Positive news surrounds the latest research in Arteriosclerosis and could this be a hint that this disease of the white matter could be soon treatable via modern methods?
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The proteins that we take through the diet provide us with the necessary amino acids for the development and maintenance of the cells and tissues of our body. Currently, dietary proteins are investigated not only from the nutritional or functional point of view, but also as raw material for obtaining peptides , 1 since any source of dietary protein is likely to provide functional peptides. However, we must be critical regarding its use, despite the fact that in some cases its functionality is not something new, since the existence of proteins in breast milk that contribute to the maturation and function of the immune system in the newborn it is a known fact for more than 50 years 2–4 .
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These functional or bioactive peptides are defined as inactive amino acid sequences within the precursor protein, which exert certain biological activities after their release by chemical or enzymatic hydrolysis 5 . Generally, they are small peptides, from 3 to 20 amino acids, although on some occasions they can exceed this length, which are released during the industrial processing of food, or during gastrointestinal digestion 6,7 . After oral administration, bioactive peptides can exert their effect, among others, on the cardiovascular, digestive, immune and nervous systems 8,9. The scientific literature shows that these peptides can cross the intestinal epithelium and reach peripheral tissues via the systemic circulation, being able to exert specific functions at the local level, in the gastrointestinal tract and at the systemic level. Within these activities, bioactive peptides could influence cell metabolism and act as vasoregulators, growth factors, hormone inducers and neurotransmitters 10 .
Bioactive peptides in food
As mentioned above, bioactive peptides are nothing more than a small sequence of amino acids encrypted in proteins; It is therefore to be expected, due to the wide range of protein foods existing in nature and especially on the market, that their intake is ensured with a balanced diet. However, their bioavailability is not so clear, since they must be released from the proteins in which they are found after undergoing the action of gastric and intestinal proteases and must be able to cross the intestinal epithelium and reach peripheral tissues through blood circulation to be able to exert its action 9–13 .
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In recent years, due to the great relevance that these peptides have obtained in the market, techniques have been developed to obtain new bioactive peptides from food proteins by means of in vitro enzymatic digestion, using proteolytic enzymes of microbial origin 12 . Moreover, recent studies have obtained modified peptides, designed from natural peptides, in order to increase the activity of the latter 14 .
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In this way, proteins from different origins (animal and vegetable) have been used for the isolation of peptides from enzymatic hydrolysates 9,15,16 , being interesting to note that depending on the protein source, the type of enzyme used and the processing conditions, the biological activity and the peptides obtained is different 17 . Among the proteins of plant origin from which bioactive peptides have been isolated, we find soy, wheat, corn, rice, barley and sunflower proteins 17 . Regarding proteins of animal origin, milk and other dairy products are the most studied bioactive peptide precursors, although these peptides have also been identified in egg ovalbumin 9, in meat 9 , in fish muscle (sardine, tuna, bonito) 18 and in royal jelly 19 .
Beneficial properties of bioactive peptides
Antimicrobial and immunomodulatory properties
The association between nutrition and immunity has long been recognized. There are studies that show that bioactive peptides derived from different protein sources exert immunomodulatory effects in vitro and in vivo . However, most studies focus on evaluating the effect of peptides and hydrolysates of specific proteins on the immune system, and only a limited number of investigations examine their impact on nonspecific (innate) immunity. Immunomodulatory peptides are naturally released from the proteins that contain them during the digestion process in the gastrointestinal tract, which affects the immune response and cell function in it.
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The most studied bioactive peptides with antimicrobial and immunomodulatory properties are those that come from milk and dairy products . This effect seems to be related to the net positive charge of these peptides, which are structurally organized and cause the formation of ion channels in the membrane of microorganisms 21 , altering their permeability and causing cell death 22 .
ovotransferrin are found in milk and also in eggs. Both transferrins have antibacterial activity against a wide variety of microorganisms. This activity can be exerted through at least three different mechanisms 23–25 :
Sequestering iron and preventing its use by bacteria.
Producing alterations in the bacterial wall.
By stimulating phagocytosis by macrophages and monocytes.
Bioactive peptides with antimicrobial activity exert an inhibitory effect on target microorganisms also through interaction with anionic intracellular components such as DNA and RNA, which inhibits protein synthesis and cell division of microorganisms. On the other hand, some peptides are involved in autolytic activation in target microorganisms 26 .
Peptides derived from milk caseins also show in vitro antimicrobial activity against a wide range of microorganisms, including Staphylococcus spp and Streptococcus pyogenes . In vivo studies show protective effects of israicin (derived from casein) against S. aureus and Candida albicans in mice and against mastitis in cattle and sheep 27,28 .
It has also been described that lactoferrin is capable of inhibiting the replication of viruses such as type I T-cell leukemia, cytomegalovirus, hepatitis C virus or type I herpes simplex virus 14 .
What is Lysozyme
Lysozyme, also present in milk and eggs, has antimicrobial and immunoregulatory activity, being able to improve chronic sinusitis and normalize the humoral and cellular response in patients with chronic bronchitis when combined with immunotherapy. In addition, it improves the immune response in immunosuppressed cancer patients. It has been suggested that the immunomodulation produced by lysozyme may be the result of stimulation of phagocytic function and hydrolysis of peptidoglycan products that may act as adjuvants or immunomodulators 25,29–31 .
Other foods, although not as studied as dairy products, also contain peptides with immunomodulating activity, as is the case of royal jelly from which peptides have been isolated that stimulate the proliferation of human monocytes, 32 peptides derived from rice proteins and soy that stimulate non-specific immune systems 33 and peptides from buckwheat and pepper 34,35 .
Peptides with opiate activity, also called exorphins, are defined as peptides that have affinity for opiate receptors and act, by binding to receptors, as exogenous modulators of intestinal motility, epithelial permeability and hormone release. These peptides have been isolated from cereals, milk and animal tissues 11.
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The most studied opioid peptides are those derived from milk proteins (caseins) 11,14 . Once absorbed, these peptides can travel to the brain and other organs and exert pharmacological activities similar to morphine or opium. This may be why human newborns generally become calm and sleepy after drinking milk. In contrast to the casomorphins, some peptides produced by the breakdown of κ-casein can act as opioid antagonists, that is, they can inhibit the effect of substances such as morphine 36 .
In adult humans, the effects of these peptides are usually limited to the gastrointestinal tract, as they are either not absorbed or escape enzymatic degradation in the intestinal wall 37 . However, there are studies that suggest that some of them (β-casomorphins) can be transported from the blood to the brain stem 38 and to the cardiovascular system in infants 37 .
Milk Peptides Work
Milk peptides may participate in appetite regulation, modifying the endocrine activity of the pancreas to increase insulin production 39 . Studies in rats indicate that β-casomorphins can modulate food intake, stimulating fat intake and reducing the intake of diets rich in carbohydrates 40 . In this sense, also some peptides derived from wheat gluten administered intravenously and orally in rats gave rise to postprandial stimulation of insulin release 41 .
Part of the function of the casomorphins could be the reduction of intestinal motility, which would allow the maximum production of other bioactive peptides 42 . In adult humans, opiate fragments have been detected in the intestinal content after ingestion of cow’s milk 43 , but not detected, however, in the blood serum. The confirmation in man of the effects detected in experimental animals would open a new field of application of these opiate peptides in the prevention and treatment of intestinal disorders.
Antioxidants are not only important in preventing oxidation in foods, but also at a physiological level. Free radicals are molecules that are in continuous formation in cells and are naturally neutralized by the body’s antioxidant defenses. However, there are factors that produce an imbalance in the number of free radicals, and an excess of these can lead to cell aging or the development of diseases 44 . All this has led to the search for natural antioxidant compounds to prevent oxidation by free radicals.
The study of antioxidant peptides present in foods has been a challenge in recent years, having identified numerous peptides that have antioxidant activity in different foods 45,46 and in derivatives of them, such as gelatin hydrolysates 47 , egg white hydrolysates 48 and dairy products 49 , among others. These peptides act by preventing other molecules from binding to oxygen, by reacting-interacting faster with free radicals than with the rest of the molecules present in a certain microenvironment of the plasma membrane, cytosol, nucleus or extracellular fluid 50 .
Hyperlipidemia, especially hypercholesterolemia, is one of the most important risk factors contributing to the development of cardiovascular diseases.
It has recently been shown that soy peptides may be responsible, at least in part, for its hypocholesterolemic activity, since it has been observed that soy protein hydrolysates showed a greater decrease in plasma cholesterol than intact soy protein 51 .
This hypocholesterolemic effect of bioactive peptides is attributed to two actions:
Bioactive peptides inhibit cholesterol absorption, possibly due to the repression of the micellar solubility of cholesterol 52 .
Some peptides can upregulate LDL receptors, which are chronically suppressed by hypercholesterolemia or dietary cholesterol administration 53 .
In addition to peptides derived from soybeans, other bioactive peptides with a hypocholesterolemic effect have been obtained from B – Lactoglobulin, pork protein hydrolyzate 54,55 and vegetable protein (Brassica carinata) 56 .
Peptides with activity on the cardiovascular system
The main described effects of bioactive peptides on the cardiovascular system are related to their antithrombotic and antihypertensive activity.
Platelet aggregation is a critical step in thrombus formation and is mediated by the binding of fibrinogen and its receptor, the platelet membrane glycoprotein GPIIb/IIIa, which involves the recognition of the sequence Arg-Gli-Asp ( RGD) of fibrinogen. It is conceivable, therefore, that peptides containing the RGD sequence may be capable of antagonizing fibrinogen coupling to GPIIb/IIIa, resulting in inhibition of platelet aggregation. In the RGD sequence, a cationic unit, in this case the guanidino group from the side chain of Arg and the β-carboxylic acid backbone of Asp, is required for inhibitory activity. Furthermore, the distance between these cationic and anionic functional groups is an important factor in potency. Fibrinogen binds to GPIIb/IIIa sites.57 . Therefore, peptides that are fibrinogen antagonists and bind GPIIb/IIIa are useful in the prevention of thrombosis and in post-angioplasty or post-thrombolytic treatment regimens.
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The main isolated peptides with antithrombotic activity are present in milk. At the molecular level, the coagulation of blood and milk show great similarity. In milk, the coagulation mechanism is defined by the interaction of k-casein with chymosin, and the blood coagulation process is defined by the interaction of fibrinogen with thrombin.
Certain peptide sequences of κ-CN, called casoplatelins, are similar to the fibrinogen γ chain 58 . Peptides derived from bovine κ-CN have been shown in vitro to be inhibitors of platelet aggregation and of the binding of the γ chain of human fibrinogen to the specific receptor on the platelet membrane 59 . These peptides are capable of binding to specific receptors located on the surface of platelets, thus preventing thrombus formation.
Peptides derived from lactoferrin also have antithrombotic activity through another mechanism different from that of casein, inhibiting, in a dose-dependent manner, platelet aggregation induced by ADP, due to the homology with the fragment f(572-575) of the fibrinogen α chain 60 . It has been shown in vivo that this fragment inhibits the formation of thrombi in the coronary artery of dogs 61 and prolongs the bleeding time in the mesenteric artery of hamsters 62 .
In the plasma of newborns fed with breast milk or infant formulas made with cow’s milk, peptide sequences have been found in sufficient concentration to exert the antithrombotic effect in vivo, which demonstrates their release from milk proteins during the process of gastrointestinal digestion 63 . More recent studies have shown the presence of antithrombotic peptides in the stomach, duodenum, and later in the blood of adults who had ingested milk or yogurt 63 .
Hypertension is the leading cause of disease in industrialized countries. 35% of mortality in these countries is due to this disease or one of its renal, cardiac or cerebral complications. Due to this, foods that present peptides with antihypertensive activity are of great interest.
The most studied antihypertensive mechanism as activity of bioactive peptides is the inhibition of the activity of the angiotensin converting enzyme (ACE). ACE is an enzyme that catalyzes the conversion of angiotensin I (decapeptide) to angiotensin II (octapeptide).
Angiotensin II is a compound with high vasoconstrictor power. Its action causes the rapid contraction of the arterioles and, therefore, the increase in blood pressure, since it stimulates the secretion of aldosterone by the adrenal glands, a hormone that induces the excretion of potassium and the retention of sodium and water and causes the increase in extracellular volume, and neutralization of renin production. Renin releases the decapeptide angiotensin I from the renin-angiotensin system. This system is perhaps the most important of the different vasoconstrictor and vasodilator mechanisms involved in the regulation of blood pressure 64 .
ACE acts simultaneously on the kinin-kallikrein system catalyzing the degradation of bradykinins, compounds with a powerful vasodilator action, and in this way increases blood pressure. The increased availability of bradykinins due to ACE inhibition may be partially responsible for the beneficial effect of ACE inhibition on blood pressure.
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Some works have focused on the production and isolation of ACE-inhibiting peptides from proteins from different foods 65–67 . Some authors have found that, in fermented products, peptides with ACE inhibitory activity could also have antioxidant activity, suggesting the presence of multifunctional activity in these compounds 68,69. Exogenous competitive inhibitors of this enzyme have been sought from different sources (fish, corn, gelatin, snake venom, wine, etc.). The origin of these protein sources encompasses both the plant kingdom and the animal kingdom. Competitive inhibitors compete with the substrate for the active site of the enzyme. In this case, the increase in the concentration of the substrate leads to a decrease in the ability of the inhibitor to compete with it. On the other hand, non-competitive inhibitors bind to the enzyme in a zone other than the active center, deforming it, in such a way that it prevents the bond with the substrate, this type of inhibition being independent of the substrate concentration. Depending on the type of inhibitor, competitive or non-competitive inhibition can occur 65 .
Several endogenous peptides that act as inhibitors and competitive substrates of ACE have been identified, such as enkephalins, bradykinins and substance P. Extracts from Bothrops jararaca snake venom were studied as the first exogenous ACE inhibitors . Currently, a synthetic derivative, captopril (D-3-mercapto-2-methylpropanoyl-1-proline; IC50=0,006μM), obtained after studying the hypothetical model of the enzyme’s active site, is the most widely used drug in the control of hypertension .
Another of the enzymes involved in the regulation of blood pressure is the endothelin converting enzyme (ECE). This enzyme catalyzes the formation of endothelin-1 from its precursor. Endothelin-1 is a powerful vasoconstrictor, which favors the increase in blood pressure; therefore, inhibition of ECE produces an antihypertensive effect. Peptides that inhibit this enzyme have only been described from a digestive hydrolyzate of bonito 71 , but the high content and wide variety of proteins present in milk could open a new field of study aimed at identifying dairy peptides with this activity. .
During the last 20 years, many ACE-inhibiting peptides with in vivo antihypertensive properties have been identified in foods.
ACE inhibitor peptides in dairy
A large number of ACE-inhibiting peptides have been isolated from dairy products (cheese, milk, fermented milk…). Some of them have shown antihypertensive effects in spontaneously hypertensive experimental animals and in patients with hypertension. Table 1 shows the antihypertensive activity of different milk proteins.
ACE inhibitory activity of milk proteins
Protein peptide fragment ECA IC50μmol/l
α s1 -casein f(25-27) 2,0
α s2 -casein f(174-179) 4,3
β-casein f(74-76) 5,0
κ-caseina f(185-190) 52,0
α-lactoalbumin f(104-108) 77,0
β-lactoglobulina f(142-148) 42,6
Fuente: FitzGerald et al 76
ACE IC 50 : concentration of peptide that inhibits the activity of the angiotensin converting enzyme at 50%.
Maruyama and Suzuki 72 were the first to isolate an ACE-inhibiting peptide (called CEI 12) from a casein hydrolyzate (dodecapeptide, IC50=77μM). Subsequently, other ACE-inhibiting peptides have been isolated from different dairy products, especially fermented dairy products.
Yamamoto et al 73 have shown that milks fermented with L. helveticus are the ones that exhibit the greatest ACE inhibitory activity, due to the high extracellular proteolytic activity of this strain. Other peptides with inhibitory activities have been identified in milks fermented by Lactobacillus delbrueckii sp . bulgaricus or Lactobacillus lactis sp . cremoris 74 and in kefir, a fermented milk prepared from a culture broth that includes lactic acid bacteria, a strain of Saccharomyces kefir and some species of acetic acid bacteria, although in this the ACE inhibitory activity is low 75. It appears that the peptides found in kefir are not the main substances involved in its antihypertensive effects.
Studies carried out on cheeses have shown a strong ACE inhibitory activity observed after a protease digestion process 76 . The proteolysis that takes place during cheese ripening could increase the rate of ACE inhibitory activity to a certain level, beyond which this inhibitory activity decreases 77 due to the transformation of bioactive peptides into inactive molecules and amino acids 78 . The optimum ripening time for the production of bioactive peptides is different for each type of cheese. As an example, we could talk about 8 months for a Manchego type cheese 79 .
Table 2 80 shows some of the products that exist on the market and that offer claims about the reduction of blood pressure in humans, the doses used and the initial blood pressure of the subjects in the studies.
Clinical studies with dairy products and peptides that have an antihypertensive effect in humans
Product Active component (dose) Initial blood pressure of the subjects Effect on systolic blood pressure
Calpis (fermented milk) IPP (1,04 mg)VPP (1,42 mg) hypertensive –9.4 mmHg (4 weeks)–14.1 mmHg (8 weeks)
Calpis (fermented milk) IPP (1,15 mg)VPP (1,98 mg) average hypertension –4.3 mmHg (2 weeks)–5.2 mmHg (4 weeks)
Ameal peptide (hydrolyzed caseins) IPP+VPP (1,8 mg)IPP+VPP (2,5 mg)IPP+VPP (3,6 mg) High normal blood pressure Moderate hypertension –6.3 mmHg (6 weeks)–6.7 mmHg (6 weeks)–10.1 mmHg (6 weeks)
Evolution/Kaiku Vitabrand (leche fermentada) IPP (2,25 mg)VPP (3-3,75 mg) moderate hypertension –14.9 mmHg (8 weeks)
Evolution/Kaiku Vitabrand (leche fermentada IPP (2,25 mg)VPP (3-3,75 mg) hypertensive –6.7 mmHg (21 weeks)
Evolution/Kaiku Vitabrand (leche fermentada) IPP (2,4-2,7 mg)VPP (2,4-2,7 mg) moderate hypertension –16 mmHg (8-10 weeks)–11 mmHg (5-7 weeks)
Biozate 1 (whey protein hydrolyzate) 20 g of hydrolyzate hypertensive –11 mmHg (-7mmHg DBP) compared to control.
Source: López Fandiño 77 .
Peptides derived from marine products
Some ACE-inhibiting peptides have been obtained by enzymatic protein digestion from tuna muscle protein 81 , sardine muscle 82 , dried bonito 83 , algae 84 and other marine products.
Some protein hydrolysates have shown effects in vitro (via ACE inhibition) and in vivo (antihypertensive effects) ( table 3 ). The administration of a bonito muscle hydrolyzate to spontaneously hypertensive rats has made it possible to suppress hypertension after a period of five weeks of treatment using a dose of 15 to 60mg / kg 60 .
Hydrolyzed marine products with antihypertensive activity
Fuente IC 50 Dose ΔPS (mmHg)
Bonito 29μg m.s/ml 15mg/kg/day –23 after 7 weeks
Tuna 0,63μg p/ml 5,000mg/kg/day –65 after 16 days
Sardine 27,1 mg/g 117 mg/kg/ –33 after 1 hour
Algal hydrolysates are also an important source of biologically active peptides, some of which have been identified as exhibiting ACE-inhibitory activities ( table 3 ). These results may partly explain the antihypertensive effects observed in spontaneously hypertensive rats (SHR) 83,85 . Other ACE inhibitory peptides have been identified in fish hydrolysates, but very few have been evaluated in vivo .
ACE-inhibiting peptides have been found in many plant sources, including soybeans 9 , wheat germ 86 and chickpeas 87 .
A hexapeptide was isolated from wheat gluten which showed antagonistic activity towards angiotensin I in vivo . Recently, a gluten hydrolyzate has reduced blood pressure in spontaneously hypertensive rats 2h after intravenous administration 88 .
Hydrolysis of rapeseed proteins revealed that the presence of ACE inhibitory peptides can show an antihypertensive effect in vivo . This hydrolyzate, administered to SHR rats, significantly reduces blood pressure 2h after oral administration (0.15g/kg) 89 . The antihypertensive effect of a soy regimen when administered to SHR 90 rats has also been demonstrated . In the same way, the digestion of the main storage proteins of chickpea seeds produces ACE-inhibiting peptides 91 .
Oshima et al 91 were the first to identify ACE-inhibiting peptides from dietary proteins. In recent years, studies have been carried out describing the existence of peptides with antihypertensive activity in other food sources, such as pork and chicken muscle, eggs, garlic, gelatin, sake, wine, bacterial autolysates, liver, squid, mushrooms, royal jelly and some fruits and teas 11.92 . However, the information on bioactive peptides generated from the proteins of these foods is still limited.
At present, some peptides with vasodilator and ACE-inhibitory activity have been described, which come from hydrolyzed ovalbumin with different enzymes. For example, chronic administration (12 weeks) to SHR rats of an egg yolk hydrolyzate has eliminated the development of hypertension at doses of 20, 100, and 500mg/kg administered orally daily. Higher doses administered to animals have decreased mean systolic and diastolic pressures by about 10% compared to control animals 93 .
Bioavailability of bioactive peptides
The potential hypotensive effect of ACE-inhibiting peptides depends on their ability to reach the organs where they are going to perform their function intact. As has already been mentioned, many studies have been carried out in which the ACE inhibitor activity of these peptides is evaluated, but it is difficult to establish a direct relationship between the capacity to inhibit ACE in vitro and the antihypertensive activity in vivo . The study of the bioavailability of bioactive peptides is essential when designing functional foods with physiological properties 94 . It is known that dipeptides and tripeptides can be transported through the intestinal mucosa, although there is also evidence that larger peptides can be absorbed in the small intestine.63 . It has been shown, therefore, that some peptides with ACEI and antihypertensive activity are capable of being absorbed in the gastrointestinal tract, accumulating in various organs, so they could exert their mechanism of action systemically 19 . However, it is postulated that certain antihypertensive peptides may not be absorbed in the intestinal tract, exerting a direct function in the intestinal lumen, or they may exert their function through interaction with receptors found in the intestinal wall.
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Once absorbed, the high number of peptidases found in the blood means that the time during which certain peptides remain stable in the plasma is very short. However, there is some evidence that peptides with ACE inhibitor activity can be absorbed in the digestive tract and transported through the bloodstream without being hydrolyzed by blood proteases 13 .