RESUMO
Dipeptidyl peptidase IV (DPP-IV) inhibitory peptides were screened and identified from yak hemoglobin for the first time by in silico analysis, molecular docking, and in vitro evaluation. Results showed that yak hemoglobin had a high potential to produce DPP-IV inhibitory peptides based on the sequence alignment and bioactive potential evaluation. Furthermore, "pancreatic elastase + stem bromelain" was the optimal combined-enzymatic strategy by simulated proteolysis. Additionally, 25 novel peptides were found from its simulated hydrolysate, among which 10 peptides had high binding affinities with DPP-IV by molecular docking. Most of these peptides were also in silico characterized with favorable physicochemical properties and biological potentials, including relatively low molecular weight, high hydrophobicity, several net charges, good water solubility, nontoxicity, acceptable sensory quality, and good human intestinal absorption. Finally, six novel DPP-IV inhibitory peptides were identified via in vitro assessment, among which EEKA (IC50 = 235.26 µM), DEV (IC50 = 339.45 µM), and HCDKL (IC50 = 632.93 µM) showed the strongest capacities. The hydrogen bonds and electrostatic attractions formed with core residues within the S2 pocket of DPP-IV could be mainly responsible for their inhibition performances. This work provided a time-saving method and broadened application for yak by-products development as sources of functional foods.
Assuntos
Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Animais , Bovinos , Humanos , Simulação de Acoplamento Molecular , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/química , Peptídeos/química , HemoglobinasRESUMO
Traditional Chinese medicine (TCM) possesses unique advantages in the management of blood glucose and lipids. However, there is still a significant gap in the exploration of its pharmacologically active components. Integrated strategies encompassing deep-learning prediction models and active validation based on absorbable ingredients can greatly improve the identification rate and screening efficiency in TCM. In this study, the affinity prediction of 11,549 compounds from the traditional Chinese medicine system's pharmacology database (TCMSP) with dipeptidyl peptidase-IV (DPP-IV) based on a deep-learning model was firstly conducted. With the results, Gardenia jasminoides Ellis (GJE), a food medicine with homologous properties, was selected as a model drug. The absorbed components of GJE were subsequently identified through in vivo intestinal perfusion and oral administration. As a result, a total of 38 prototypical absorbed components of GJE were identified. These components were analyzed to determine their absorption patterns after intestinal, hepatic, and systemic metabolism. Virtual docking and DPP-IV enzyme activity experiments were further conducted to validate the inhibitory effects and potential binding sites of the common constituents of deep learning and sequential metabolism. The results showed a significant DPP-IV inhibitory activity (IC50 53 ± 0.63 µg/mL) of the iridoid glycosides' potent fractions, which is a novel finding. Genipin 1-gentiobioside was screened as a promising new DPP-IV inhibitor in GJE. These findings highlight the potential of this innovative approach for the rapid screening of active ingredients in TCM and provide insights into the molecular mechanisms underlying the anti-diabetic activity of GJE.
Assuntos
Aprendizado Profundo , Inibidores da Dipeptidil Peptidase IV , Gardenia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Gardenia/química , Glicosídeos Iridoides/química , Dipeptidil Peptidases e Tripeptidil Peptidases , Dipeptidil Peptidase 4 , Simulação de Acoplamento MolecularRESUMO
Dipeptidyl peptidase IV (DPP-IV) is an enzyme responsible for the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1). DPP-IV plays a significant role in regulating blood glucose levels by modulating the activity of GLP-1. In the context of diabetes, DPP-IV inhibitors effectively block the activity of DPP-IV, hence mitigating the degradation of GLP-1. This, in turn, leads to an extension of GLP-1's duration of action, prolongs gastric emptying, enhances insulin sensitivity, and ultimately results in the reduction of blood glucose levels. Nonetheless, reported adverse events of DPP-IV inhibitors on T2DM patients make it essential to understand the activity and mechanism of these drugs, particularly viewed from the perspective of finding the effective and safe add-on medicinal plants, to be implemented in clinical practice. This review is intended to bring forth a thorough overview of plants that work by reducing DPP-IV activity, from computational technique, enzymatic study, animal experiments, and studies in humans. The articles were searched on PubMed using "Plants", "DPP-IV", "DPP-IV inhibitor", "GLP-1", "Type 2 diabetes", "diabetes", "in silico", "in vitro", "in vivo", "studies in human", "clinical study" as the query words, and filtered for ten years of publication period. Eighteen plants showed inhibition against DPP-IV as proven by in silico, in vitro, and in vivo studies; however, only ten plants were reported for efficacy in clinical studies. Several plant-based DPP-IV inhibitors, eg, Allium sativum, Morus Alba, Curcuma longa, Pterocarpus marsupium, and Taraxacum officinale, have established their functional role in inhibiting DPP-IV and have proven their effectiveness through studies in humans earning them a prominent place in therapeutic discovery.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Plantas Medicinais , Animais , Humanos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidase 4/metabolismo , Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêuticoRESUMO
Diabetes is highly linked to the occurrence of Alzheimer disease (AD), which is characterized by beta amyloid peptide (Aß) and hyperphosphorylation of tau (p-tau), and neuron damage particularly in hippocampus. Type 2 diabetes (T2D) is featured by insulin resistance, and phosphorylation of Ser307-IRS-1 is regarded as a resistance marker. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are effective tools for treating T2D. Previously, we reported subfractions of Abelmoschus esculentus (AE, okra) (F1 rich in quercetin glycosides; F2 composed of polysaccharide) attenuated DPP-4 and its downstream signals of insulin resistance, thus preventing Aß-induced neuron damage. Since autophagy could be protective, we now explore if AE works to modulate neuron autophagy by regulating DPP-4 and insulin resistance and, thus, improves the hippocampal function and behavior. We demonstrated that AE subfractions attenuate Aß-induced insulin resistance and the expression of p-tau and normalize the autophagy and survival of hippocampal neurons. The action of AE may be attributed to the downregulation of DPP-4, which plays a critical role in mediating insulin resistance and hinders neuron autophagy. The in vivo findings reveal that the hippocampal insulin resistance appears to link with loss of memory, reduction of curiosity, and depression, whereas treatment with AE significantly improves the insulin sensitivity and hippocampal function. Noteworthy, even at only 5 µg/mL, F2 seems to exhibit a meaningful effect. In conclusion, we suggest that AE attenuates insulin resistance and recovers neuron autophagy which are regulated by DPP-4, thus preventing the damage to the hippocampus, improving recognition and emotion. AE may be an effective adjuvant or supplement to prevent insulin resistance-associated pathogenesis of AD if these results can be confirmed in human clinical trials.
Assuntos
Abelmoschus , Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4 , Doença de Alzheimer/tratamento farmacológico , Autofagia , Hipocampo , NeurôniosRESUMO
Dipeptidyl peptidase IV (DPP-IV) is an integrated type II transmembrane protein that reduces endogenous insulin contents and increases plasma glucose levels by hydrolyzing glucagon-like peptide-1 (GLP-1). Inhibition of DPP-IV regulates and maintains glucose homeostasis, making it an attractive drug target for the treatment of diabetes II. Natural compounds have tremendous potential to regulate glucose metabolism. In this study, we examined the DPP-IV inhibitory activity of a series of natural anthraquinones and synthetic structural analogues on DPP-IV using fluorescence-based biochemical assays. The inhibitory efficiency differed among anthraquinone compounds with different structures. Alizarin (7), aloe emodin (11), emodin (13) emerged the outstanding inhibitory potential for DPP-IV with IC50 values lower than 5 µM. To clarifying the inhibitory mechanism, inhibitory kinetics were performed, which showed that alizarin red S (8) and 13 were effective non-competitive inhibitors of DPP-IV, while alizarin complexone (9), rhein (12), and anthraquinone-2-carboxylic acid (23) were mixed inhibitors. Emodin was determined as inhibitor with the strongest DPP-IV-binding affinity determined via molecular docking. Structure-activity relationship (SAR) demonstrated that hydroxyl group at C-1 and C-8 sites and hydroxyl, hydroxymethyl or carboxyl group at the C-2 or C-3 site were very essential for DPP-IV inhibition, replacement of hydroxyl group with amino group at C-1 could led to an increase of the inhibitory potential. Further fluorescence imaging showed that both compounds 7 and 13 significantly inhibited DPP-IV activity in RTPEC cells. Overall, the results indicated that anthraquinones would be a natural functional ingredient for inhibiting DPP-IV and provided new ideas for searching and developing potential antidiabetic compounds.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Emodina , Humanos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Simulação de Acoplamento Molecular , Emodina/farmacologia , Emodina/uso terapêutico , Estrutura Molecular , Hipoglicemiantes/farmacologia , Relação Estrutura-Atividade , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismoRESUMO
The antidiabetic effects of green tea have been demonstrated in clinical trials and epidemiological studies. This study investigated the antidiabetic effects of green tea extract (GTE) and its underlying molecular mechanisms using a leptin receptor-deficient db/db mouse model (Leprdb/db). Treatment with GTE for 2 weeks improved glucose tolerance and insulin sensitivity in Leprdb/db mice. In addition, GTE treatment reduced the body weight and adiposity of Leprdb/db mice. Furthermore, GTE treatment reduced pro-inflammatory gene expression, including nuclear factor kappa B (NF-κB) in white adipose tissue (WAT), and also reduced dipeptidyl peptidase-4 (DPP4) expression levels in WAT as well as in the serum. The promoter region of Dpp4 contains the NF-κB binding site, and DPP4 was found to be a direct target of NF-κB. Consistently, in vitro treatment of cells with GTE or its main constituent epigallocatechin gallate reduced lipopolysaccharide-induced NF-κB/DPP4 expression in 3T3-L1 adipocytes and RAW264.7 cells. Overall, our data demonstrated that GTE exerts an anti-diabetic effect by regulating the expression levels of NF-κB and DPP4 in WAT.
Assuntos
Dipeptidil Peptidase 4 , Hipoglicemiantes , Camundongos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/metabolismo , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/uso terapêutico , Tecido Adiposo/metabolismo , Chá/químicaRESUMO
AIMS: Bulbine natalensis (BN) and Bulbine frutescens (BF) are recommended in South African traditional medicine to treat diabetes, but their modes of action are unknown. This study assessed the phenolic acid profiles, mineral composition and in vitro functional effects of BN and BF to better understand their glucose-lowering capabilities. METHODS: Phenolic acid and mineral composition of BN and BF methanolic extracts were determined by HPLC and inductively coupled plasma optical emission spectroscopy respectively. Antioxidant capacity was assessed by potassium ferricyanide reducing power and 2,2-diphenyl-2-picrylhydrazyl radical scavenging assays, and inhibition of alpha-amylase, alpha-glucosidase, pancreatic lipase and DPP4 was evaluated by standard enzyme assays. The effects of BN and BF extracts on insulin secretion were investigated using static incubations of isolated mouse islets and molecular docking analysis was used to identify interactions of BN and BF with partners that could mediate stimulatory effects on insulin secretion. RESULTS: Methanolic extracts of BN and BF contained high concentrations of protocatechuic and gallic acids, and high levels of Zn, Mn and Cr. The extracts inhibited alpha-glucosidase, alpha-amylase, pancreatic lipase and DPP4 activities, and they also inhibited free radical generation. Both extracts significantly potentiated glucose-stimulated insulin secretion without significantly affecting basal insulin secretion or islet cell viability. Protocatechuic acid, the most abundant phenolic acid in the extracts, showed high affinity for PKA, PKC, DPP4 and CaMK II in the docking analysis. CONCLUSIONS: BN and BF have multiple beneficial effects on glucoregulatory pathways and they, or their derivatives, could be developed to treat type 2 diabetes.
Assuntos
Asphodelaceae , Diabetes Mellitus Tipo 2 , Animais , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores de Glicosídeo Hidrolases , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Dipeptidil Peptidase 4 , Fenóis/farmacologia , alfa-Amilases , Antioxidantes/farmacologia , Antioxidantes/química , Lipase , GlucoseRESUMO
OBJECTIVE: To investigate the protective effects and molecular mechanisms of Lizhong decoction (, LZD) against non-alcoholic fatty liver disease (NAFLD). METHODS: Male Wistar rats were fed a high-fat diet for four weeks to induce NAFLD, and were administered LZD by gavage for four weeks. Potential therapeutic targets for NAFLD were analyzed using network pharmacology. Liver pathology was evaluated using Oil Red O and hematoxylin-eosin staining. Furthermore, mitochondrial function, lipid metabolism, oxidative stress, and inflammatory response were examined. RESULTS: Rats with NAFLD exhibited high levels of hepatic damage and cholesterol deposition. Moreover, apoptosis was increased, superoxide dismutase and glutathione content were reduced, malondialdehyde content was increased, and the protein expression of inflammatory cytokines and p-c-Jun N-terminal kinase was increased. The LZD treatment ameliorated mitochondrial dysfunction, reduced liver damage, inhibited oxidative stress and inflammatory response, upregulated peroxisome proliferator-activated receptor (PPAR)-γ expression, and suppressed dipeptidyl peptidase 4 (DPP4) expression in the liver. CONCLUSION: It was found that LZD alleviates NAFLD by activating PPAR-γ and inhibiting DPP4.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/farmacologia , Dipeptidil Peptidase 4/uso terapêutico , Metabolismo dos Lipídeos , Fígado , Masculino , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/genética , Ratos , Ratos WistarRESUMO
The employment of proteases directly from enzymes or indirectly from microorganisms during fermentation for the purpose of proteolysis of food proteins has been the conventional trend for the derivation of bioactive peptides from food matrices. However, recent studies have shown that inherent protease enzymes can be activated for this activity for vegetable foods using the sprouting process. The benefits of ease of operation, and reduced processing costs are formidable advantages for the optimal consideration of this technique. On another note, the demand for functional foods with therapeutic health effects has increased in recent years. Globally, plant foods are perceived as dietetic choices bearing sufficient quantities of concomitant nutraceuticals. In this manuscript, the sprouting route for the isolation of peptides and glucosinolates, and for the enhancement of total phenolic contents, polyunsaturated fatty acid profiles, and other bioactive constituents was explored. Advances regarding the phytochemical transformations in the course of sprouting, the therapeutic functionalities, and microbiological safety concerns of vegetable sprouts are delineated. In addition, consumption of vegetable sprouts has been shown to be more efficient in supplying nutraceutical components relative to their unsprouted counterparts. Biochemical mechanisms involving the inhibition of digestive enzymes such as α-amylase, ß-glucosidase, and dipeptidyl peptidase IV (DPP-IV), single electron transfer, and metal chelation, for impartation of health benefits, have been reported to occur from bioactive components isolated from vegetable sprouts. PRACTICAL APPLICATIONS: Sprouting initiates proteolysis of vegetable proteins for the release of bioactive peptides. Abiotic stresses can be used as elicitors during the sprouting process to achieve enhanced phytochemical profiles of sprouts. Sprouting is a relatively more convenient approach to the improvement of the health benefits of vegetable foods. Vegetable sprouts are potential for the management of metabolic syndrome disorders.
Assuntos
Celulases , Hipoglicemiantes , Antioxidantes/farmacologia , Suplementos Nutricionais , Dipeptidil Peptidase 4 , Glucosinolatos/análise , Peptídeo Hidrolases , Peptídeos/química , Peptídeos/farmacologia , Proteínas de Vegetais Comestíveis , Verduras , alfa-AmilasesRESUMO
There are numerous cultivars of tea (Camellia sinensis L.), but the differences in their anti-hyperglycemic-related effects are largely unknown. The inhibition of the dipeptidyl peptidase (DPP)-IV enzyme plays an essential role in controlling hyperglycemia in diabetes by blocking the degradation of incretin hormones, which is necessary for insulin secretion. In this study, we examined the DPP-IV inhibitory activity of leaf extracts from diverse Japanese green tea cultivars. The inhibitory rates differed among tea extracts. Metabolic profiling (MP), using liquid chromatography-mass spectrometry, of all cultivars revealed compositional differences among cultivars according to their DPP-IV inhibitory capacity. Epigallocatechin-3-O-(3-O-methyl)gallate, kaempferol-3-O-rutinoside, myricetin-3-O-glucoside/galactoside, and theogallin were newly identified as DPP-IV inhibitors. The bioactivity of a tea extract was potentiated by adding these ingredients in combination. Our results show that MP is a useful approach for evaluating the DPP-IV inhibitory potency of green tea and for determining bioactivity-related ingredients and combinations.
Assuntos
Camellia sinensis , Inibidores da Dipeptidil Peptidase IV , Camellia sinensis/química , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV/química , Metabolômica/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Chá/químicaRESUMO
Atrophic rhinitis (AR) is a chronic disease that causes severe structural changes to the nasal mucosa leading to squamous epithelial metaplasia. However, treatment regarding AR remains a major challenge. We used network pharmacology and molecular docking methods to explore the potential mechanisms of the Yiqi Qingre Ziyin method to modulate neuropeptides in the treatment of AR. The active ingredients of the Yiqi Qingre Ziyin method and their targets of action were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database Analysis Platform (TCMSP). Disease targets for AR were obtained from four databases: GeneCards, PharmGKB, DrugBank, and Online Mendelian Inheritance in Man (OMIM). A total of 59 active ingredients, 39 potential targets, and 76 relevant neuropeptides were obtained after deduplication. We constructed target interaction networks with the STRING database. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the 14 potential target proteins. We used Cytoscape software to construct the "drug-active ingredient-potential target" and "ingredient-target-pathway" networks of the Yiqi Qingre Ziyin method for treating AR. Molecular docking results suggest that dipeptidyl peptidase 4 (DPP4), opioid receptor gene d1 (OPRD1), and opioid receptor m1 (OPRM1) are key targets for the Yiqi Qingre Ziyin method. Therefore, this study proposed a potential mechanism for the treatment of AR by affecting the expression of neuropeptide-related genes (including DPP4, OPRD1, and OPRM1), which may potentially improve the immune microenvironment of the nasal mucosa.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Neuropeptídeos/metabolismo , Rinite Atrófica/tratamento farmacológico , Simulação por Computador , Bases de Dados Genéticas , Dipeptidil Peptidase 4 , Células Epiteliais/patologia , Ontologia Genética , Humanos , Metaplasia/patologia , Mucosa Nasal/imunologia , Mucosa Nasal/lesõesRESUMO
This study aimed at exploring dipeptidyl peptidase-IV (DPP-IV) inhibitory peptides from silkworm pupae proteins by in silico analysis and in vitro assessments. In silico analysis of 274 silkworm pupae proteomes indicated that DPP-IV inhibitory peptides can be released from silkworm pupae proteins. In vitro assessments revealed that pepsin and bromelain led to better production of DPP-IV inhibitory peptides from silkworm pupae protein. Notably, peptide fractions (<1 kDa) from pepsin- and bromelain-treated hydrolysates exhibited more potent DPP-IV inhibitory activities. Two novel DPP-IV inhibitory peptides (Leu-Pro-Pro-Glu-His-Asp-Trp-Arg and Leu-Pro-Ala-Val-Thr-Ile-Arg) were identified by LC-MS/MS with IC50 values of 261.17 and 192.47 µM, respectively. Enzyme kinetics data demonstrated that these two peptides displayed a mixed-type DPP-IV inhibition mode, which was further validated by molecular docking data. Overall, in silico analysis combined with in vitro assessments can serve as an effective and rapid approach for discovery of DPP-IV peptides from silkworm pupae proteins.
Assuntos
Bombyx , Inibidores da Dipeptidil Peptidase IV , Animais , Bombyx/metabolismo , Cromatografia Líquida , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Simulação de Acoplamento Molecular , Peptídeos/química , Pupa/metabolismo , Espectrometria de Massas em TandemRESUMO
ß-Boswellic acid (ß-BA) and 11-keto-ß-boswellic acid (ß-KBA) are crucial bioactive compounds, mostly isolated from frankincense. These compounds are known for their potent anticancer and anti-inflammatory activities. Herein, we have explored the complete anti-diabetic potential of ß-BA and ß-KBA with detailed parameters. This research revealed that treatment with ß-BA and ß-KBA at a dose of 1, 2, and 10 mg/kg body weight for 21 days significantly improved body weight loss, water consumption, and specifically the concentration of blood glucose level (BGL) in diabetic animals, which indicated that the ß-BA and ß-KBA possess strong anti-diabetic activities. Serum total superoxide dismutase (SOD) and malondialdehyde (MDA) assays were also performed to evaluate the antioxidant effects. The biochemical analysis revealed that these compounds improve an abnormal level of several biochemical parameters like serum lipid values including total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C) to a normal level and the high-density lipoprotein cholesterol level (HDL-C). To understand the mechanism of action of ß-BA and ß-KBA, their most probable biological targets were searched through the inverse docking approach. Our computational analysis reflects that among other probable targets, the Dipeptidyl peptidase 4 (DPP-4) enzyme could be one of the possible binders of ß-BA and ß-KBA to produce their anti-diabetic activities. These in-silico results were validated by an in-vitro experiment. It indicates that the anti-diabetic effects of ß-BA and ß-KBA are produced by the inhibition of DDP-4. Thus, these anti-diabetic, antioxidant, and anti-hyperlipidemic effects of ß-BA and ß-KBA suggest these compounds as potential therapeutics for diabetic conditions.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Animais , Glicemia/efeitos dos fármacos , Boswellia , Dipeptidil Peptidase 4/farmacologia , Relação Dose-Resposta a Droga , Lipídeos/sangue , Malondialdeído/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Estreptozocina , Superóxido Dismutase/efeitos dos fármacos , Triterpenos/administração & dosagem , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Hypertension and diabetes are two kinds of senile diseases which often occur simultaneously. The commonly used drugs in clinic may produce certain side effects. Food-derived polypeptide is a kind of polypeptide with great development potential, which has many functions of regulating human physiological function. Beer is rich in nutrition but there are few researches on bioactive peptides in beer. RESULTS: In this study, a rapid virtual screening method was established to obtain bioactive peptides from Tsingtao draft beer. The peptide sequence was analyzed by ultra-performance liquid chromatography-quadrupole-Orbitrap-tandem mass spectrometry (UPLC-Q-Orbitrap-MS2 ), and 50 peptides were identified. Eight peptides with potential biological activities were screened by using Peptide Ranker software and previous literature references. On the basis of absorption prediction, toxicity prediction, and molecular docking analysis, LNFDPNR and LPQQQAQFK were finally confirmed. The molecular docking results showed that two peptides could bind angiotensin-converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV) tightly by hydrogen bonding and hydrophobic interaction. The in vitro activity evaluation results showed that two peptides had obvious ACE and DPP-IV inhibitory activity. CONCLUSION: This study established a method for rapidly screening bioactive peptides from Tsingtao draft beer, screened two ACE and DPP-IV inhibitory peptides in beer and analyzed their active action mechanism. This article may have great theoretical significance and practical value to further explore the health function of beer. © 2021 Society of Chemical Industry.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Cerveja/análise , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Avaliação Pré-Clínica de Medicamentos/métodos , Peptídeos/química , Peptidil Dipeptidase A/química , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos/instrumentação , Humanos , Hipoglicemiantes/química , Espectrometria de Massas , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: The prevalence of diabetes mellitus worldwide has increased in recent decades. Maintaining the level of blood glucose is the most basic and important issue for diabetics. This study aimed to investigate the hypoglycemic activity of a combination of hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea (ACH) and Chlorella sorokiniana (PCH). RESULTS: Combined supplementation of ACH and PCH synergistically inhibited α-glucosidase and DPP4 activities in vitro. After 4 weeks of treatment with ACH and/or PCH, the plasma glucose concentration and insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), total cholesterol (TC) and triglyceride (TG) levels significantly decreased. The hypoglycemic peptides in ACH and PCH were purified and assayed for α-glucosidase and DPP4 activity. The hypoglycemic peptides in ACH and PCH effectively decreased α-glucosidase and DPP4 activities. In silico assays showed that these two peptide types have different docking poses, which determined their inhibitory effect against α-glucosidase and DPP4 activity. CONCLUSION: Combined treatment with hypoglycemic peptide-enriched ACH and PCH could modulate blood glucose by synergistically inhibiting α-glucosidase and DPP4 activities. © 2021 Society of Chemical Industry.
Assuntos
Chlorella/química , Corbicula/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Peptídeos/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Sinergismo Farmacológico , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hipoglicemiantes/química , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , alfa-Glucosidases/química , alfa-Glucosidases/metabolismoRESUMO
The medicinal plants may serve as natural alternatives to synthetic antidiabetic medications such as dipeptidyl peptidase-IV (DPP-IV) inhibitors, which are commonly prescribed in clinical practise. The medicinal plants: Commiphora mukul and Phyllanthus emblica have considerable DPP-IV inhibitory efficacy, according to our findings. The present study is an extension of the previous study conducted in our laboratory and was designed to confirm the antidiabetic effects of C. mukul and P. emblica in the streptozotocin diabetes model and elucidate the active principles responsible for DPP-IV inhibition. C. mukul (Guggul) and P. emblica (Amla) have the ability to inhibit DPP-IV and have anti-diabetic properties in a Type 2 diabetes mellitus experimental model. The binding sites and affinity of the active principles of C. mukul (Gluggusterone E, Gluggusterone Z) and P. emblica (Pzrogallol, beta-glucogallin, and gallic acid) responsible for DPP-IV enzyme inhibition were identified using in silico studies and compared to Vildagliptin, a synthetic DPP-IV inhibitor. The Vildagliptin and therapy groups had significantly lower glycated hemoglobin and DPP-IV levels. The anti-diabetic effect of C. mukul and P. emblica is due to their DPP-IV inhibitory action. The DPP-IV inhibitory action of Gluggusterone E, Gluggusterone Z, and beta-Glucogallin was found to be superior to Vildagliptin in docking tests.
Assuntos
Commiphora , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Phyllanthus emblica , Extratos Vegetais/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Modelos Animais de Doenças , Humanos , Hipoglicemiantes/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Folhas de Planta , Ratos , Ratos WistarRESUMO
Dipeptidyl peptidase-4 (DPP-4) inhibitors are becoming an essential drug in the treatment of type 2 diabetes mellitus; however, some classes of these drugs exert side effects, including joint pain and pancreatitis. Studies suggest that these side effects might be related to secondary inhibition of DPP-8 and DPP-9. In this study, we identified DPP-4-inhibitor hit compounds selective against DPP-8 and DPP-9. We built a virtual screening workflow using a quantitative structure-activity relationship (QSAR) strategy based on artificial intelligence to allow faster screening of millions of molecules for the DPP-4 target relative to other screening methods. Five regression machine learning algorithms and four classification machine learning algorithms were applied to build virtual screening workflows, with the QSAR model applied using support vector regression (R2pred 0.78) and the classification QSAR model using the random forest algorithm with 92.2% accuracy. Virtual screening results of > 10 million molecules obtained 2 716 hits compounds with a pIC50 value of > 7.5. Additionally, molecular docking results of several potential hit compounds for DPP-4, DPP-8, and DPP-9 identified CH0002 as showing high inhibitory potential against DPP-4 and low inhibitory potential for DPP-8 and DPP-9 enzymes. These results demonstrated the effectiveness of this technique for identifying DPP-4-inhibitor hit compounds selective for DPP-4 and against DPP-8 and DPP-9 and suggest its potential efficacy for applications to discover hit compounds of other targets.
Assuntos
Inteligência Artificial , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Inibidores da Dipeptidil Peptidase IV/química , Avaliação Pré-Clínica de Medicamentos , HumanosRESUMO
CONTEXT: Melicope latifolia (DC.) T. G. Hartley (Rutaceae) was reported to contain various phytochemicals including coumarins, flavonoids, and acetophenones. OBJECTIVE: This study investigates the antidiabetic and antioxidant effects of M. latifolia bark extracts, fractions, and isolated constituents. MATERIALS AND METHODS: Melicope latifolia extracts (hexane, chloroform, and methanol), fractions, and isolated constituents with varying concentrations (0.078-10 mg/mL) were subjected to in vitro α-amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory assay. Molecular docking was performed to study the binding mechanism of active compounds towards α-amylase and DPP-4 enzymes. The antioxidant activity of M. latifolia fractions and compounds were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and ß-carotene bleaching assays. RESULTS: Melicope latifolia chloroform extract showed the highest antidiabetic activity (α-amylase IC50: 1464.32 µg/mL; DPP-4 IC50: 221.58 µg/mL). Fractionation of chloroform extract yielded four major fractions (CF1-CF4) whereby CF3 showed the highest antidiabetic activity (α-amylase IC50: 397.68 µg/mL; DPP-4 IC50: 37.16 µg/mL) and resulted in ß-sitosterol (1), halfordin (2), methyl p-coumarate (3), and protocatechuic acid (4). Isolation of compounds 2-4 from the species and their DPP-4 inhibitory were reported for the first time. Compound 2 showed the highest α-amylase (IC50: 197.53 µM) and ß-carotene (88.48%) inhibition, and formed the highest number of molecular interactions with critical amino acid residues of α-amylase. The highest DPP-4 inhibition was exhibited by compound 3 (IC50: 911.44 µM). DISCUSSION AND CONCLUSIONS: The in vitro and in silico analyses indicated the potential of M. latifolia as an alternative source of α-amylase and DPP-4 inhibitors. Further pharmacological studies on the compounds are recommended.
Assuntos
Inibidores da Dipeptidil Peptidase IV/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Rutaceae/química , alfa-Amilases/antagonistas & inibidores , Antioxidantes/química , Antioxidantes/farmacologia , Simulação por Computador , Dipeptidil Peptidase 4 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Extratos Vegetais/isolamento & purificação , alfa-Amilases/químicaRESUMO
Alcalase hydrolyzates were prepared from the albumin (AH) and globulin (GH) fractions of eight chickpea (Cicer arietinum L.) genotypes from Mexico and 10 from other countries. Protein content, antioxidant activity (AA) (ABTS, DPPH), and degree of hydrolysis were evaluated and the best genotype was selected by principal component analysis. The hydrolyzates of the chosen genotype were analyzed for its antidiabetic potential measured as inhibition of α-amylase, α-glucosidase, and dipeptidyl peptidase-4 (DPP4). Peptide profiles were obtained by liquid chromatography-mass spectrometry (UPLC-DAD-MS), and the most active peptides were analyzed by molecular docking. The average antioxidant activity of albumin hydrolyzates was higher than that of globulin hydrolyzates. ICC3761 was the selected genotype and peptides purified from the albumin hydrolyzate showed the best antioxidant activity and antidiabetic potential (FEI, FEL, FIE, FKN, FGKG, and MEE). FEI, FEL, and FIE were in the same chromatographic peak and this mixture showed the best ABTS scavenging (78.25%) and DPP4 inhibition (IC50 = 4.20 µg/ml). MEE showed the best DPPH scavenging (47%). FGKG showed the best inhibition of α-amylase (54%) and α-glucosidase (56%) and may be a competitive inhibitor based on in silico-predicted interactions with catalytic amino acids in the active site of both enzymes. These peptides could be used as nutraceutical supplements against diseases related to oxidative stress and diabetes. PRACTICAL APPLICATION: This study showed that chickpea protein hydrolyzates are good sources of peptides with antidiabetic potential, showing high antioxidant activity and inhibition of enzymes related to carbohydrate metabolism and type 2 diabetes. These hydrolyzates could be formulated in functional foods for diabetes.
Assuntos
Antioxidantes/química , Cicer/química , Hipoglicemiantes/química , Peptídeos/química , Proteínas de Plantas/química , Cromatografia Líquida , Cicer/genética , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Genótipo , Humanos , Espectrometria de Massas , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Hidrolisados de Proteína/química , Sementes/química , Sementes/genética , alfa-Amilases/química , alfa-Glucosidases/químicaRESUMO
OBJECTIVE: To provide the scientific basis for the utility of rhizome of Trillium govanianum as nutraceutical supplements in managing physiological glycemic levels. METHODS: The in vitro enzyme inhibitory activity of the extract, fractions, and the isolated steroidal saponins from the rhizome part of T. govanianum was carried out against α-amylase, α-glucosidase, and dipeptidyl peptidase IV. The molecular interactions, binding score, and pharmacokinetic parameters (absorption, distribution metabolism, and excretion) of steroidal saponins were analyzed by the Schrodinger molecular docking software. KEY FINDINGS: Current study explained that the extract, fractions, and isolated steroidal saponins from T. govanianum possess good α-amylase and α-glucosidase inhibitory activity while moderate dipeptidyl peptidase IV inhibitory activity. Moreover, in vitro results revealed that borassoside E (IC50 7.15 ± 1.78 µM), protodioscin (IC50 6.72 ± 0.04 µM), and diosgenin (IC50 12.75 ± 2.70 µM) are most effective in inhibiting the activity of α-amylase, α-glucosidase, and dipeptidyl peptidase IV, respectively. Current in silico and in vitro studies established an association between the steroidal saponins from T. govanianum and their molecular interactions with α-amylase, α-glucosidase, and dipeptidyl peptidase IV. CONCLUSION: The results of this investigation suggest that fractions and steroidal saponins from T. govanianum exhibit good antidiabetic activity which could be used as nutraceutical supplements for the management of systemic glucose level.