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1.
J Agric Food Chem ; 71(30): 11476-11490, 2023 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-37384918

RESUMO

Pomegranate (Punica granatum L.) is associated with numerous health benefits due to its high levels of antioxidant polyphenolic substances. Since pomegranate extract has been shown to inhibit angiotensin-converting enzyme (ACE), the potential inhibitory effect of most of its main constituents against ACE is unknown. Therefore, we tested the activities of 24 major compounds, the majority of which significantly inhibited ACE. Notably, pedunculagin, punicalin, and gallagic acid were the most effective ACE inhibitors with IC50 values of 0.91, 1.12, and 1.77 µM, respectively. As demonstrated in molecular docking studies, compounds block ACE by forming multiple hydrogen bonds and hydrophobic interactions with catalytic residues and zinc ions in ACE's C- and N-domains, consequently inhibiting ACE's catalytic activity. Also, the most active pedunculagin stimulated nitric oxide (NO) production, activated the endothelial nitric oxide synthase enzyme (eNOS), and significantly increased eNOS protein expression levels up to 5.3-fold in EA.hy926 cells. Furthermore, pedunculagin increased in cellular calcium (Ca2+) concentration promoted eNOS enzyme activation and reduced the production of reactive oxygen species (ROS). In addition, the active compounds improved glucose uptake in insulin-resistant C2C12 skeletal muscle cells in a dose-dependent manner. The results of these computational, in vitro, and cellular experiments provide further evidence to the traditional medicine that involves using pomegranates to treat cardiovascular diseases like hypertension.


Assuntos
Hipertensão , Punica granatum , Inibidores da Enzima Conversora de Angiotensina/química , Simulação de Acoplamento Molecular , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Peptidil Dipeptidase A/metabolismo , Antioxidantes/química
2.
Bioorg Chem ; 129: 106137, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36108590

RESUMO

Pomegranate (Punica granatum L.) extract has been reported to inhibit cholinesterase and the ß-site amyloid precursor protein cleaving enzyme 1 (BACE1); however, most of its constituents' potential inhibition of these enzymes remains unknown. Thus, we investigated the anti-Alzheimer's disease (anti-AD) potential of 16 ellagitannin and gallotannin, and nine anthocyanin derivatives' inhibition of BACE1, AChE, and BChE, and gallagic acid inhibited both the best. Further, a kinetic study identified different modes of inhibition, and a molecular docking simulation revealed that active compounds inhibited these three enzymes with low binding energy through hydrophilic and hydrophobic interactions in the active site cavities. Gallagic acid and castalagin decreased Aß peptides secretion from neuroblastoma cells that overexpressed human ß-amyloid precursor protein significantly by 10 µM. Further, treatment with gallagic acid and castalagin reduced BACE1 and APPsß expression levels significantly without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Co-incubation of Aß42 with gallagic acid reduced Aß42-induced intracellular reactive oxygen species (ROS) production significantly. Our results suggest that pomegranate constituents, specifically gallagic acid, may be useful in developing therapeutic treatment modalities for AD.


Assuntos
Doença de Alzheimer , Punica granatum , Humanos , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/uso terapêutico , Simulação de Acoplamento Molecular , Colinesterases , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo
3.
Bioorg Chem ; 102: 104061, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32653611

RESUMO

Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC50 = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highestaffinityforthemixed and competitivetypeof inhibitorsof poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5-50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and ß-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavonoides/uso terapêutico , Glucose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Hipoglicemiantes/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , alfa-Glucosidases/metabolismo , Animais , Flavonoides/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Camundongos , Ratos , Transdução de Sinais
4.
Chem Biol Interact ; 309: 108707, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194956

RESUMO

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of ß-amyloid (Aß) in the form of senile plaques, and Aß insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aß25-35-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 µM Aß25-35 for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aß. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsß, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Butirilcolinesterase/metabolismo , Flavanonas/química , Glicosídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Acetilcolinesterase/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/farmacologia , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Sítios de Ligação , Butirilcolinesterase/química , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/química , Cinética , Simulação de Acoplamento Molecular , Células PC12 , Fragmentos de Peptídeos/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos , Relação Estrutura-Atividade
5.
Chem Biol Interact ; 305: 180-194, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30928401

RESUMO

Didymin is a naturally occurring orally active flavonoid glycoside (isosakuranetin 7-O-rutinoside) found in various citrus fruits, which has been previously reported to possess a wide variety of pharmacological activities including anticancer, antioxidant, antinociceptive, neuroprotective, hepatoprotective, inflammatory, and cardiovascular. However, there have not been any reports concerning its anti-diabetic potential until now. Therefore, we evaluated the anti-diabetic potential of didymin via inhibition of α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), rat lens aldose reductase (RLAR), human recombinant AR (HRAR), and advanced glycation end-product (AGE) formation inhibitory assays. Didymin strongly inhibited PTP1B, α-glucosidase, HRAR, RLAR, and AGE in the corresponding assays. Kinetic study revealed that didymin exhibited a mixed type inhibition against α-glucosidase and HRAR, while it competitively inhibited PTP1B and RLAR. Docking simulations of didymin demonstrated negative binding energies and close proximity to residues in the binding pocket of HRAR, RLAR, PTP1B and α-glucosidase, indicating that didymin have high affinity and tight binding capacity towards the active site of these enzymes. Furthermore, we also examined the molecular mechanisms underlying the anti-diabetic effects of didymin in insulin-resistant HepG2 cells which significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells. In addition, didymin activated insulin receptor substrate (IRS)-1 by increasing phosphorylation at tyrosine 895 and enhanced the phosphorylations of phosphoinositide 3-kinase (PI3K), Akt, and glycogen synthasekinase-3(GSK-3). Interestingly, didymin reduced the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, two key enzymes involved in the gluconeogenesis and leading to a diminished glucose production. The results of the present study clearly demonstrated that didymin will be useful for developing multiple target-oriented therapeutic modalities for treatment of diabetes, and diabetes-associated complications.


Assuntos
Flavonoides/farmacologia , Glucose/metabolismo , Glicosídeos/farmacologia , Hipoglicemiantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sítios de Ligação , Domínio Catalítico , Citrus/química , Citrus/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Gluconeogênese/efeitos dos fármacos , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicosídeos/química , Glicosídeos/metabolismo , Células Hep G2 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Resistência à Insulina , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
6.
Exp Mol Med ; 51(2): 1-18, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755593

RESUMO

We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) and cholinesterases involved in the pathogenesis of Alzheimer's disease (AD). (2R)-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC50 of 29.6, 16.2 and 48.1 µM, respectively. The Ki values and binding energies (kcal/mol) between pterosins and BACE1, AChE, and BChE corresponded to the respective IC50 values. (2R)-Pterosin B was a noncompetitive inhibitor against human BACE1 and BChE as well as a mixed-type inhibitor against AChE, binding to the active sites of the corresponding enzymes. Molecular docking simulation of mixed-type and noncompetitive inhibitors for BACE1, AChE, and BChE indicated novel binding site-directed inhibition of the enzymes by pterosins and the structure-activity relationship. (2R)-Pterosin B exhibited a strong BBB permeability with an effective permeability (Pe) of 60.3×10-6 cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,3 R)-pteroside C significantly decreased the secretion of Aß peptides from neuroblastoma cells that overexpressed human ß-amyloid precursor protein at 500 µM. Conclusively, our study suggested that several pterosins are potential scaffolds for multitarget-directed ligands (MTDLs) for AD therapeutics.


Assuntos
Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Ligantes , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Permeabilidade , Proteínas Recombinantes , Relação Estrutura-Atividade
7.
Prev Nutr Food Sci ; 21(3): 208-220, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27752497

RESUMO

The aim of this study was to investigate the protective effects of juice powders from sweet orange [Citrus sinensis (L.) Osbeck], unshiu mikan (Citrus unshiu Marcow), and mini tomato (Solanum lycopersicum L.), and their major flavonoids, hesperidin, narirutin, and rutin in tert-butyl hydroperoxide (t-BHP)-induced oxidative stress in HepG2 cells. The increased reactive oxygen species and decreased glutathione levels observed in t-BHP-treated HepG2 cells were ameliorated by pretreatment with juice powders, indicating that the hepatoprotective effects of juice powders and their major flavonoids are mediated by induction of cellular defense against oxidative stress. Moreover, pretreatment with juice powders up-regulated phase-II genes such as heme oxygenase-1 (HO-1), thereby preventing cellular damage and the resultant increase in HO-1 expression. The high-performance liquid chromatography profiles of the juice powders confirmed that hesperidin, narirutin, and rutin were the key flavonoids present. Our results suggest that these fruit juice powders and their major flavonoids provide a significant cytoprotective effect against oxidative stress, which is most likely due to the flavonoid-related bioactive compounds present, leading to the normal redox status of cells. Therefore, these fruit juice powders could be advantageous as bioactive sources for the prevention of oxidative injury in hepatoma cells.

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