RESUMO
Multifunctional peptides derived from various food sources, including ancestral grains, hold significant promise for managing metabolic syndrome. These bioactive peptides exhibit diverse properties that collectively contribute to improving the components of metabolic syndrome. In this study, we investigated the in vitro multifunctionality of six peptides (PW, PM, SW, PPG, PW, and IW) identified through in silico analysis and chemically synthesized. These peptides were evaluated for their potential to address metabolic syndrome-related activities such as antidiabetic, antiobesity, antihypertensive, and antioxidative properties. Assessment included their capacity to inhibit key enzymes associated with these activities, as well as their free radical scavenging and cellular antioxidative activities. Principal component analysis was employed to cluster the peptides according to their multifunctionality. Our results revealed that peptides containing tryptophan (SW, PW, and IW) exhibited the most promising multifunctional attributes, with SW showing particularly high potential. This multifunctional peptide represents a promising avenue for addressing metabolic syndrome.
Assuntos
Síndrome Metabólica , Peptídeos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologiaRESUMO
In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.
Assuntos
Anti-Hipertensivos , Benzimidazóis , Simulação de Acoplamento Molecular , Ratos Endogâmicos SHR , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Ratos , Relação Estrutura-Atividade , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Receptor Tipo 1 de Angiotensina/metabolismo , Estrutura Molecular , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo L/metabolismoRESUMO
The aim of this study was to investigate the potential of Amaranthus cruentus flavonoids (quercetin, kaempferol, catechin, hesperetin, naringenin, hesperidin, and naringin), cinnamic acid derivatives (p-coumaric acid, ferulic acid, and caffeic acid), and benzoic acids (vanillic acid and 4-hydroxybenzoic acid) as antioxidants, antidiabetic, and antihypertensive agents. An analytical method for simultaneous quantification of flavonoids, cinnamic acid derivatives, and benzoic acids for metabolomic analysis of leaves and inflorescences from A. cruentus was developed with HPLC-UV-DAD. Evaluation of linearity, limit of detection, limit of quantitation, precision, and recovery was used to validate the analytical method developed. Maximum total flavonoids contents (5.2 mg/g of lyophilized material) and cinnamic acid derivatives contents (0.6 mg/g of lyophilized material) were found in leaves. Using UV-Vis spectrophotometry, the maximum total betacyanin contents (74.4 mg/g of lyophilized material) and betaxanthin contents (31 mg/g of lyophilized material) were found in inflorescences. The leaf extract showed the highest activity in removing DPPH radicals. In vitro antidiabetic activity of extracts was performed with pancreatic α-glucosidase and intestinal α-amylase, and compared to acarbose. Both extracts exhibited a reduction in enzyme activity from 57 to 74%. Furthermore, the in vivo tests on normoglycemic murine models showed improved glucose homeostasis after sucrose load, which was significantly different from the control. In vitro antihypertensive activity of extracts was performed with angiotensin-converting enzyme and contrasted to captopril; both extracts exhibited a reduction of enzyme activity from 53 to 58%. The leaf extract induced a 45% relaxation in an ex vivo aorta model. In the molecular docking analysis, isoamaranthin and isogomphrenin-I showed predictive binding affinity for α-glucosidases (human maltase-glucoamylase and human sucrase-isomaltase), while catechin displayed binding affinity for human angiotensin-converting enzyme. The data from this study highlights the potential of A. cruentus as a functional food.
Assuntos
Amaranthus , Anti-Hipertensivos , Hipoglicemiantes , Metabolômica , Extratos Vegetais , Folhas de Planta , Amaranthus/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Cromatografia Líquida de Alta Pressão , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/química , Metabolômica/métodos , Animais , Antioxidantes/farmacologia , Antioxidantes/química , Masculino , Ratos , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/análiseRESUMO
An acidic beverage was formulated with xanthan gum (XG), pectin (P) and brewer spent grain (BSG) peptides with antioxidant and antihypertensive properties. The impact of hydrocolloids levels on peptide bioaccessibility was studied. Peptides were obtained from BSG using Purazyme and Flavourzyme enzymes. BSG peptides were fractionated by ultrafiltration (UF) and four fractions were obtained: F1 (>10 kDa), F2 (10-5 kDa), F3 (1-5 kDa), and F4 (<1 kDa). F3 showed the highest protein purity, ferulic acid content, proportion of amphipathic peptides, and bioactive properties (ABTS+ radical scavenging and ACE-I inhibitory activity). The identified peptides from F3 by tandem mass spectrometry were 138. In silico analysis showed that 26 identified peptides had ABTS+ inhibitory activity, while 59 ones presented good antihypertensive properties. The effect of XG and P levels on bioaccessibility of F3 peptides in the formulated beverages was studied by a central composite experimental design. It was observed that F3 peptides interacted with hydrocolloids by electrostatic forces at pH of formulated beverages. The addition of hydrocolloids to formulation modulated the release of the antioxidant peptides and protected the degradation of ACE-I inhibitory peptides from F3 during simulated gastrointestinal digestion. Finally, the level of hydrocolloids that produced intermediate viscosities in the formulated beverages improved the bioaccessibility of the F3 peptides.
Assuntos
Anti-Hipertensivos , Antioxidantes , Benzotiazóis , Polissacarídeos Bacterianos , Ácidos Sulfônicos , Anti-Hipertensivos/química , Antioxidantes/análise , Hidrólise , Inibidores da Enzima Conversora de Angiotensina/química , Pectinas/análise , Hidrolisados de Proteína/química , Peptídeos/química , Grão Comestível/química , Coloides/análiseRESUMO
Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT1 receptor), reducing oxidative stress and intracellular calcium flux, a mechanism implied in cell contraction. These results were accompanied by the reduction of the contractile capacity of mesangial cells. In vivo experiments showed that the complex causes a significant decrease in systolic blood pressure after 8 weeks of treatment in spontaneously hypertensive rats (SHR). The reduction of heart hypertrophy was evidenced by echocardiography, the histologic cross-sectional area of cardiomyocytes, collagen content, the B-type natriuretic peptide (BNP) marker and connective tissue growth factor (CTGF) and the matrix metalloproteinase 2 (MMP-2) expression. Besides, the complex restored the redox status. In this study, we demonstrated that the complexation with Zn(II) improves the antihypertensive and cardiac effects of the parental drug.
Assuntos
Anti-Hipertensivos , Hipertensão , Hipertrofia Ventricular Esquerda , Zinco , Animais , Ratos , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Pressão Sanguínea , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Metaloproteinase 2 da Matriz , Miócitos Cardíacos , Ratos Endogâmicos SHR , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Zinco/farmacologiaRESUMO
Fish protein hydrolysates (FPHs) can be obtained from substrates such as fish muscle, skin, and wastes and assign value to these fish by-products. Proteolytic enzymes catalyze the hydrolysis of these fish substrates' peptide bonds resulting in smaller peptides that present several bioactive properties. Hydrolysates' bioactive properties are a function of the fish species used as the substrate, the enzyme selectivity or specificity, pH and temperature applied in the reaction, etc. Furthermore, many pre-treatment methods are being applied to fish protein substrates to improve their enzyme susceptibility and increase the number of smaller bioactive peptides. This review addresses the production of FPHs and the main bioactive properties evaluated recently in the literature and emphasizes the substrate treatments by high-pressure processing, microwave, ultrasound, and thermal treatments to achieve better bioactivity making essential amino acids more available in peptides. The bioactive properties most found in FPHs were antioxidants, antimicrobials, anticancer, and antihypertensive. These bioactivities may vary depending on the conditions of hydrolysis, fish species, and fractionation and isolation of specific peptides.New technologies for the treatment of by-products can reduce process losses and achieve better results by cleavage of proteins. Conversely, encapsulation and film utilization can improve bioactivity, bioavailability, and controlled release when applied to foods, resulting in improved health.
Assuntos
Peixes , Hidrolisados de Proteína , Animais , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Disponibilidade Biológica , Peixes/metabolismo , Peptídeos/química , Anti-Hipertensivos/química , Hidrólise , Antioxidantes/químicaRESUMO
Hypertension is a factor that contributes to the risk of chronic diseases. The inhibition of angiotensin-I converting enzyme (ACE) is a useful therapeutic approach to the hypertension treatment. The algae have been an alternative for the production of ACE inhibitory (ACEi) peptides from enzymatic hydrolysis due to their protein-rich biomass. The aim of this study was to systematically review the literature regarding the production, composition and activity of ACEi peptides derived from algae proteins. Systematic database searches identified 648 related articles. Among these, only 14 were selected according to the eligibility criteria to this review. Macroalgae are more studied than microalgae as sources of ACEi peptides. Furthermore, hydrolysates by thermolysin or bromelain exhibited the highest ACEi activity compared to other enzymes. The main features of the peptides with high ACE inhibition are low molecular weight, short amino acids sequence and non-competitive inhibition pattern. In vivo studies using hydrolysates and peptides derived from algae proteins showed antihypertensive activity in spontaneously hypertensive rats (SHR). Thus, it is suggested that ACEi peptides derived from algae can be considered as potential antihypertensive.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Hipertensão , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinas/uso terapêutico , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Peptídeos/farmacologia , RatosRESUMO
The present study investigates the chemical composition, anti-inflammatory, and antihypertensive activities, inâ vitro, from extracts of Cuphea lindmaniana and Cuphea urbaniana leaves. The extraction was performed ultrasound-assisted, and UHPLC/MS analysis was in positive mode ionization. The anti-inflammatory activity of the extracts and miquelianin were assayed at concentrations 0.001-10â µg/mL by chemotaxis on rat polymorphonuclear neutrophils. The antihypertensive activity was performed by angiotensin-converting enzyme (ACE) inhibition. From the nineteen proposed compounds, six of them are described for the first time in this genus. The extracts displayed antichemotactic effect with a reduction of 100 % of the neutrophil migration, inâ vitro, in most concentrations. The ACE-inhibition presented results ranging from 19.58 to 22.82 %. In conclusion, C. lindmaniana and C. urbaniana extracts contain a rich diversity of flavonoids and display inâ vitro anti-inflammatory and antihypertensive potential. Thus, this study could serve as a scientific baseline for further investigation, on developmental novel products with therapeutic actions.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/farmacologia , Cuphea/química , Neutrófilos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Angiotensinas/antagonistas & inibidores , Angiotensinas/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Polifenóis/química , Polifenóis/isolamento & purificação , RatosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Aloysia polystachya (Griseb) Moldenke (Verbenaceae), popularly known as "burrito", is a South American species widely prescribed by local Brazilian healers for the treatment of cardiovascular diseases. However, its antihypertensive and cardioprotective effects are still unknown. AIM: To evaluate the role of the ethanol-soluble fraction of A. polystachya leaves (ESAP) against hypertension in spontaneously hypertensive rats (SHRs), as well as its safety, morphoanatomical and phytochemical aspects. MATERIALS AND METHODS: First, the leaves and stems of A. polystachya were analyzed by optical and scanning electron microscopy in order to provide anatomical data for quality control. Then, ESAP was obtained and its chemical profile was analyzed by LC-DAD-MS. In addition, the cytotoxic and acute toxicity potential of ESAP were evaluated in six cell lines and in female Wistar rats, respectively. Next, female spontaneously hypertensive rats (SHRs) received ESAP (30, 100, 300 mg/kg), hydrochlorothiazide (25 mg/kg), or vehicle once daily for 28 days. Weekly kidney function was monitored by analyzing urinary parameters. At the end of the 28-day treatment, the electrocardiographic profile, blood pressure, and renal and mesenteric vascular reactivity were evaluated. Relative organ (heart, kidney, and liver) weights and biochemical parameters were also evaluated. Finally, the heart, kidneys, and aorta were collected for determination of the tissue redox state, cardiac morphometry, and histopathological analysis. RESULTS: The chemical profile of ESAP was composed by organic acids, a nucleoside, methoxylated flavones and glycosylated compounds including phenolic acids, phenylpropanoids, iridoids and monoterpenes. No signs of toxicity were observed in all cell's lines nor in female Wistar rats submitted to this trial. All SHRs from the negative control group presented a reduction in renal function, alterations in the renal and mesenteric vascular reactivity, and electrocardiographic and morphometric changes typical of ventricular hypertrophy. Oral prolonged ESAP-administration in SHRs was able to reverse renal, electrocardiographic and hemodynamic changes induced by hypertension. Moreover, ESAP-treatment was able to modulate the vascular and renal arterial reactivity and tissue redox state. The aforementioned data were accompanied by reduction of cardiac hypertrophy. CONCLUSION: In this study, we present important anatomical and phytochemical data that contributed to the correct identification and quality control of A. polystachya. In addition, we have shown that ESAP is safe after acute administration and present significant cardioprotective effects (at 30, 100, and 300 mg/kg doses) in SHRs after prolonged treatment.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Verbenaceae , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Brasil , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Etanol/química , Etnofarmacologia , Feminino , Coração/efeitos dos fármacos , Coração/fisiologia , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiologia , Fígado/efeitos dos fármacos , Fígado/patologia , Miocárdio/patologia , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Folhas de Planta/química , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Solventes/químicaRESUMO
Preeclampsia is a hypertensive disorder that occurs during pregnancy. It is a complex disease with unknown pathogenesis and the leading cause of fetal and maternal mortality during pregnancy. Using all drugs currently under clinical trial for preeclampsia, we extracted all their possible targets from the DrugBank and ChEMBL databases and labeled them as "targets". The proteins labeled as "off-targets" were extracted in the same way but while taking all antihypertensive drugs which are inhibitors of ACE and/or angiotensin receptor antagonist as query molecules. Classification models were obtained for each of the 55 total proteins (45 targets and 10 off-targets) using the TPOT pipeline optimization tool. The average accuracy of the models in predicting the external dataset for targets and off-targets was 0.830 and 0.850, respectively. The combinations of models maximizing their virtual screening performance were explored by combining the desirability function and genetic algorithms. The virtual screening performance metrics for the best model were: the Boltzmann-Enhanced Discrimination of ROC (BEDROC)α=160.9 = 0.258, the Enrichment Factor (EF)1% = 31.55 and the Area Under the Accumulation Curve (AUAC) = 0.831. The most relevant targets for preeclampsia were: AR, VDR, SLC6A2, NOS3 and CHRM4, while ABCG2, ERBB2, CES1 and REN led to the most relevant off-targets. A virtual screening of the DrugBank database identified estradiol, estriol, vitamins E and D, lynestrenol, mifrepristone, simvastatin, ambroxol, and some antibiotics and antiparasitics as drugs with potential application in the treatment of preeclampsia.