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1.
J Sci Food Agric ; 100(1): 315-324, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525262

RESUMO

BACKGROUND: In order to utilize tilapia skin gelatin hydrolysate protein, which is normally discarded as industrial waste in the process of fish manufacture, we study the in vivo and in vitro angiotensin-I-converting enzyme (ACE) inhibitory activity of the peptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP). The aim was to provide a pharmacological basis of the development of minimal side effects of ACE inhibitors by comparative analysis with captopril in molecular docking. RESULTS: This peptide from protein-rich wastes showed excellent ACE inhibitory activity (IC50  = 2.577 µmol L-1 ) and exhibited a mixed noncompetitive inhibitory pattern with Lineweaver-Burk plots. Furthermore, LSGYGP and captopril groups both showed significant decreases in blood pressure after 6 h and maintained good digestive stability over 4 h. Molecular bond interactions differentiate competitive captopril upon hydrogen bond interactions and Zn(II) interaction. The C-terminal Pro generates three interactions (hydrogen bonds, hydrophilic interactions and Van der Waals interactions) in the peptide and effectively interacts with the S1 and S2 pockets of ACE. CONCLUSION: LSGYGP, with an IC50 value of 2.577 µmol L-1 , has an antihypertensive effect in spontaneously hypertensive rats. Through comparison with captopril, this study revealed that LSGYGP may be a potential food-derived ACE inhibitory peptide and could act as a functional food ingredient to prevent hypertension. © 2019 Society of Chemical Industry.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Captopril/química , Hipertensão/tratamento farmacológico , Peptídeos/química , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Captopril/administração & dosagem , Ciclídeos , Digestão , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Cinética , Masculino , Simulação de Acoplamento Molecular , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Ratos , Ratos Endogâmicos SHR
2.
Georgian Med News ; (294): 37-41, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31687946

RESUMO

Premenstrual syndrome (PMS) is a common problem of women in reproductive age. Genetic aspects of this pathology are not completely clear. The aim of the article is devoted to the study of the frequency of ID polymorphism of angiotensin-converting enzyme gene ACE in patients with premenstrual syndrome. The object of the study were 50 women in reproductive age with the diagnosis of PMS, 25 of them had mild form of the disease, 25 - severe one. 25 persons without PMS were controls. Polymerase chain reaction was used to study ACE gene polymorphism. We determined an equal distribution of ACE gene genotypes between women with PMS and without this pathology (DD genotype was established in 24% of controls and 30% women with PMS, ID genotype - 60% and 46% respectively, II genotype - 16% and 24%). However, DD genotype was found in 2.17 times more often in patients with severe form of the disease (52%) compared to healthy persons. Thus, women with DD genotype of ACE gene have the tendency to the development of severe PMS (χ2=3.06, p=0.08; OR=3.43, 95% CI 1.02-11.47, p=0.045).


Assuntos
Predisposição Genética para Doença , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Síndrome Pré-Menstrual/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Peptidil Dipeptidase A/metabolismo , Reação em Cadeia da Polimerase , Síndrome Pré-Menstrual/fisiopatologia
3.
Hypertension ; 74(5): 1181-1191, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31564162

RESUMO

Brain renin angiotensin system within the paraventricular nucleus plays a critical role in balancing excitatory and inhibitory inputs to modulate sympathetic output and blood pressure regulation. We previously identified ACE2 and ADAM17 as a compensatory enzyme and a sheddase, respectively, involved in brain renin angiotensin system regulation. Here, we investigated the opposing contribution of ACE2 and ADAM17 to hypothalamic presympathetic activity and ultimately neurogenic hypertension. New mouse models were generated where ACE2 and ADAM17 were selectively knocked down from all neurons (AC-N) or Sim1 neurons (SAT), respectively. Neuronal ACE2 deletion revealed a reduction of inhibitory inputs to AC-N presympathetic neurons relevant to blood pressure regulation. Primary neuron cultures confirmed ACE2 expression on GABAergic neurons synapsing onto excitatory neurons within the hypothalamus but not on glutamatergic neurons. ADAM17 expression was shown to colocalize with angiotensin-II type 1 receptors on Sim1 neurons, and the pressor relevance of this neuronal population was demonstrated by photoactivation. Selective knockdown of ADAM17 was associated with a reduction of FosB gene expression, increased vagal tone, and prevented the acute pressor response to centrally administered angiotensin-II. Chronically, SAT mice exhibited a blunted blood pressure elevation and preserved ACE2 activity during development of salt-sensitive hypertension. Bicuculline injection in those models confirmed the supporting role of ACE2 on GABAergic tone to the paraventricular nucleus. Together, our study demonstrates the contrasting impact of ACE2 and ADAM17 on neuronal excitability of presympathetic neurons within the paraventricular nucleus and the consequences of this mutual regulation in the context of neurogenic hypertension.


Assuntos
Proteína ADAM17/metabolismo , Angiotensina II/farmacologia , Hipertensão/fisiopatologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/genética , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Hipertensão/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Optogenética/métodos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/patologia , Distribuição Aleatória , Sistema Renina-Angiotensina/efeitos dos fármacos
4.
J Dairy Sci ; 102(12): 10760-10771, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31521344

RESUMO

Over the past decades, several studies investigated the health-promoting functions of milk peptides. However, to date many hurdles still exist regarding the widespread use of milk-derived bioactive peptides, as they may be degraded during gastrointestinal digestion. Thus, the aim of our study was to in vitro digest intact whey protein isolate (WPI) and casein proteins (CNP), mimicking in vivo digestion, to investigate their bioactive effects and to identify the potential peptides involved. Whey protein isolate and CNP were digested using a pepsin-pancreatin protocol and ultra-filtered (3-kDa cutoff membrane). A permeate (<3 kDa) and a retentate (>3 kDa) were obtained. Soy protein was included as a control (CTR). Angiotensin-1-converting enzyme inhibitory (ACE1-I) and antioxidant activity (AOX) were assessed and compared with those observed in undigested proteins and CTR. Furthermore, the permeate was characterized by nano-liquid chromatography electrospray ionization tandem mass spectrometry (LC-nano ESI MS/MS) using a shotgun peptidomic approach, and retentate was further digested with trypsin and analyzed by MS using a shotgun proteomic approach to identify potentially bioactive peptides. Further, the effects of WPI, CNP, and CTR retentate on cell metabolic activity and on mucus production (MUC5AC and MUC2 gene expression) were assessed in intestinal goblet HT29-MTX-E12 cells. Results showed that WPI permeate induced a significant ACE1-I inhibitory effect [49.2 ± 0.64% (SEM)] compared with undigested WPI, CNP permeate, and retentate or CTR permeate (10.40 ± 1.07%). A significant increase in AOX (1.58 ± 0.04 and 1.61 ± 0.02 µmol of trolox AOX equivalents per mg of protein, respectively) upon digestion was found in WPI. Potentially bioactive peptides associated with ACE1-I and antihypertensive effects were identified in WPI permeate and CNP retentate. At specific concentrations, WPI, CNP, and CTR retentate were able to stimulate metabolic activity in HT29-MTX-E12 cells. Expression of MUC5AC was increased by CNP retentate and unaltered by WPI retentate; MUC2 expression was significantly increased by 0.33 mg/g of CNP and reduced by 1.33 mg/g of CNP. Our results confirm that milk proteins may be rich sources of bioactive compounds, with the greatest beneficial potential of CNP at the intestinal goblet cell level.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Antioxidantes/metabolismo , Digestão , Proteínas do Leite/metabolismo , Mucinas/genética , Peptidil Dipeptidase A/metabolismo , Animais , Caseínas/metabolismo , Cromatografia Líquida , Expressão Gênica , Células HT29 , Humanos , Leite/metabolismo , Proteínas de Soja/metabolismo , Espectrometria de Massas em Tandem , Soro do Leite/metabolismo
5.
J Agric Food Chem ; 67(37): 10313-10320, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31502448

RESUMO

A peptide fraction with molecular masses below 3 kDa (PSH-3 kDa) from a peach seed hydrolysate demonstrated high angiotensin converting enzyme (ACE) inhibitory activity (concentration to inhibit 50% ACE (IC50) = 16.4 µg/mL) in our previous work. This work proposes a further study of this highly active fraction. RP-HPLC enabled two fractions (F3 and F4) with high inhibitory activity (IC50 = 2.0 ± 0.5 and 1.2 ± 0.2 µg/mL, respectively) to be isolated. Peptide analysis by LC-Q-TOF-MS/MS using reverse-phase and hydrophilic interaction chromatography enabled 33 peptides within both fractions to be identified. Among them, peptide isoleucine-tyrosine-serine-proline-histidine (IYSPH) showed the highest capacity. The lack of cytotoxicity of peptides was demonstrated in three different cell lines (HeLa, HT-29, and HK-2). Oral administration of PSH-3 kDa fraction or peptide IYSPH caused a significant systolic blood pressure reduction (-30 mmHg) on spontaneously hypertensive rats after 3-6 h treatment.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Hipertensão/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Prunus persica/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Masculino , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/isolamento & purificação , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR , Sementes/química
6.
J Sci Food Agric ; 99(15): 6822-6832, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31385307

RESUMO

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitory peptides were found to alleviate acute hepatitis significantly. In this study, we purified and identified ACE inhibitory peptide from cashew to evaluate its protective role on alcohol-induced acute hepatitis in mice. RESULTS: The ACE inhibitory peptides were purified by using consecutive chromatographic techniques. One of these peptides (FETISFK) exhibited the highest ACE inhibition rate (91.04 ± 0.31%). In vivo, the results showed that ACE inhibitory peptide decreased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) caused by alcohol exposure. Moreover, it could increase the activities of superoxide dismutase (SOD) and glutathione (GSH), and decrease the level of malondialdehyde (MDA). It was also found to down-regulate markedly the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). It could also decrease the expression of ACE, angiotensin II (AngII) and angiotensin II type 1 receptor (AT1 R). CONCLUSION: These findings support the view that the ACE inhibitory peptide alleviated acute hepatitis by down-regulating the ACE-AngII-AT1 R axis, broadening the research approach to prevent acute hepatitis, and providing experimental data for the development and utilization of cashews. © 2019 Society of Chemical Industry.


Assuntos
Anacardium/química , Inibidores da Enzima Conversora de Angiotensina/química , Hepatite/tratamento farmacológico , Peptídeos/química , Extratos Vegetais/química , Doença Aguda/terapia , Álcoois/efeitos adversos , Angiotensina II/genética , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Hepatite/enzimologia , Hepatite/etiologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Nozes/química , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Mar Drugs ; 17(8)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398788

RESUMO

Angiotensin-I-converting enzyme (ACE) inhibitory peptides derived from natural products have shown a blood pressure lowering effect with no side effects. In this study, two novel ACE inhibitory peptides (His-Leu-His-Thr, HLHT and Gly-Trp-Ala, GWA) were purified from pearl oyster (Pinctada fucata martensii) meat protein hydrolysate with alkaline protease by ultrafiltration, polyethylene glycol methyl ether modified immobilized metal ion affinity medium, and reverse-phase high performance liquid chromatography. Both peptides exhibited high ACE inhibitory activity with IC50 values of 458.06 ± 3.24 µM and 109.25 ± 1.45 µM, respectively. Based on the results of a Lineweaver-Burk plot, HLHT and GWA were found to be non-competitive inhibitor and competitive inhibitor respectively, which were confirmed by molecular docking. Furthermore, the pearl oyster meat protein hydrolysate exhibited an effective antihypertensive effect on SD rats. These results conclude that pearl oyster meat protein is a potential resource of ACE inhibitory peptides and the purified peptides, HLHT and GWA, can be exploited as functional food ingredients against hypertension.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Pinctada/química , Hidrolisados de Proteína/química , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Hipertensão/tratamento farmacológico , Masculino , Carne , Simulação de Acoplamento Molecular , Pinctada/metabolismo , Hidrolisados de Proteína/metabolismo , Ratos , Ratos Sprague-Dawley , Ultrafiltração/métodos
8.
Oxid Med Cell Longev ; 2019: 5868935, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396301

RESUMO

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPßCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPßCD) or HPßCD/Ang-(1-7) in the last 6 weeks. FAT-HPßCD/empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPßCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPßCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.


Assuntos
Angiotensina I/farmacologia , Antioxidantes/farmacologia , Síndrome Metabólica/patologia , Fragmentos de Peptídeos/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Catalase/genética , Catalase/metabolismo , Ciclodextrinas/farmacologia , Dieta Hiperlipídica , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/veterinária , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
9.
Molecules ; 24(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430869

RESUMO

Protein hydrolysates from fish by-products have good process suitability and bioavailability in the food industry. The objective of this work was to develop a method for protein recovery from fish scales and evaluate the hydrolysis of the scale protein. The effect of the hydrothermal process on protein recovery, degree of hydrolysis (DH) and structural properties of the hydrolysates was investigated. Results showed that hydrothermal treatment could enhance protein recovery of tilapia scales without demineralization and dramatically improve the DH of the hydrolysates. The hydrothermal treated scales showed a better protein recovery (84.81%) and DH (12.88%) and released peptides more efficiently than that of the conventional treated samples. The obtained gelatin hydrolysates mainly distributed in the range of 200-2000 Da with an angiotensin I-converting enzyme (ACE) IC50 value of 0.73 mg/mL. The ACE inhibitory activity of gelatin hydrolysates was stable under high temperature, pH and gastrointestinal proteases. Hydrothermal treatment followed by enzymatic hydrolysis offers a potential solution for preparation of gelatin hydrolysates for food ingredients from fish processing by-products.


Assuntos
Peixes/metabolismo , Gelatina/química , Hidrolisados de Proteína/química , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Hidrólise , Peptídeo Hidrolases/química , Peptídeos/química , Peptidil Dipeptidase A/metabolismo
10.
Life Sci ; 235: 116796, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470003

RESUMO

AIM: Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. METHODS: Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis. KEY FINDINGS: Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats. CONCLUSION: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Estresse Oxidativo , Peptidil Dipeptidase A/química , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/química
11.
Hypertension ; 74(4): 975-982, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378101

RESUMO

Low birth weight is associated with a greater prevalence of hypertension in women by age 60; yet, the mechanisms involved are unknown. We previously reported that hypertension in female growth-restricted offspring that is associated with early reproductive senescence and a shift in the testosterone-to-estradiol ratio at 12 months of age is abolished by AR (androgen receptor) blockade in conjunction with downregulation of renal AT1aR (angiotensin type 1a receptor) mRNA expression. These data suggest androgen-mediated activation of the renin-angiotensin system contributes to the pathogenesis of hypertension that develops in female growth-restricted offspring with aging. Thus, this study tested the hypothesis that androgen-mediated increased blood pressure is specific to female growth-restricted offspring. Control and growth-restricted rats underwent sham or ovariectomy at 10 months of age. Vehicle or flutamide (8 mg/kg/day; subcutaneous), an AR antagonist, was administered at 11.5 months of age for 2 weeks followed by measurement of blood pressure. Loss of ovarian hormones was associated with a 10 mm Hg increase in blood pressure in control compared with intact counterparts accompanied by a 1.8-fold increase in renal AT1aR mRNA expression. Treatment with flutamide had no effect on blood pressure or renal AT1aR mRNA expression in ovariectomized controls. Although blood pressure was significantly decreased in flutamide-treated ovariectomized growth-restricted, flutamide had no effect on the increase in renal AT1aR mRNA expression. Therefore, these findings suggest the effect of AR blockade on blood pressure is specific to intact growth-restricted offspring and that mechanisms of postmenopausal hypertension may differ between normal and low birth weight women.


Assuntos
Antagonistas de Androgênios/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Retardo do Crescimento Fetal/fisiopatologia , Flutamida/farmacologia , Hipertensão/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Determinação da Pressão Arterial , Estradiol/sangue , Feminino , Retardo do Crescimento Fetal/metabolismo , Hipertensão/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ovariectomia , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/metabolismo , Testosterona/sangue
12.
Int J Mol Sci ; 20(15)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31390839

RESUMO

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin-angiotensin system (RAS) and transforming growth factor ß (TGFß) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3-/- mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3-/- mice by olmesartan treatment. Upregulation of TGFß and activation of its downstream in Col4a3-/- mice were attenuated by olmesartan in Col4a3-/- mice. Intriguingly, TGFß expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3-/- mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3-/- mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFß-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFß feedback loop to counterbalance intrarenal RAS activation.


Assuntos
Anti-Hipertensivos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Tetrazóis/farmacologia , Fator de Crescimento Transformador beta/genética , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Biópsia , Modelos Animais de Doenças , Fibrose , Túbulos Renais/patologia , Camundongos , Camundongos Knockout , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Proteínas ras/genética , Proteínas ras/metabolismo
13.
Ulus Travma Acil Cerrahi Derg ; 25(4): 350-354, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31297773

RESUMO

BACKGROUND: Chest injuries, accounting for 25% of all trauma-related deaths, are one of the main causes of death in young adults. Our priority is the early identification of life-threatening injuries both immediate and delayed. The role of various biomarkers, such as Clara cell protein 16, von Willebrand factor, interleukin-6, tumor necrosis factor, and angiopoietin, has been studied in trauma-related acute respiratory distress syndrome (ARDS). Serum angiotensin-converting enzyme (ACE) levels have been studied in non-trauma-related ARDS. The aim of this prospective observational study was to evaluate the role of ACE levels as a prognostic marker in thoracic trauma. METHODS: A prospective observational study was conducted to evaluate serum ACE levels in thoracic trauma patients and to explore its prognostic potential with regard to clinical outcome. A total of 48 thoracic trauma patients were included in the study. RESULTS: The mean ACE level in the study population was 66.54+-11.18. A strong positive correlation was found among serum ACE levels and Thoracic Trauma Severity Score (TTSS). CONCLUSION: Our study demonstrates that serum ACE levels are increased in thoracic trauma patients with higher levels, indicating the severe nature of trauma in concordance with increased TTSS scores.


Assuntos
Peptidil Dipeptidase A/metabolismo , Traumatismos Torácicos/enzimologia , Acidentes por Quedas , Acidentes de Trânsito , Adolescente , Adulto , Idoso , Biomarcadores , Feminino , Humanos , Escala de Gravidade do Ferimento , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/sangue , Prognóstico , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Síndrome do Desconforto Respiratório do Adulto/enzimologia , Traumatismos Torácicos/diagnóstico , Traumatismos Torácicos/etiologia , Traumatismos Torácicos/mortalidade , Ferimentos Penetrantes/complicações , Adulto Jovem
14.
Plast Reconstr Surg ; 144(2): 372-384, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348346

RESUMO

BACKGROUND: We investigated expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 by the embryonic stem cell-like population on the endothelium of the microvessels and perivascular cells within keloid-associated lymphoid tissues. METHODS: Immunohistochemical staining for prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 was performed on 11 formalin-fixed, paraffin-embedded sections of keloid tissue samples. Immunofluorescence staining was performed on three keloid tissue samples by co-staining with OCT4, CD34, ERG, and tryptase. Real-time quantitative polymerase chain reaction was performed on five keloid tissue samples and four keloid-derived primary cell lines. Western blotting was performed on the four keloid-derived primary cell lines for mRNA and protein expression of these proteins, respectively. RESULTS: Immunohistochemical and immunofluorescence staining showed expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 in all 11 keloid tissue samples. Prorenin receptor and angiotensin II receptor 1 were expressed on the endothelium and the pericyte layer of the microvessels and perivascular cells, angiotensin II receptor 2 was localized to the endothelium of the microvessels and the tryptase-positive perivascular cells, and angiotensin-converting enzyme was localized to the endothelium of the microvessel, within the keloid-associated lymphoid tissues. Real-time quantitative polymerase chain reaction showed transcripts of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid tissue samples and keloid-derived primary cell lines, whereas angiotensin II receptor 2 was detected in keloid tissue samples only. Western blotting confirmed the presence of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid-derived primary cell lines. CONCLUSION: Prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 were expressed by the embryonic stem cell-like population within the keloid-associated lymphoid tissues, suggesting that this primitive population may be a potential therapeutic target by modulation of the renin-angiotensin system.


Assuntos
Células-Tronco Embrionárias/metabolismo , Queloide/metabolismo , Sistema Renina-Angiotensina/fisiologia , Adolescente , Adulto , Antígenos CD34/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Feminino , Imunofluorescência , Humanos , Queloide/patologia , Masculino , Pessoa de Meia-Idade , Fator 3 de Transcrição de Octâmero/metabolismo , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Superfície Celular/metabolismo , Regulador Transcricional ERG/metabolismo , Adulto Jovem
15.
Eur J Med Chem ; 180: 99-110, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301567

RESUMO

Biologically active or bioactive peptides are unique amino acid sequences found encrypted in food proteins. These peptides, upon hydrolysis, can exert positive physiological effects on human health, different from that of their native protein. These effects are brought about by their interaction with specific targets in the body, thereby, mimicking physiologically relevant peptides. Peptides are derived from food proteins, they are popular natural alternatives for the management of common metabolic disorders. In the present study, we aimed to identify bioactive peptide sequences (less than 3 kDa) from fat globule membrane protein (FGMP) hydrolysates of buffalo colostrum using a combination of empirical, computational and in vitro methods. The empirical approach aided in the identification of 89 FGMP peptides (m/z-415 to 2939) which were annotated and profiled for bioactivity. Few lead peptides were analyzed by molecular docking for the inhibitory potential of Angiotensin Converting Enzyme (ACE) and Dipeptidyl Peptidase-IV (DPP-IV). A heptapeptide (m/z-723.3) synthesized was found to inhibit ACE (IC50: 74.27 µM) and DPP-IV (IC50: 3.83 mM).


Assuntos
Dipeptidil Peptidase 4/metabolismo , Descoberta de Drogas , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade
16.
Food Chem ; 299: 124985, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279127

RESUMO

Dietary protein peptides from quinoa yoghurt beverage (QYB) fermented with probiotic lactic acid bacteria strains play a protective role against diabetes and hypertension. In this study, the α-glucosidase and ACE inhibitory activities of germination-based protein hydrolysates of QYB were investigated. All protein hydrolysates exhibited a dose and strain-dependent inhibition on the enzymes. The inhibition of α-glucosidase was the highest in QLCSY13 (IC50 = 8.86 mg/mL), while ACE inhibition was the highest in QLCZ (IC50 = 0.03 mg/mL). Overall, QLCSY13 had the highest inhibitory activities, which was ascribed to its relatively higher amino acid contents and hydrophobicity. In addition, the ACE and α-glucosidase inhibitory activities of peptide fractions identified by RP-HPLC were 127 ±â€¯4.29 mg/mL and 10.39 ±â€¯4.73 mg/mL respectively. Among the potent inhibitory peptide sequences identified, both LAHMIVAGA and VAHPVF significantly had α-glucosidase and ACE inhibitory activities. Consequently, dietary protein peptides present in QYB had anti-hypertensive and anti-diabetic potentials.


Assuntos
Bebidas/microbiologia , Lactobacillus casei/metabolismo , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/farmacologia , Iogurte/microbiologia , alfa-Glucosidases/metabolismo , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fermentação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Hidrolisados de Proteína/química
17.
Plant Foods Hum Nutr ; 74(3): 405-413, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273642

RESUMO

The aim of this work was to evaluate the ability of broken rice, an underutilized industrial by-product, as a potential functional and health promoting ingredient. With this purpose, the ability to inhibit the angiotensin converting enzyme and renin of a rice protein hydrolyzate (RPH) obtained from a high-protein variety of broken rice (var. Nutriar FCAyF) was analyzed (IC50 = 0.87 and 2.7 mg/mL, respectively). RPH was separated by gel permeation chromatography and in a second purification step by RP-HPLC. The sequence of antihypertensive peptides presented in two RP-HPLC fractions was analyzed. Peptides capable of interacting with the active sites of both enzymes were identified. In this study, we demonstrate that the hydrolysis treatment improves functional and biological properties of rice proteins. Protein preparations obtained from a by-product of rice industry, such as broken rice, are a promising ingredient with potentially good biological properties.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/isolamento & purificação , Oryza/química , Peptídeos/isolamento & purificação , Renina/antagonistas & inibidores , Anti-Hipertensivos/farmacologia , Cromatografia Líquida de Alta Pressão , Promoção da Saúde , Hidrólise , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Renina/metabolismo
18.
Biomed Environ Sci ; 32(6): 419-426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262387

RESUMO

OBJECTIVE: Silicosis, caused by inhalation of silica dust, is the most serious occupational disease in China and the aim of present study was to explore the protective effect of Ang (1-7) on silicotic fibrosis and myofibroblast differentiation induced by Ang II. METHODS: HOPE-MED 8050 exposure control apparatus was used to establish the rat silicosis model. Pathological changes and collagen deposition of the lung tissue were examined by H.E. and VG staining, respectively. The localizations of ACE2 and α-smooth muscle actin (α-SMA) in the lung were detected by immunohistochemistry. Expression levels of collagen type I, α-SMA, ACE2, and Mas in the lung tissue and fibroblasts were examined by western blot. Levels of ACE2, Ang (1-7), and Ang II in serum were determined by ELISA. Co-localization of ACE2 and α-SMA in fibroblasts was detected by immunofluorescence. RESULTS: Ang (1-7) induced pathological changes and enhanced collagen deposition in vivo. Ang (1-7) decreased the expressions of collagen type I and α-SMA and increased the expressions of ACE2 and Mas in the silicotic rat lung tissue and fibroblasts stimulated by Ang II. Ang (1-7) increased the levels of ACE2 and Ang (1-7) and decreased the level of Ang II in silicotic rat serum. A779 enhanced the protective effect of Ang (1-7) in fibroblasts stimulated by Ang II. CONCLUSION: Ang (1-7) exerted protective effect on silicotic fibrosis and myofibroblast differentiation induced by Ang II by regulating ACE2-Ang (1-7)-Mas axis.


Assuntos
Angiotensina II/sangue , Angiotensina I/uso terapêutico , Pulmão/metabolismo , Miofibroblastos/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Silicose/prevenção & controle , Actinas/metabolismo , Angiotensina I/sangue , Angiotensina I/farmacologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Silicose/metabolismo , Silicose/patologia
19.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356181

RESUMO

Local renin-angiotensin systems (RAS) are found in many tissues. The main physiological effects of RAS are driven by the balance between two pathways: the angiotensin-converting enzyme I - angiotensin II receptor type 1 (ACE1-AT1R) axis and the angiotensin-converting enzyme 2 - Mas-receptor (ACE2-MAS) axis. The local intestinal RAS functions both as a paracrine regulator and as a regulator of inflammation. The expression of local RAS is known to change with age in many tissues, but age-related changes in the intestinal RAS have not been studied comprehensively. The present study characterized age-related changes in two main pathways of local RAS in the jejunum and colon of young and adult rats, in normotensive and hypertensive strains. The main finding was that 33-week-old rats exhibit an increased ratio of ACE1/ACE2 activities and protein quantity ratios compared to young rats. As the relationship of ACE1 and ACE2 mediated pathways drives the total physiological effects of RAS, the results indicate that the function of intestinal RAS changes with age. It is possible that age-related increase in ACE1-AT1R axis introduces more pro-inflammatory and fibrogenic conditions in the intestine.


Assuntos
Hipertensão/fisiopatologia , Intestinos/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/fisiologia , Hipertensão/metabolismo , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/metabolismo
20.
J Vet Sci ; 20(3): e18, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31161736

RESUMO

This study aimed to assess the effects of dehydration on echocardiographic indices in healthy cats: specifically, it aimed to assess the effects of volume depletion on diastolic function. Nine experimental cats were subjected to both a dehydration and placebo protocol separated by a 21-day washout period. Echocardiography was performed at baseline and on completion of each protocol. Results were compared between the two protocols. Volume depletion was induced by intravenous administration of furosemide. Volume depletion showed a significant association with increased interventricular septal and left ventricular free wall thickness at end-diastole, decreased left ventricular internal diameter at end-diastole, and left atrial diameter at end-systole. The peak early (E) and late (A) diastolic filling velocities, and the peak early diastolic velocities (E') were significantly decreased by dehydration. Volume depletion did not affect peak longitudinal strain rate during early diastole, E/A, or E/E'. Volume depletion significantly affected the echocardiographic diastolic indices and conventional echocardiographic parameters in healthy cats.


Assuntos
Gatos/fisiologia , Desidratação/enzimologia , Desidratação/patologia , Ecocardiografia , Animais , Velocidade do Fluxo Sanguíneo/fisiologia , Desidratação/induzido quimicamente , Diástole/fisiologia , Furosemida , Peptidil Dipeptidase A/metabolismo , Função Ventricular Esquerda/fisiologia
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