina Oxidase/metabolismo , Adulto , Biomarcadores/metabolismo , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Urinálise , Adulto Jovem
10.
Oxid Med Cell Longev ; 2019: 3765643, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428225

RESUMO

Oxidative stress is a key feature in the pathophysiology of sickle cell disease. Endurance training has been shown to reduce oxidative stress in the heart and the liver of sickle mice. However, the effects of endurance training on skeletal muscles, which are major producers of reactive oxygen species during exercise, are currently unknown. The aim of this study was to evaluate the effect of sickle genotype on prooxidant/antioxidant response to individualized endurance training in skeletal muscles of sickle mice. Healthy and homozygous Townes sickle mice were divided into trained or sedentary groups. Maximal aerobic speed and V̇O2 peak were determined using an incremental test on a treadmill. Trained mice ran at 40% to 60% of maximal aerobic speed, 1 h/day, 5 days/week for 8 weeks. Oxidative stress markers, prooxidant/antioxidant response, and citrate synthase enzyme activities were assessed in the gastrocnemius, in the plantaris, and in the soleus muscles. Maximal aerobic speed and V̇O2 peak were significantly reduced in sickle compared to healthy mice (-57% and -17%; p < 0.001). NADPH oxidase, superoxide dismutase, and catalase activities significantly increased after training in the gastrocnemius of sickle mice only. A similar trend was observed for citrate synthase activity in sickle mice (p = 0.06). In this study, we showed an adaptive response to individualized endurance training on the prooxidant/antioxidant balance in the gastrocnemius, but neither in the plantaris nor in the soleus of trained sickle mice, suggesting an effect of sickle genotype on skeletal muscle response to endurance treadmill training.


Assuntos
Músculo Esquelético/metabolismo , Estresse Oxidativo , Condicionamento Físico Animal , Anemia Falciforme/genética , Anemia Falciforme/patologia , Anemia Falciforme/veterinária , Animais , Catalase/metabolismo , Citrato (si)-Sintase/metabolismo , Camundongos , Camundongos Transgênicos , NADPH Oxidases/metabolismo , Consumo de Oxigênio , Superóxido Dismutase/metabolismo , Regulação para Cima , Xantina Oxidase/metabolismo
11.
Pestic Biochem Physiol ; 159: 127-135, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400774

RESUMO

Pesticides cardiotoxicity in case of diabetic-induced cardiac complications is unidentified. The probable amelioration role of propolis is gauged against the cardiotoxic effects of chlorpyrifos in the diabetic rats through paraoxonase-1 (PON1) and xanthine oxidase (XO) genes dysregulation. Fifty-six male rats were distributed (n = 7) into eight groups. The first one saved as control whereas the 2nd, 3rd, and 4th were kept for propolis aqueous extract (100 mg/kg), diabetes (60 mg/kg streptozotocin) and chlorpyrifos (2.5 mg/kg), respectively. The 5th was diabetes/chlorpyrifos combination, while 6th, 7th, and 8th were intubated with propolis for four weeks after diabetic induction, chlorpyrifos intoxication, and their combination, respectively. The plasma glucose, lipid profiles, cardiac enzymes and interleukin-6 (IL-6) significantly elevated, while insulin decreased in the diabetic and combination groups. Although the cardiac acetylcholinesterase, total thiols, and PON1 significantly reduced after diabetic and/or chlorpyrifos gavage, the protein carbonyl, superoxide dismutase, catalase, and XO significantly elevated. The mRNA genes expression of PON1 and XO have also confirmed the enzymatic activities. Interestingly, propolis significantly restored the hyperglycemia, hypoinsulinemia, hyperlipidemia, IL-6 elevations, and antioxidant defense system disorder. These records revealed that the immunomodulatory, anti-diabetic and antioxidant tasks are fine pointers for the cardiovascular defender of propolis especially during diabetes and/or pesticides exposure.


Assuntos
Arildialquilfosfatase/metabolismo , Clorpirifos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Própole/uso terapêutico , Xantina Oxidase/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Inseticidas/uso terapêutico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos
12.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340570

RESUMO

As a traditional natural medicine for treating many kinds of diseases, Gnetum parvifolium showed apparent inhibition on xanthine oxidase (XO). In this study, ultrafiltration combined with liquid chromatography-mass spectrometry (LC-MS) is used for the screening of XO inhibitors from Gnetum parvifolium. Their antioxidation, XO inhibition, and enzymic kinetic parameters are also determined. Finally, piceatannol (1), rhaponiticin (2), resveratrol (3), and isorhapontigenin (4) are screened out and identified as XO inhibitors from the extract of Gnetum parvifolium. Four inhibitors show better inhibition than allopurinol and good radical scavenging abilities. However, the antioxidant activities are weaker than ascorbic acid. The kinetic parameters illustrate the inhibition mode of XO by piceatannol is competitive type, while the inhibition modes for rhaponiticin, resveratrol and isorhapontigenin are uncompetitive types. In order to evaluate the difference among samples obtained in China, the amounts of four inhibitors and related activities in 20 samples are assessed and analyzed by partial least squares analysis. The results indicate piceatannol contribute the highest coefficients in three kinds of activities. Based on these findings, more comprehensive research on pharmaceutical and biochemical activities of these four XO inhibitors could be conducted in future.


Assuntos
Gnetum/química , Resveratrol/isolamento & purificação , Estilbenos/isolamento & purificação , Xantina Oxidase/antagonistas & inibidores , Alopurinol/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Depuradores de Radicais Livres/isolamento & purificação , Depuradores de Radicais Livres/farmacologia , Ensaios de Triagem em Larga Escala , Cinética , Análise dos Mínimos Quadrados , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Resveratrol/farmacologia , Estilbenos/farmacologia , Ultrafiltração , Xantina Oxidase/metabolismo
13.
Chem Biol Interact ; 310: 108721, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233715

RESUMO

OBJECTIVE: Increasing consumption of fructose is a major contributor to epidemic metabolic syndrome (MS), and the risk of renal disorders and/or injuries remains high among individuals with MS particularly during pregnancy. Glutamine (GLT) has been demonstrated to have a modulatory effect in MS and/or insulin resistance (IR). This study investigated the effect of GLT on renal lipid accumulation and glutathione depletion induced by high fructose-enriched drink (FED) in pregnant rats and also tested the hypothesis that the renoprotective role of GLT is by suppression of adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway. METHODS: Pregnant Wistar rats weighing between 160 and 180 g were allotted into Control, GLT, FED and FED + GLT groups (6 rats/group). The groups received distilled water (vehicle, p. o.), 1 g/kg bw GLT (p.o.), 10% Fructose (w/v) and 10% Fructose (w/v) plus 1 g/kg bw GLT (p.o.) respectively, daily for 19 days. RESULTS: Data showed that FED caused IR, increased body weight gain, blood glucose, plasma insulin, creatinine, urea, lipid accumulation, lipid peroxidation, lactate production, aspartate transaminase and alanine aminotransferase, depressed Glucose-6-phosphate dehydrogenase, sodium-potassium-ATPase activities and glutathione. These alterations were accompanied by increased activity of ADA/XO/UA pathway. However, the FED-induced renal injury and its correlates were normalized by GLT supplementation. CONCLUSION: The present results demonstrate that renal lipid accumulation and glutathione depletion-driven renal injury in pregnant rats is accompanied by increased activity of ADA/XO/UA pathway. The findings also suggest that GLT would confer protection against renal injury by protecting against lipid accumulation and glutathionedepletion, at least in part, through suppression of ADA/XO/UA pathway.


Assuntos
Glutamina/farmacologia , Glutationa/análise , Resistência à Insulina , Lipídeos/análise , Neuroproteção/efeitos dos fármacos , Adenosina Desaminase/metabolismo , Animais , Feminino , Frutose/efeitos adversos , Glutationa/efeitos dos fármacos , Síndrome Metabólica , Gravidez , Ratos , Ratos Wistar , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismo
14.
Diabetes Metab Syndr ; 13(3): 2021-2024, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235130

RESUMO

AIM: This study evaluated the activity of xanthine oxidase in Nigerians with type 2 diabetic mellitus as well as its relationship with lipid peroxidation, inflammatory bio markers and glycemic control indices. METHODS: Two hundred and thirty seven (237) subjects, comprising of one hundred and fifty seven (157) DM subjects and eighty (80) aged matched controls participated in this study. Blood samples were collected from the participants for the estimations of xanthine oxidase activity, uric acid, malon diadehyde (MDA), erythrocyte sedimentation rate (ESR), high sensitive c - reactive protein (hs CRP), glucose, fructosamine and glycosylated hemoglobin by standard methods. RESULTS: The results of this study showed a significantly increased activity of xanthine oxidase in DM (0.044 ±â€¯0.05µ/mg) compared with apparently healthy controls (0.028 ±â€¯0.00 µ/mg). The mean plasma levels of MDA (42.40 ±â€¯2.50µmol/l) and uric acid (7.22 ±â€¯0.20 mg/dl) in DM were significantly higher (p ≤ 0.05) than healthy non DM group. The mean levels of hs CRP in DM (4.09 ±â€¯0.91µg/ml) was significantly higher than controls (1.30 ±â€¯0.50µg/ml, p = 0.009). While no association of xanthine oxidase was observed with glycemic control indices and hs CRP, a negative association of xanthine oxidase was observed with MDA (r = -0.514, p = 0.000). CONCLUSION: Increased activity of xanthine oxidase in DM was associated with increased lipid peroxidation and could be a salient entity towards the onset on complications.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/epidemiologia , Peroxidação de Lipídeos , Estresse Oxidativo , Xantina Oxidase/metabolismo , Adulto , Idoso , Glicemia/análise , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Seguimentos , Frutosamina/metabolismo , Hemoglobina A Glicada/análise , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Prognóstico , Ácido Úrico/metabolismo
15.
Saudi J Kidney Dis Transpl ; 30(3): 723-725, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249241

RESUMO

Adenine phosphoribosyltransferase deficiency is an inherited condition presenting from infancy to late adulthood. The common features are recurrent kidney and urinary tract stones and obstructive symptoms. The stones are characteristically radiolucent. 2, 8-Dihydroxyadenine (2, 8-DHA) formation is blocked by xanthine oxidase blocker allopurinol. Here, we report the case of an eight-month-old baby girl who presented with obstructive acute kidney injury secondary to calculi which was treated with surgical removal of stone. The analysis of the calculi revealed 2, 8-DHA crystals.


Assuntos
Lesão Renal Aguda/etiologia , Adenina Fosforribosiltransferase/deficiência , Adenina/análogos & derivados , Cálculos Renais/etiologia , Erros Inatos do Metabolismo/complicações , Urolitíase/complicações , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/cirurgia , Adenina/metabolismo , Alopurinol/uso terapêutico , Cristalização , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Lactente , Cálculos Renais/diagnóstico , Cálculos Renais/metabolismo , Cálculos Renais/cirurgia , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/tratamento farmacológico , Resultado do Tratamento , Urolitíase/diagnóstico , Urolitíase/tratamento farmacológico , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
16.
J Ethnopharmacol ; 242: 112040, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31252094

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lychnophora pinaster, known as "Brazilian arnica" is used in folk medicine as alcoholic extract to treat inflammation, pain, rheumatism and bruises. AIM OF THE STUDY: Evaluate the effects of the Lychnophora pinaster's ethanolic extract and its chemical constituents on inflammation and hyperuricemia. MATERIALS AND METHODS: Ethanolic and hexanic extracts were obtained from the aerial parts of L. pinaster. Sesquiterpene E-lychnophoric acid was isolated from hexanic extract and identified by RMN, GC/MS and IR. In vivo anti-hyperuricemic and anti-inflammatory effects of the ethanolic extracts from L. pinaster (40, 125, 375 mg/kg), E-lychnophoric acid and other constituents previous isolated from L. pinaster and identified in the ethanolic extract by HPLC/UV/DAD (rutin, quercetin and vitexina flavonoids, caffeic, cinnamic and chlorogenic acids, lupeol and stigmasterol, at dose of 15 mg/kg) were assayed by experimental model of oxonate-induced hyperuricemia in Swiss mice, liver xanthine oxidase (XOD) inhibition and by MSU-induced paw edema in mice. RESULTS: Ethanolic extract and all its components presented anti-hyperuricemic activity by inhibiting the hepatic xanthine oxidase activity. Ethanolic extract and its chemical constituents, except quercetin and vitexin, were able to reduce paw edema size induced by urate crystals. Hypouricemic and anti-inflammatory results obtained for the ethanolic extract (40, 125, 375 mg/kg) and E-lychnophoric acid (15 mg/kg) were similar those obtained for standard drugs, allopurinol (10 mg/kg) and indomethacin (3 mg/kg). CONCLUSION: Ethanolic extract and E-lychnophoric, chlorogenic, cinnamic and caffeic acids, rutin, lupeol and stigmasterol presented anti-inflammatory and anti-hyperuricemic actvities. These compounds are responsible for the activities presented by the ethanolic extract of L. pinaster. Ethanolic extract and its chemical constituents can be considered promising agents in the therapeutic of inflammation, hyperuricemia and gout.


Assuntos
Anti-Inflamatórios/uso terapêutico , Asteraceae , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Etanol/química , Supressores da Gota/química , Supressores da Gota/farmacologia , Hexanos/química , Hiperuricemia/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Componentes Aéreos da Planta , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Solventes/química , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
17.
Phytochemistry ; 164: 228-235, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181354

RESUMO

Terminthia paniculata (Sanyeqi) is widely used for treating inflammation and rheumatic arthritis in the folk areas of Yunnan province, China. Its total extract was first revealed with xanthine oxidase (XO) inhibitory activity in vitro and anti-hyperuricemic effect in vivo. Bioassay-guided separation on Fr. A5 yielded six chalcone-flavonone heterodimers, termipaniculatones A-F. Their structures were elucidated based on extensive spectroscopic analyses involving HRESIMS, 1D and 2D NMR, UV, IR and [α]D, and the absolute configuration of termipaniculatone F was verified by ECD calculation. Termipaniculatones A and E showed obvious XO inhibitory activity with IC50 values of 55.6 and 89.5 µM, respectively, which took effects via a mix-type mode. A molecular modeling study revealed that termipaniculatone A was well located into the active site of XO by interacting with Glu802, Arg880, Thr1010 and Val1011 residues. Termipaniculatone A showed anti-hyperuricemic effects by decreasing serum uric acid levels and inhibiting XO activity in both serum and liver on potassium oxonate (PO)-induced hyperuricemia mice, and anti-inflammatory activity through alleviating paw swelling on monosodium urate (MSU)-induced mice, at the concentration of 20 mg/kg. This is the first time to reveal the anti-hyperuricemic and anti-acute gouty arthritis potency of T. paniculata and the characteristic biflavonoids as active constituents, which provides valuable information for searching new XO inhibitors from natural sources.


Assuntos
Anacardiaceae/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Gotosa/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hiperuricemia/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Chalcona/química , Chalcona/isolamento & purificação , Chalcona/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ácido Oxônico/antagonistas & inibidores , Relação Estrutura-Atividade , Ácido Úrico/antagonistas & inibidores , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
18.
Mar Drugs ; 17(6)2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185695

RESUMO

The purpose of this study was to investigate the preventive effects of fucoidan (Fc) and fucoxanthin (Fx) on hyperuricemic rats. Sprague Dawley (SD) rats were randomly assigned to seven groups: a control group, a hyperuricemia (HUA) group, low- and high-dose Fx groups, a Fc group, a combination Fc and Fx group, and a positive control group. Three weeks after the interventions, each group was given potassium oxonate (PO) and hypoxanthine (HX) to induce HUA in all groups except for the control group, and the rats were then sacrificed. Blood and urine were analyzed for biochemical properties, and differences in urine volume were determined. Livers and kidneys were collected to analyze xanthine oxidase (XO) activity and the expression of uric acid (UA) transporter-related proteins (GLUT9, ABCG2, OAT1, URAT1). The results show that HUA was successfully induced by PO/HX after 4 h of administration. The activity of XO was significantly reduced by a combination of Fc and Fx. In the combination group, both ABCG2 and OAT1 increased significantly, whereas GLUT9 and URAT1 decreased significantly. In summary, the combination of Fc and Fx can inhibit the activity of XO in the liver and regulate the expression of proteins related to UA transporter in the kidney to reduce the UA level in serum.


Assuntos
Hiperuricemia/induzido quimicamente , Ácido Oxônico , Polissacarídeos/farmacologia , Xantofilas/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Polissacarídeos/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Xantina Oxidase/metabolismo , Xantofilas/uso terapêutico
19.
Int J Biol Macromol ; 135: 864-876, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31163243

RESUMO

Xanthine oxidase is an important enzyme of purine catabolism pathway and has been associated directly in pathogenesis of gout and indirectly in many pathological conditions like cancer, diabetes and metabolic syndrome. In this research Hesperidin, a bioactive flavonoid was explored to determine the capability of itself and its derivatives to inhibit xanthine oxidase. The design and synthesis of Hesperidin derivatives hybridized with hydrazines to form hydrazides and anilines was performed with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential. The enzyme kinetic studies performed on newly synthesized derivatives showed a potential inhibitory effect on XO ability in competitive manner with IC50 value ranging from 00.263 µM - 14.870 µM and 3HDa1 was revealed as most active derivative. Molecular simulation revealed that new Hesperidin derivatives interacted with the amino acid residues PHE798, GLN1194, ARG912, THR585, SER1080 and MET1038 positioned inside the binding site of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential. Taking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.


Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hesperidina/síntese química , Hesperidina/farmacologia , Xantina Oxidase/antagonistas & inibidores , Antioxidantes/química , Antioxidantes/metabolismo , Compostos de Bifenilo/química , Domínio Catalítico , Desenho de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Hesperidina/química , Hesperidina/metabolismo , Peróxido de Hidrogênio/química , Cinética , Simulação de Acoplamento Molecular , Picratos/química , Ligação Proteica , Relação Estrutura-Atividade , Xantina Oxidase/química , Xantina Oxidase/metabolismo
20.
J Pharmacol Sci ; 140(1): 109-112, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31155393

RESUMO

Cancer cachexia is a systemic wasting syndrome characterized by anorexia and loss of body weight. The xanthine oxidase (XO) inhibitor febuxostat is one of the promising candidates for cancer cachexia treatment. However, cachexic symptoms were not alleviated by oral administration of febuxostat in our cancer cachexia model. Metabolomic analysis with brains of our cachexic model showed that purine metabolism was activated and XO activity was increased, and thus suggested that febuxostat would not reach the brain. Accordingly, targeting XO in the brain, which controls appetite, may be an effective strategy for treatment of cancer cachexia.


Assuntos
Encéfalo/enzimologia , Encéfalo/metabolismo , Caquexia/tratamento farmacológico , Febuxostat/administração & dosagem , Neoplasias/complicações , Xantina Oxidase/metabolismo , Administração Oral , Animais , Caquexia/enzimologia , Caquexia/etiologia , Caquexia/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos BALB C , Purinas/metabolismo , Xantina Oxidase/fisiologia
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