RESUMO
The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (Ki) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with -7.83 and - 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Peptidil Dipeptidase A , Zea mays , Animais , Humanos , Masculino , Ratos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células CACO-2 , Digestão/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Glutens/química , Glutens/metabolismo , Hidrólise , Hipertensão/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Peptídeos/química , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Ratos Endogâmicos SHR , Zea mays/química , Zea mays/metabolismoRESUMO
BACKGROUND: People of all nationalities and social classes are now affected by the growing issue of hypertension. Over time, there has been a consistent rise in the fatality rate. A range of therapeutic compounds, on the other hand, are often used to handle hypertension. OBJECTIVES: The objectives of this study are first to design potential antihypertensive drugs based on the DHP scaffold, secondly, to analyse drug-likeness properties of the ligands and investigate their molecular mechanisms of binding to the model protein Cav1.2 and finally to synthesise the best ligand. MATERIALS AND METHODS: Due to the lack of 3D structures for human Cav1.2, the protein structure was modelled using a homology modelling approach. A protein-ligand complex's strength and binding interaction were investigated using molecular docking and molecular dynamics techniques. DFT-based electronic properties of the ligand were calculated using the M06-2X/ def2- TZVP level of theory. The SwissADME website was used to study the ADMET properties. RESULTS: In this study, a series of DHP compounds (19 compounds) were properly designed to act as calcium channel blockers. Among these compounds, compound 16 showed excellent binding scores (-11.6 kcal/mol). This compound was synthesised with good yield and characterised. To assess the structural features of the synthesised molecule quantum chemical calculations were performed. CONCLUSION: Based on molecular docking, molecular dynamics simulations, and drug-likeness properties of compound 16 can be used as a potential calcium channel blocker.
Assuntos
Bloqueadores dos Canais de Cálcio , Canais de Cálcio Tipo L , Di-Hidropiridinas , Desenho de Fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Di-Hidropiridinas/farmacologia , Di-Hidropiridinas/química , Di-Hidropiridinas/síntese química , Humanos , Canais de Cálcio Tipo L/metabolismo , Teoria da Densidade Funcional , Ligantes , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Simulação por ComputadorRESUMO
The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.
Assuntos
Anti-Hipertensivos , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Anti-Hipertensivos/farmacologia , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Bisoprolol/farmacologia , Bisoprolol/uso terapêutico , Nitrosaminas , Masculino , Hidroclorotiazida/farmacologia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Carcinoma Basocelular/genética , Antiarrítmicos/farmacologia , Feminino , Reprogramação MetabólicaRESUMO
The relationship between glaucoma and hypertension is complex. Intraocular pressure is the main modifiable risk factor for glaucoma. Literature describes hypertension as being linked to glaucomatous damage, although the mechanisms are not fully understood. Therefore, glaucoma screening is recommended for hypertensive individuals over 60 years old. The relationships between ocular, arterial pressure, and ocular perfusion pressure, and their impact on optic nerve perfusion, make coordinated management of these elements crucial. Hypertension, hypotension, extreme variability, nocturnal dipping, and overtreatment with antihypertensive drugs can increase the incidence and/or progression of glaucoma. This critical review discusses the causative, clinical, and therapeutic elements to consider in the management of these two pathologies.
La relation entre le glaucome et l'hypertension artérielle (HTA) est complexe. La pression intraoculaire est le principal facteur de risque modifiable du glaucome. Selon la littérature, l'HTA entraînerait un dommage glaucomateux, sans que les mécanismes soient entièrement compris. Le dépistage du glaucome est ainsi recommandé chez les hypertendus de plus 60 ans. La relation entre pression oculaire, artérielle et pression de perfusion oculaire, ainsi que leur impact sur la perfusion du nerf optique, rendent fondamentale la gestion coordonnée de ces deux pathologies. L'HTA, l'hypotension artérielle, la variabilité extrême ou le dipping nocturne, tout comme le surtraitement par antihypertenseurs, peuvent augmenter l'incidence et/ou la progression du glaucome.. Cette revue critique discute des éléments causatifs, cliniques et thérapeutiques à considérer dans la prise en charge de ces deux pathologies.
Assuntos
Glaucoma , Hipertensão , Humanos , Pessoa de Meia-Idade , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Progressão da Doença , Glaucoma/epidemiologia , Glaucoma/etiologia , Glaucoma/fisiopatologia , Glaucoma/terapia , Hipertensão/complicações , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Hipertensão/terapia , Pressão Intraocular/efeitos dos fármacos , Pressão Intraocular/fisiologia , Fatores de RiscoRESUMO
Hypertension is a major risk factor for heart disease and stroke. Garlic has a long history of use in traditional medicine for various conditions, including hypertension. This narrative review examined the scientific evidence on the efficacy of garlic in lowering blood pressure. It explores the historical uses of garlic in different cultures for medicinal purposes and delves into the phytochemical composition of garlic, highlighting key components, like allicin and ajoene, that are believed to contribute to its potential health benefits. Clinical studies that investigated the effects of garlic and garlic-based supplements on blood pressure are presented, with the findings suggesting that garlic consumption may modestly reduce blood pressure, particularly in individuals with mild hypertension. Potential mechanisms of action include increased nitric oxide production, improved endothelial function, and antioxidant properties. While garlic may offer some benefits for blood pressure management, it should not be considered a substitute for conventional antihypertensive medications. Further large-scale, long-term clinical trials are warranted to establish the efficacy of garlic in managing hypertension, including the optimal dosage and formulation.
Assuntos
Anti-Hipertensivos , Pressão Sanguínea , Alho , Hipertensão , Alho/química , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Pressão Sanguínea/efeitos dos fármacos , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Dissulfetos/farmacologia , Ácidos Sulfínicos/farmacologia , Suplementos Nutricionais , Fitoterapia , Extratos Vegetais/farmacologia , Antioxidantes/farmacologia , SulfóxidosRESUMO
Studies have demonstrated the therapeutic effects of Lindera plants. This study was undertaken to reveal the antihypertensive properties of Lindera erythrocarpa leaf ethanolic extract (LEL). Aorta segments of Sprague-Dawley rats were used to study the vasodilatory effect of LEL, and the mechanisms involved were evaluated by treating specific inhibitors or activators that affect the contractility of blood vessels. Our results revealed that LEL promotes a vasorelaxant effect through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, blocking the Ca2+ channels, opening the K+ channels, and inhibiting the vasoconstrictive action of angiotensin II. In addition, the effects of LEL on blood pressure were investigated in spontaneously hypertensive rats by the tail-cuff method. LEL (300 or 1000 mg/kg) was orally administered to the rats, and 1000 mg/kg of LEL significantly lowered the blood pressure. Systolic blood pressure decreased by -20.06 ± 4.87%, and diastolic blood pressure also lowered by -30.58 ± 5.92% at 4 h in the 1000 mg/kg LEL group. Overall, our results suggest that LEL may be useful to treat hypertensive diseases, considering its vasorelaxing and hypotensive effects.
Assuntos
Anti-Hipertensivos , Pressão Sanguínea , GMP Cíclico , Hipertensão , Lindera , Óxido Nítrico , Extratos Vegetais , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Animais , Anti-Hipertensivos/farmacologia , Extratos Vegetais/farmacologia , Óxido Nítrico/metabolismo , Pressão Sanguínea/efeitos dos fármacos , GMP Cíclico/metabolismo , Masculino , Hipertensão/tratamento farmacológico , Ratos , Lindera/química , Canais de Potássio/metabolismo , Canais de Potássio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , Folhas de Planta/química , Vasodilatação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Torsemide, a loop diuretic, is increasingly recognized for its role in managing essential hypertension. Its mechanism of action involves inhibiting the reabsorption of sodium and chloride ions in the ascending loop of Henle in the kidneys. By doing so, torsemide promotes diuresis, which refers to increased urine production, and subsequently lowers blood pressure. Studies have shown that torsemide is comparably effective to other antihypertensive agents in lowering blood pressure, with the added benefit of potentially improving renal function. However, while torsemide shows promise in hypertensive management, further research is necessary to fully understand its long-term effects and to establish optimal dosing strategies. Future research should focus on clarifying its role in long-term blood pressure control and refining its use in clinical practice to maximize efficacy and minimize adverse effects.
Assuntos
Hipertensão Essencial , Hipertensão , Torasemida , Humanos , Hipertensão Essencial/tratamento farmacológico , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/administração & dosagem , Diuréticos/uso terapêutico , Diuréticos/farmacologia , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Pressão Sanguínea/efeitos dos fármacosRESUMO
Hypertension and cancers are the most common causes of death in humans, as well as common co-diseases among elderly population. Studies have shown that hypertension is associated with carcinogenesis. The renin-angiotensin-aldosterone system (RAAS) is a crucial regulatory system of blood pressure, fluid, and electrolyte homeostasis, which plays an essential role in the pathogenesis of hypertension, whose mechanism is relatively clear. Studies have indicated that RAAS also widely exists in cancer tissues of different systems, which can affect the risk of cancers by stimulating cancer angiogenesis, participating in cancer-related oxidative stress, and regulating cancer-related immunity. Therefore, inhibiting RAAS activity seems beneficial to decreasing the risk of cancers. As one of the most commonly used antihypertensive drugs, RAAS inhibitors have been widely used in clinical practice. However, the conclusions of clinical studies on the relationship between RAAS inhibitors and cancers are not entirely consistent, which has been widely concerned by clinicians. The latest findings suggest that while RAAS inhibitors may reduce the risk of digestive cancers, respiratory cancers, urological cancers, gynecological cancers, and skin cancers, ACEIs may increase the risk of lung cancer, endometrial cancer, basal cell carcinoma, and squamous cell carcinoma. This article comprehensively reviews animal experiments, clinical studies, and meta-analyses on the relationship between RAAS inhibitors and cancers, to provide references for related studies in the future.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Neoplasias , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologiaRESUMO
Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. α-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such α-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects.
Assuntos
Doxazossina , Células Endoteliais , Hipertensão , Receptores de Fatores de Crescimento do Endotélio Vascular , Animais , Cães , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Doxazossina/farmacologia , Doxazossina/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteômica/métodos , Pressão Sanguínea/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêuticoRESUMO
Hypertension is a risk factor for cardiovascular diseases such as coronary artery disease, heart failure, and stroke. Lignosus rhinocerus (Cooke) Ryvarden (also known as tiger milk mushroom), has been reported to exhibit a range of pharmacological effects, such as anti-inflammatory, anti-proliferative, antioxidative, immunomodulatory and anti-asthmatic activities. Thus far, there is limited research that has explored its ability to mediate vascular effects in vivo. Therefore, this study investigated the antihypertensive and vascular protective effects of L. rhinocerus TM02® sclerotia supplementation in spontaneously hypertensive rats (SHR). Wistar Kyoto (WKY) rats served as a normotensive control group. SHR were orally administered with L. rhinocerus TM02® sclerotia (100 mg/kg and 300 mg/kg, respectively) for 8 weeks, and blood pressure was monitored every 2 weeks. Vascular function was evaluated using an organ bath (aorta) and wire myograph (renal artery) at the treatment endpoint. The levels of reactive oxygen species (ROS) and nitric oxide (NO) in the aorta and renal artery were evaluated using dihydroethidium (DHE) and difluoro fluorescein acetate (DAF-FM) fluorescence assays, respectively. Total plasma nitrate/nitrite and tumor necrosis factor alpha (TNF-α) levels were evaluated via colorimetric assays. In vivo treatment with L. rhinocerus TM02® sclerotia significantly attenuated the increase in systolic blood pressure (SBP). It also alleviated vascular dysfunction and decreased elevated ROS in the aorta and renal arteries of the treated SHRs. Moreover, L. rhinocerus TM02® sclerotia attenuated plasma TNF-α level but increased total plasma nitrate/nitrite, albeit slightly, coupled with significantly increased NO at the vascular level. Collectively, the present study demonstrated that L. rhinocerus TM02® sclerotia supplementation exerted blood pressure lowering effects, partly attributed to improvements in vascular function via reduction in vascular oxidative stress.
Assuntos
Pressão Sanguínea , Hipertensão , Estresse Oxidativo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Animais , Estresse Oxidativo/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Ratos , Masculino , Pressão Sanguínea/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico/sangue , Anti-Hipertensivos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Suplementos Nutricionais , Aorta/efeitos dos fármacos , Aorta/fisiopatologiaRESUMO
BACKGROUND: To determine key enzymes enabling treprostinil palmitil (TP) conversion to treprostinil and the main converting sites in the respiratory system. RESEARCH DESIGN AND METHODS: We performed in vitro activity assays to identify lung enzymes hydrolyzing TP, and cell-based assays and immunostainings to establish the likely locations within the lung. RESULTS: Lipoprotein lipase (LPL) had greater activity than the other tested lung enzymes. Excess LPL activity was present both in vitro and at the target TP dose in vivo. CONCLUSIONS: LPL is likely the key enzyme enabling TP conversion. The rate-limiting step is likely the accessibility of TP and not the enzyme activity.
Assuntos
Anti-Hipertensivos , Epoprostenol , Lipase Lipoproteica , Pulmão , Pós , Administração por Inalação , Epoprostenol/análogos & derivados , Epoprostenol/administração & dosagem , Epoprostenol/farmacologia , Epoprostenol/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Humanos , Animais , Pulmão/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , CamundongosRESUMO
Chronic kidney disease (CKD) is a burden in low- and middle-income countries, and a late diagnosis with systemic arterial hypertension (SAH) is the major complication of CKD. C-phycoerythrin (CPE) is a bioactive compound derived from Phormidium persicinum that presents anti-inflammatory and antioxidant effects in vitro and nephroprotective effects in vivo. In the current study, we determine the antihypertensive effect of CPE in a 5/6 nephrectomy-induced CKD model using twenty normotensives male Wistar rats, grouped into four groups (n = 5): sham; sham + CPE; 5/6 nephrectomy (NFx); and NFx + CPE. Treatment started a week post-surgery and continued for five weeks, with weekly hemodynamic evaluations. Following treatment, renal function, oxidative stress, and the expression of vascular dysfunction markers were assessed. The renal function analysis revealed CKD hyperfiltration, and the hemodynamic evaluation showed that SAH developed at the third week. AT1R upregulation and AT2R downregulation together with Mas1/p-Akt/p-eNOS axis were also observed. CPE treatment mitigated renal damage, preserved renal function, and prevented SAH with the modulation of the vasodilative AT1R, AT2R, and Mas1/pAKT/peNOS axis. This result reveals that CPE prevented CKD progression to SAH by avoiding oxidative stress and vascular dysfunction in the kidneys.
Assuntos
Hipertensão , Rim , Estresse Oxidativo , Ficoeritrina , Ratos Wistar , Insuficiência Renal Crônica , Animais , Estresse Oxidativo/efeitos dos fármacos , Masculino , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Ratos , Rim/efeitos dos fármacos , Rim/metabolismo , Hipertensão/tratamento farmacológico , Ficoeritrina/farmacologia , Modelos Animais de Doenças , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologiaRESUMO
The subcritical water extraction of Undaria pinnatifida (blade, sporophyll, and root) was evaluated to determine its chemical properties and biological activities. The extraction was conducted at 180 °C and 3 MPa. Root extracts exhibited the highest phenolic content (43.32 ± 0.19 mg phloroglucinol/g) and flavonoid content (31.54 ± 1.63 mg quercetin/g). Sporophyll extracts had the highest total sugar, reducing sugar, and protein content, with 97.35 ± 4.23 mg glucose/g, 56.44 ± 3.10 mg glucose/g, and 84.93 ± 2.82 mg bovine serum albumin (BSA)/g, respectively. The sporophyll contained the highest fucose (41.99%) and mannose (10.37%), whereas the blade had the highest galactose (48.57%) and glucose (17.27%) content. Sporophyll had the highest sulfate content (7.76%). Key compounds included sorbitol, glycerol, L-fucose, and palmitic acid. Root extracts contained the highest antioxidant activity, with IC50 values of 1.51 mg/mL (DPPH), 3.31 mg/mL (ABTS+), and 2.23 mg/mL (FRAP). The root extract exhibited significant α-glucosidase inhibitory activity with an IC50 of 5.07 mg/mL, indicating strong antidiabetic potential. The blade extract showed notable antihypertensive activity with an IC50 of 0.62 mg/mL. Hence, subcritical water extraction to obtain bioactive compounds from U. pinnatifida, supporting their use in functional foods, cosmetics, and pharmaceuticals is highlighted. This study uniquely demonstrates the variation in bioactive compound composition and bioactivities across different parts of U. pinnatifida, providing deeper insights. Significant correlations between chemical properties and biological activities emphasize the use of U. pinnatifida extracts for chronic conditions.
Assuntos
Antioxidantes , Extratos Vegetais , Undaria , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Antioxidantes/química , Undaria/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Água/química , Raízes de Plantas/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Flavonoides/química , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/química , Fenóis/isolamento & purificação , Fenóis/farmacologia , Fenóis/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Algas ComestíveisRESUMO
The main objective of this work was to investigate the impact of ultrasonication assisted enzymatic treatment on the physicochemical and bioactive properties of broad bean (BBP), lentil bean (LBP), and mung bean (MBP) protein isolates. The protein was extracted using alkaline acid precipitation method, ultrasonicated at a frequency of 20 kHz, temperature 20-30 °C and then hydrolysed using alcalase enzyme (1 % w/w, pH 8.5, 30 min, 55 οC). The generated hydrolysates were characterized by degree of hydrolysis (DH), SDS, FTIR, surface hydrophobicity, amino acid composition, antioxidant and antihypertensive properties. Results showed that the degree of hydrolysis was found to increase in ultrasonicated protein hydrolysate (18.9 to 40.71 %) in comparison to non- ultrasonicated protein hydrolysate (11 to 16.3 %). SDS-PAGE results showed significant changes in protein molecular weight profiles (100-11kDa) in comparison to their natives. However, no substantial change was found in ultrasonicated and non-ultrasonicated protein hydrolysates. The FTIR spectrum showed structural alterations in ultrasonicated and non-ultrasonicated protein hydrolysates, suggesting modifications in secondary structure such as amide A, amide I and amide II regions. The essential amino acid content varied in the range of 60.09 mg/g to 73.77 mg/g and 28.73 to 50.26 mg/g in case of ultrasonicated and non-ultrasonicated protein hydrolysates, and non-essential content varied in the range of 49.42 to 65.93 mg/g and 43.12 to 47.12 mg/g. Both antioxidant and antihypertensive activities were found to increase significantly in ultrasonicated and non-ultrasonicated protein hydrolysates in comparison to their native counterparts, highlighting their potential as functional ingredients for management of hypertension. It was concluded that ultrasonication assisted enzymatic hydrolysis is an efficient approach for production of bioactive pulse protein hydrolysates with enhanced nutracutical properties, thus offering promising avenues for their utilization in the food industry and beyond.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Antioxidantes , Hidrolisados de Proteína , Hidrolisados de Proteína/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antioxidantes/química , Antioxidantes/metabolismo , Hidrólise , Sonicação , Subtilisinas/metabolismo , Subtilisinas/química , Interações Hidrofóbicas e Hidrofílicas , Aminoácidos/química , Aminoácidos/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Peso MolecularRESUMO
This study investigates the characterization, mechanisms of action, structure-activity relationships, and in vivo antihypertensive effects of ACE inhibitory peptides derived from sufu hydrolysate following simulated gastrointestinal digestion. Sufu was enzymatically digested using pepsin, trypsin, and chymotrypsin to mimic gastrointestinal conditions, followed by ultrafiltration to fractionate the peptides based on molecular weight. The fraction under 1 kDa exhibited the highest ACE inhibitory activity. LC-MS/MS analysis identified 119 peptide fragments, with bioinformatics screening highlighting 41 peptides with potential ACE inhibitory properties. Among these, two peptides, AWR and LLR, were selected and synthesized for in vitro validation, displaying IC50 values of 98.04 ± 2.56 µM and 94.01 ± 5.07 µM, respectively. Stability tests showed that both peptides maintained their ACE inhibitory activity across various temperatures and pH levels. Molecular docking and Highest Occupied Molecular Orbital analysis indicated strong binding interactions between these peptides and ACE, with the second-position tryptophan in AWR and the N-terminal leucine in LLR identified as key bioactive sites. These findings were further supported by molecular dynamics simulations, which confirmed the stability of the peptide-ACE complexes. In vivo studies using spontaneously hypertensive rats demonstrated significant reductions in both systolic and diastolic blood pressure, indicating that AWR and LLR have strong antihypertensive potential. This study illustrates that ultrafiltration, combined with LC-MS/MS and bioinformatics analysis, is an effective approach for the rapid screening of ACE inhibitory peptides. These results not only enhance our understanding of sufu-derived peptides but also offer promising implications for hypertension management.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Peptídeos , Ratos Endogâmicos SHR , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/química , Animais , Ratos , Peptídeos/química , Peptídeos/farmacologia , Masculino , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Espectrometria de Massas em TandemRESUMO
Hypertension is the most prevalent non-communicable disease, affecting billions of people worldwide. Discovery and development of natural antihypertensive lead compounds or drugs are important to resolve the limitations of existing antihypertensive drug safety and resistance. This investigation verified that carnosic acid (CA), an important active ingredient of rosemary, an edible spice plant, indicates a significant anti-hypertensive activity in spontaneous hypertension rats by targeting AT1R. Moreover, our research indicated that CA shared a comparable antagonistic mechanism with established synthetic angiotensin II receptor blockers (ARBs), as it occupies the binding sites of Angiotensin II (AngII) at His6 and Pro7 within the AT1R's ligand-binding pocket. Notably, CA exerted better anti-hypertensive activity since it could not break the Asn1113.35-Asn2957.46 hydrogen bond to stabilize the AT1R inactive state. As the first potent AT1R antagonist identified in a natural food source, CA is poised to become a novel anti-hypertensive lead compound, distinguished by its unique skeleton structure different from conventional ARBs. This research lays a valuable theoretical groundwork for the future exploration of CA and rosemary extract in both fundamental studies and clinical applications.
Assuntos
Abietanos , Anti-Hipertensivos , Hipertensão , Abietanos/farmacologia , Abietanos/química , Animais , Ratos , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Masculino , Receptor Tipo 1 de Angiotensina/metabolismo , Simulação de Acoplamento Molecular , Ratos Endogâmicos SHR , Pressão Sanguínea/efeitos dos fármacos , Sítios de LigaçãoRESUMO
Angiotensin I-converting enzyme (ACE) regulates blood pressure through the renin-angiotensin system. Douchi, a traditional fermented soybean condiment, may have antihypertensive effects, but research on ACE inhibitory peptides from Douchi hydrolysates is limited. We hypothesized that enzymatic treatment could enhance ACE inhibitory peptide diversity and efficacy. We tested ten single enzymes and four combinations, finding pepsin-trypsin-chymotrypsin most effective. Hydrolysates were purified using Sephadex G-15 and reversed-phase HPLC, and peptides were identified via LC-MS/MS. Five peptides (LF, VVF, VGAW, GLFG, NGK) were identified, with VGAW as the most potent ACE inhibitor (IC50 46.6 ± 5.2 µM) showing excellent thermal and pH stability. Lineweaver-Burk plots confirmed competitive inhibition, and molecular docking revealed eight hydrogen bonds between VGAW and ACE. In hypertensive rats, VGAW significantly reduced blood pressure at 12.5, 25, and 50 mg/kg. These findings highlight Douchi as a source of ACE inhibitory peptides and suggest VGAW as a promising functional food ingredient.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Pressão Sanguínea , Hipertensão , Peptídeos , Peptidil Dipeptidase A , Ratos Endogâmicos SHR , Animais , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Ratos , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/isolamento & purificação , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Masculino , Pressão Sanguínea/efeitos dos fármacos , Simulação de Acoplamento Molecular , Humanos , Glycine max/química , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , HidróliseRESUMO
Preeclampsia (PE) is a hypertensive pregnancy syndrome associated with target organ damage and increased cardiovascular risks, necessitating antihypertensive therapy. However, approximately 40% of patients are nonresponsive to treatment, which results in worse clinical outcomes. This study aimed to compare circulating proteomic profiles and identify differentially expressed proteins among 10 responsive (R-PE), 10 nonresponsive (NR-PE) patients, and 10 healthy pregnant controls (HP). We also explored correlations between these proteins and clinical data. Plasma protein relative quantification was performed using mass spectrometry, followed by bioinformatics analyses with the UniProt database, PatternLab for Proteomics 4.0, and MetaboAnalyst software (version 6.0). Considering a fold change of 1.5, four proteins were differentially expressed between NR-PE and R-PE: one upregulated (fibronectin) and three downregulated (pregnancy-specific beta-1-glycoprotein 1, complement C4B, and complement C4A). Between NR-PE and HP, six proteins were differentially expressed: two upregulated (clusterin and plasmin heavy chain A) and four downregulated (apolipoprotein L1, heparin cofactor II, complement C4B, and haptoglobin-related protein). Three proteins were differentially expressed between R-PE and HP: one downregulated (transthyretin) and two upregulated (apolipoprotein C1 and hemoglobin subunit beta). These findings suggest a complex interplay of these proteins involved in inflammatory, immune, and metabolic processes with antihypertensive therapy responsiveness and PE pathophysiology.
Assuntos
Anti-Hipertensivos , Pré-Eclâmpsia , Proteômica , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Adulto , Proteômica/métodos , Proteoma/metabolismo , Biomarcadores/sangue , Biologia Computacional/métodos , Estudos de Casos e ControlesRESUMO
Hypertension (HP) is a health condition that overloads the heart and increases the risk of heart attack and stroke. In an infarction, the lack of oxygen causes an exclusive use of glycolysis, which becomes a crucial source of ATP for the heart with a higher glucose uptake mediated by glucose transporters (GLUTs). Due to the unpleasant effects of antihypertensives, new drugs need to be researched to treat this disease. This study aimed to evaluate the cardioprotective effect of three novel antihypertensive compounds (LQMs, "Laboratorio de Química Medicinal") synthesized from Changrolin under hypoxic conditions with the participation of two primary cardiac GLUT1 and GLUT4 using a high-salt diet HP model. The model used a diet with 10% salt to increase arterial blood pressure in Wistar rats. In isolated cardiomyocytes from these rats, glucose uptake was measured during hypoxia, evaluating the participation of GLUTs with or without the animals' previous treatment with LQM312, 319, and 345 compounds. In silico calculations were performed to understand the affinity of the compounds for the trafficking of GLUTs. Results: Control cells do shift to glucose uptake exclusively in hypoxia (from 1.84 ± 0.09 µg/g/h to 2.67 ± 0.1 µg/g/h). Meanwhile, HP does not change its glucose uptake (from 2.38 ± 0.24 µg/g/h to 2.33 ± 0.26 µg/g/h), which is associated with cardiomyocyte damage. The new compounds lowered the systolic blood pressure (from 149 to 120 mmHg), but only LQM312 and LQM319 improved the metabolic state of hypoxic cardiomyocytes mediated by GLUT1 and GLUT4. In silico studies suggested that Captopril and LQM312 may mimic the interaction with the AMPK γ-subunit. Therefore, these compounds could activate AMPK, promoting the GLUT4 trafficking signaling pathway. These compounds are proposed to be cardioprotective during hypoxia under HP.
Assuntos
Anti-Hipertensivos , Transportador de Glucose Tipo 4 , Glucose , Hipertensão , Miócitos Cardíacos , Ratos Wistar , Animais , Ratos , Anti-Hipertensivos/farmacologia , Hipertensão/metabolismo , Hipertensão/tratamento farmacológico , Glucose/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Masculino , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Transportador de Glucose Tipo 1/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Hipóxia/metabolismo , Hipóxia/tratamento farmacológico , Transporte Biológico/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Pressão Sanguínea/efeitos dos fármacosRESUMO
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.