Antihypertensive peptides of animal origin: A review

Many bioactive peptides trigger certain useful antihypertensive activities in the living body system and there is a mounting worldwide interest in the therapeutic potential of these bioactive peptides for exploitation in vivo against the hypertension. Studies suggest the antihypertensive properties for many bioactive peptides of animal origin with underlying mechanisms ranging from inhibition of angiotensin-converting enzyme to additional mechanisms to lower blood pressure such as opioid-like activities and mineral-binding and antithrombotic properties. Antihypertensive peptides are the most extensively studied of all the bioactivities induced by food protein hydrolysates, highlighting their importance in human health and disease prevention and treatment. There exist enormous opportunities for the production of novel peptide-based products in biopharmaceutical manufacturing industries for the treatment, prevention, and mitigation of hypertension. Numerous products have already struck on the global market and many more are in process. This article focuses on antihypertensive peptides identified in the meat, fish, blood, milk, dairy products, and egg and their probable application as novel ingredients in the development of functional food products as dietary treatment of hypertension.     

A Review of Protein Hydrolysates and Bioactive Peptides Deriving from Wastes Generated by Fish Processing

Fish wastes offer tremendous unexploited potential for value adding for such materials, collagen, gelatin, and hydrolysate. Additionally, fish waste may be suitable for the production of bioactive peptides that exhibit strong antihypertensive, antioxidative, and anticancer activities. This paper reviews the production of purified bioactive peptides from various fish waste protein hydrolysates via enzymatic hydrolysis after enzyme screening and optimization. The purification of bioactive peptides is carried out using ultra- and gel filtration as well as the RP-HPLC method. Purified peptide characterizations in terms of molecular weight, amino acid sequence, and composition are also provided, illustrating that peptides with low molecular weight and short amino acid sequences are more potent as bioactive peptides. Hence, further studies are encouraged to examine the bioactivity and bioavailability of protein peptides derived from fish wastes, especially those with anticancer characteristics.     

Production of angiotensin I converting enzyme inhibitory (ACE-I) peptides during milk fermentation and their role in reducing hypertension

Fermented milk is a potential source of various biologically active peptides with specific health benefits. Angiotensin converting enzyme inhibitory (ACE-I) peptides are one of the most studied bioactive peptides produced during milk fermentation. The presence of these peptides is reported in various fermented milk products such as, yoghurt, cheese, sour milk, etc., which are also available as commercial products. Many of the ACE-I peptides formed during milk fermentation are resistant to gastrointestinal digestion and inhibit angiotensin converting enzyme (ACE) in the rennin angiotension system (RAS). There are various factors, which affect the formation ACE-I peptides and their ability to reach the target tissue in active form, which includes type of starters (lactic acid bacteria (LAB), yeast, etc.), substrate composition (casein type, whey protein, etc.), composition of ACE-I peptide, pre and post-fermentation treatments, and its stability during gastrointestinal digestion. The antihypertensive effect of fermented milk products has also been proved by various in vitro and in vivo (animal and human trials) experiments. This paper reviews the literature on fermented milk products as a source of ACE-I peptides and various factors affecting the production and activity of ACE-I peptides.     

A Review of Potential Marine-derived Hypotensive and Anti-obesity Peptides

Bioactive peptides are food derived components, usually consisting of 3–20 amino acids, which are inactive when incorporated within their parent protein. Once liberated by enzymatic or chemical hydrolysis, during food processing and gastrointestinal transit, they can potentially provide an array of health benefits to the human body. Owing to an unprecedented increase in the worldwide incidence of obesity and hypertension, medical researchers are focusing on the hypotensive and anti-obesity properties of nutritionally derived bioactive peptides. The role of the renin–angiotensin system has long been established in the aetiology of metabolic diseases and hypertension. Targeting the renin–angiotensin system by inhibiting the activity of angiotensin-converting enzyme (ACE) and preventing the formation of angiotensin II can be a potential therapeutic approach to the treatment of hypertension and obesity. Fish-derived proteins and peptides can potentially be excellent sources of bioactive components, mainly as a source of ACE inhibitors. However, increased use of marine sources, poses an unsustainable burden on particular fish stocks, so, the underutilized fish species and by-products can be exploited for this purpose. This paper provides an overview of the techniques involved in the production, isolation, purification, and characterization of bioactive peptides from marine sources, as well as the evaluation of the ACE inhibitory (ACE-I) activity and bioavailability.     

Nutritional,functional and biological properties of insect proteins: Processes for obtaining,consumption and future challenges

BackgroundConsuming insects as an alternative protein source is considered a future trend and a viable strategy that could potentially contribute to global food security. Insects are a non-conventional source of protein, either for human consumption directly or indirectly as a component in recomposed foods or added to feedstock mixtures. Moreover, these proteins have demonstrated a broad range of applications as peptides with antihypertensive, antimicrobial and antioxidant properties. However, aspects such as food safety and processing of these proteins need further studies for their elucidation and optimization.Scope and approachIn this review, aspects of nutritional value and risks of insect consumption are reported. Additionally, conventional processing techniques and recent advances in insect protein extraction and production are presented. The application of bioactive peptides obtained from insect protein hydrolysates is reported, focusing on their potential antihypertensive, antimicrobial and antioxidant properties.Key findings and conclusionsInsect proteins have great advantages in terms of nutritional value, total protein level and amino acid profile. However, some safety concerns must be taken into consideration in large-scale production. The conventional processing of insects proteins is very particular, depending on several aspects such as species, larval stage, and cultivation, among others. Nonetheless, recent advances in insect protein production via enzymatic hydrolysis and heterologous expression have shown a promising technology for the study and exploitation of their bioactive properties, such as the antimicrobial, antioxidant and antihypertensive (inhibition of ACE) activity of insect peptides.     

The use of high hydrostatic pressure to promote the proteolysis and release of bioactive peptides from ovalbumin

Enzymatic hydrolysis of food proteins can release peptides able to exert different biological activities. Among the bioactive peptides known so far, those with angiotensin converting enzyme (ACE)-inhibitory properties are receiving special attention due to their potential beneficial effects in the treatment of hypertension. In a previous work, we identified active peptide sequences that derived from proteolysis of ovalbumin. We have now explored the possibility of using high hydrostatic pressure to promote the release of bioactive peptides. Treatment of ovalbumin under high pressures, up to 400 MPa, with chymotrypsin, trypsin and pepsin, enhanced its hydrolysis and changed the proteolytic pattern. However, under the conditions assayed, the in vitro ACE inhibitory activity of the hydrolysates did not improve as compared with those obtained at atmospheric pressure. Nevertheless, proteolysis under pressures of 200–400 MPa accelerated the release of the peptides YAEERYPIL, FRADHPFL and RADHPFL, with demonstrated antihypertensive effects in vivo.     

Preparation,Bioavailability, and Mechanism of Emerging Activities of Ile‐Pro‐Pro and Val‐Pro‐Pro

Ile‐Pro‐Pro and Val‐Pro‐Pro are two most well‐known food‐derived bioactive peptides, initially identified as inhibitors of angiotensin I‐converting enzyme (ACE) from a sample of sour milk. These two peptides were identified in fermented and enzymatic hydrolyzed cow and non‐cow (that is, goat, sheep, buffalo, yak, camel, mare, and donkey) milk, as well as sourdough prepared from wheat, rye, and malt. Similar to other bioactive peptides, bioavailability of these peptides is low (about 0.1%), reaching picomolar concentration in human plasma; they showed blood pressure lowering activity in animals and in human, via improved endothelial function, activation of ACE2, and anti‐inflammatory property. Emerging bioactivities of these two peptides toward against metabolic syndrome and bone‐protection received limited attention, but may open up new applications of these peptides as functional food ingredients. Further studies are warranted to determine the best source as well as to identify novel enzymes (particularly from traditional fermented milk products) to improve the efficiency of production, to characterize possible peptide receptors using a combination of omics technology with molecular methods to understand if these two peptides act as signal‐like molecules, to improve their bioavailability, and to explore new applications based on emerging bioactivities.     

Food‐Originating ACE Inhibitors,Including Antihypertensive Peptides,as Preventive Food Components in Blood Pressure Reduction

This work is a literature overview on angiotensin‐converting enzyme (ACE) inhibitory/antihypertensive peptides in food protein sources. The following aspects related to peptides with the above‐mentioned bioactivity are discussed: (i) mechanism of action of ACE, (ii) the structural character of ACE inhibitors/antihypertensive peptide sequences determined by different methods, including quantitative structure–activity relationship studies, (iii) their food sources, (iv) absorption of peptides, (v) in vitro and in vivo approaches involved in the production and potential release of peptide ACE inhibitors as well as in silico methods applied in research concerning peptides.     

Bioactive Natural Constituents from Food Sources—Potential Use in Hypertension Prevention and Treatment

Prevention and management of hypertension are the major public health challenges worldwide. Uncontrolled high blood pressure may lead to a shortened life expectancy and a higher morbidity due to a high risk of cardiovascular complications such as coronary heart disease (which leads to heart attack) and stroke, congestive heart failure, heart rhythm irregularities, and kidney failure etc. In recent years, it has been recognized that many dietary constituents may contribute to human cardiovascular health. There has been an increased focus on identifying these natural components of foods, describing their physiological activities and mechanisms of actions. Grain, vegetables, fruits, milk, cheese, meat, chicken, egg, fish, soybean, tea, wine, mushrooms, and lactic acid bacteria are various food sources with potential antihypertensive effects. Their main bioactive constituents include angiotensin I-converting enzyme (ACE) inhibitory peptides, vitamins C and E, flavonoids, flavanols, cathecins, anthocyanins, phenolic acids, polyphenols, tannins, resveratrol, polysaccharides, fiber, saponin, sterols, as well as K, Ca, and P. They may reduce blood pressure by different mechanisms, such as ACE inhibition effect, antioxidant, vasodilatory, opiate-like, Ca²⁺ channel blocking, and chymase inhibitory activities. These functional foods may provide new therapeutic applications for hypertension prevention and treatment, and contribute to a healthy cardiovascular population. The present review summarizes the antihypertensive food sources and their bioactive constituents, as well as physiological mechanisms of dietary products, especially focusing on ACE inhibitory activity.     

具有临床降血压功效的乳源三肽的研究进展

高血压是人类健康的一大杀手,食品来源的血管紧张素转换酶抑制肽（angiotensin-converting enzyme inhibitory peptides,ACEIPs）因为安全性高、无毒副作用等显著优势而成为合成血管紧张素转换酶（angiotensin-converting enzyme,ACE）抑制剂类降血压药物的潜在替代品。目前已有大量基于体外ACE抑制活性的降血压肽被分离鉴定,但是经过临床研究证实对人体具有明确体内降血压功效的仅有Ile-Pro-Pro（IPP）、Val-Pro-Pro（VPP）和Leu-Pro-Pro（LPP）等少数几种。由于上述3 种三肽最初在酸牛奶中被发现,因此被合称为乳源三肽（以下简称乳三肽）,目前国外已有多种基于乳三肽的降血压功能食品上市,其降血压功效已得到了充分验证,但国内尚未发现类似产品。本文就乳三肽的功效、安全性、制备方法和新来源等进行了综述,并对现有关于乳三肽的专利进行了总结,以期为推动我国基于乳三肽第三代降血压功能食品的开发提供参考。     

Whey as a source of peptides with remarkable biological activities

The dairy industry generates increased amounts of whey from both cheese and casein production facilities. Whey presents an elevated content of lactose and proteins, which are associated with its high biological oxygen demand and decomposing potential. Despite its potential as pollutant, whey has been considered as a dairy by-product due to its nutritional, functional and bioactive properties. The use of enzyme technology may be an interesting strategy to convert whey into added-value products. The hydrolysis of whey proteins can generate bioactive peptides, which are described to perform physiological effects in vivo, such as antioxidant, antimicrobial, antihypertensive and antidiabetic activities. Bioactive peptides derived from whey proteins have been also associated with immunomodulatory, anticancer, opioid and hypocholesterolemic activities. This review presents a discussion on the main biological activities of peptides derived from whey proteins.     

Development and biological activities of marine-derived bioactive peptides: A review

Marine organisms are rich sources of structurally diverse bioactive compounds. Recently, a great deal of interest has been expressed regarding marine-derived bioactive peptides because of their numerous health beneficial effects. Moreover, many studies have reported that marine bioactive peptides can be used as antihypertensive, antioxidative, anticoagulant, and antimicrobial components in functional foods or nutraceuticals and pharmaceuticals due to their therapeutic potential in the treatment or prevention of diseases. This contribution presents an overview of the bioactive peptides derived from marine organisms and their biological activities with potential applications in different areas.     

发酵肉制品中生物活性肽的研究进展

发酵肉制品营养丰富、风味独特,深受广大消费者的喜爱。肉制品在发酵过程中受组织内源酶和微生物共同作用会发生一系列复杂的生物化学变化,其中最重要的是蛋白质降解。蛋白质降解既可以增加肉制品风味物质的种类,又提高了蛋白质的消化率,提升了产品的营养价值,并且蛋白质降解生成的部分肽类物质具有一定的生物活性及生理功能,如抗氧化、抗菌、降血压、提高人体免疫力等,因此对生物活性肽的制备与功能研究具有重要的理论与应用价值。发酵肉制品是生物活性肽的一个良好来源,本文主要综述发酵肉制品中蛋白质降解生成生物活性肽的种类、分离纯化方法及生物活性肽的功能利用,旨在为功能性发酵肉制品的研发和生产提供理论支持。     

乳蛋白生物活性肽的药理学作用及应用前景

以乳蛋白生物活性肽中酪蛋白磷酸肽为重点，就乳蛋白生物活性肽的离子载体作用、细胞凋亡诱导作用、细胞免疫调节作用、DNA合成促进作用、抗茵作用、抗高血压作用和抗血栓作用进行了阐述，并对这些药理学作用的研究进展加以介绍，同时展望了乳蛋白生物活性肽在乳品和医药工业中的应用前景：     

Indigenous marine diatoms as novel sources of bioactive peptides with antihypertensive and antioxidant properties

Several bioactive compounds from microalgae have demonstrated diverse biological activities with positive effects on human health. However, the potential of bioactive peptides as functional foods is still undervalued. Therefore, the exploration of microalgae strains as sources of bioactive peptides could reveal strong and unique bioactivities, especially when these marine sources have never been explored before. For this aim, protein extracts from six indigenous marine diatoms were subjected to enzymatic hydrolysis using four proteases (flavourzyme, pepsin, papain and trypsin). The hydrolysates were then tested for angiotensin converting enzyme (ACE)-inhibitory, antioxidant and antihypertensive properties. Results showed that papain hydrolysates from all microalgae strains exhibited strong ACE-inhibitory activities and antioxidant properties. In particular, protein hydrolysates from Bellerochea malleus were found to reduce blood pressure properties of 17 mmHg after 5 days of oral administration to SHR animals. These results revealed the potential of bioactive peptides from indigenous marine diatoms for use as functional foods or nutraceuticals.     

Antihypertensive peptides derived from milk proteins

This paper reviews the angiotensin I-converting enzyme inhibitory peptides originated from milk proteins. Focus was put on the peptides derived from milk casein by the action of some proteolytic enzymes and fermented products by lactic acid bacteria. Some of the angiotensin I-converting enzyme inhibitory peptides exhibit significant antihypertensive effects in spontaneously hypertensive rats. However, there were some antihypertensive peptides with low inhibitory activity of this enzyme. Key factors needed for the peptide to demonstrate the antihypertensive effects are discussed. Fermented milk, which has inhibitory activity of the enzyme, showed the reduction of blood pressure of hypertensive subjects. The possibility of the bioactive peptides for functional foods are also discussed.     

Effects of natural peptides from food proteins on angiotensin converting enzyme activity and hypertension

Cardiovascular diseases are the leading cause of death. The underlying pathophysiology is largely contributed by an overactivation of the renin-angiotensin-aldosterone-system (RAAS). Herein, angiotensin II (AngII) is a key mediator not only in blood pressure control and vascular tone regulation, but also involved in inflammation, endothelial dysfunction, atherosclerosis, hypertension and congestive heart failure. Since more than three decades suppression of AngII generation by inhibition of the angiotensin-converting enzyme (ACE) or blockade of the AngII-receptor has shown clinical benefit by reducing hypertension, atherosclerosis and other inflammation-associated cardiovascular diseases. Besides pharmaceutical ACE-inhibitors some natural peptides derived from food proteins reduce in vitro ACE activity. Several animal studies and a few human clinical trials have shown antihypertensive effects of such peptides, which might be attractive as food additives to prevent age-related RAAS activation. However, their inhibitory potency on in vitro ACE activity does not always correlate with an antihypertensive impact. While some peptides with high inhibitory activity on ACE-activity in vitro show no antihypertensive effect in vivo, other peptides with only a moderate ACE inhibitory activity in vitro cause such effects. The explanation for this conflicting phenomenon between inhibitory activity and antihypertensive effect remains unclear to date. This review shall critically address the effects of natural peptides derived from different food proteins on the cardiovascular system and the possible underlying mechanisms. A central aspect will be to point to conceptual gaps in the current understanding of the action of these peptides with respect to in vivo blood pressure lowering effects.     

In vitro-digested milk proteins: Evaluation of angiotensin-1-converting enzyme inhibitory and antioxidant activities,peptidomic profile,and mucin gene expression in HT29-MTX cells

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.     

Primary and secondary structure of novel ACE-inhibitory peptides from egg white protein

The primary structure of novel angiotensin converting enzyme (ACE) inhibitory peptide from egg white protein was investigated, and secondary structure of the peptide was explored for the first time. The potential effects of bioactive peptides were submitted to bioactivity screening with ACE inhibitory activity, antioxidant property, and anticoagulation activity. Bioactive peptides from egg white protein were characterized by LC tandem mass spectrometric, and secondary structures of those peptides were investigated by FT-IR. Our results showed that total 11 bioactive peptides with three new and eight known structures were identified with LC/MS/MS, which then were synthesized by Fmoc solid phase method. Peptide Thr-Asn-Gly-Ile-Ile-Arg (TNGIIR) exhibited higher activity against ACE to other two new peptides. The concentration of the peptide TNGIIR, necessary to inhibit 50% the activity of ACE was 70 μM. Results also suggested that the secondary structural differences between peptides could also influence the ACE inhibition capacity. Thus, it appears that primary and secondary structure of peptide plays the potential role inhibiting the ACE activity.     

Bioactive peptides from marine processing waste and shellfish: A review

Marine organisms such as fish and shellfish are rich sources of structurally diverse bioactive nitrogenous components. Based on emerging evidence of potential health benefits, these components show significant promise as functional food ingredients. Activities including antihypertensive, antioxidant, anti-microbial, anti-coagulant, anti-diabetic, anti-cancer, immunostimulatory, calcium-binding, hypocholesteremic and appetite suppression have been reported. Fish and shellfish waste components contain significant levels of high quality protein (10–23% (w/w)) which represents a source for biofunctional peptide mining. This review summarises the protein-derived bioactive peptides identified in marine processing waste, molluscs and crustaceans. Moreover, it highlights the potential of proteins derived from these marine organisms as substrates for the generation of biofunctional peptides. It outlines current technologies used in the production, fractionation and purification of marine protein-derived peptides and lists some commercially available products containing marine derived bioactive protein hydrolysates and peptides. Finally, bioactive proteins, non-protein peptides and amino acids found in fish and shellfish are briefly discussed.