Article

Novel Potent Decameric Peptide of Spirulina platensis Reduces Blood Pressure Levels Through a PI3K/AKT/eNOS-Dependent Mechanism

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Abstract

Considered as a superfood of the future, Spirulina platensis matrix has been extensively used because of its beneficial effect on the management of cardiovascular diseases. However, its nutraceutical properties, bioactive compounds, and molecular mechanisms are unknown. Here, we demonstrate that S platensis matrix processed in vitro by simulated gastrointestinal digestion induces direct endothelial nitric oxide (NO)-mediated vasorelaxation of resistance vessels in mice. To gain insight into the bioactive compounds responsible for this effect, we used a complex multistep peptidomic approach to fractionate the crude digest: of the 5 peptide fractions identified (A–E), only fraction E evoked vasorelaxation. High-resolution mass spectrometry–based screening revealed in E the presence of 4 main peptides (SP3–SP6 [spirulina peptides]), of which only SP6 (GIVAGDVTPI) exerted direct endothelium-dependent vasodilation of ex vivo vessels, an effect occurring via a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt) pathway converging on NO release. In vivo, administration of SP6 evoked a significant hemodynamic effect, reducing blood pressure, an action absent in eNOS (endothelial NO synthase)-deficient mice. Of note, although lower doses of SP6 had no hemodynamic effects, it still enhanced endothelial NO vasorelaxation. Finally, in an experimental model of arterial hypertension, SP6 exerted an antihypertensive effect, improving endothelial vasorelaxation associated with enhanced serum nitrite levels. Based on our results, this novel decameric peptide may extend the possible fields of application for spirulina-derived peptides and could be developed into a promising nonpharmacological approach for the containment of pathologies associated with vascular NO misregulation.

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... Vascular reactivity studies. Vascular reactivity studies were performed on second-order branches of the mesenteric artery, as previously described (58). Quantification of vasomotor response, BP, and molecular analyses were performed by a second individual who was blind to the genotype of the animal and/or the hypothesis that was being tested for each group. ...
... NO detection. NO production in response to different stimuli as reported in figure legends was assessed and imaged using 4-amino-5-methylamino-2′,7-difluorofluorescein diacetate (DAF-FM) (Invitrogen, D-23842) as previously described (58). Isolated mesenteric arteries were embedded in a freezing medium to obtain transverse sections. ...
... To evaluate the nitrite level in the organ bath solution from the pressure myograph, we used 280i Nitric Oxide Analyzer (Sievers Instruments), as previously described (58). Briefly, prior to analysis, a mixture of glacial acetic acid and 1.0 mL of 0.5 M ascorbic acid was added to the purge bath to generate a calibration curve for nitrite. ...
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Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.
... Regarding endothelial-dependent mechanisms, one plausible mechanism would be increased NO release. Our results show that the release of NO was increased in arteries from SHR, as in previous studies [36,37]. Additionally, since increased production of contractile prostanoids has been reported in hypertension [38], so the greater effect exerted by Spirulina could also be due to the decrease in the contractile factors as the endothelium is removed. ...
... Once the NO released was determined, the following step was to analyze the possible modification that Spirulina extract could exert on the sensitivity of the smooth muscle to the NO. The results show that the SNP-induced response was increased by the aqueous extract which appears to agree [36,37]. Additionally, it is important to note that the greatest increment observed in the SNP-induced relaxation after Spirulina extract incubation was observed at low concentrations of SNP, which may be considered of physiological relevance. ...
... Therefore, the content of hydrogen peroxide was analyzed, showing that the incubation with the Spirulina extract decreased the production of this particular ROS. This result agrees with most of the studies describing the general antioxidant properties of Spirulina [36,37]. There are still remaining important questions about the differences between the properties of the isolated Spirulina extracts and the properties exerted on specific biological tissues, depending also on the particular pathophysiological condition of tissues. ...
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Hypertension is a multifactorial disorder that is considered one of the major causes of premature death worldwide. This pathology is associated with functional and structural vascular alterations in which oxidative stress and decreased nitric oxide (NO) bioavailability are involved. On the other hand, the use of natural compounds, including extracts of microalgae, for the treatment of cardiovascular diseases is gaining attention. Based on the anti‐oxidant and anti‐inflammatory properties of Spirulina , the aim of this study was to investigate the effect of aqueous Spirulina extract on the release and function of NO, as well as on the expression of the antioxidant protein hemoxygenase‐1 (HO‐1), phosphorylated Akt (p‐Akt) and phosphorylated eNOS (p‐eNOS) that regulate the production of NO. For this purpose, aortic segments from male Spontaneously Hypertensive rats (SHR) and its normotensive counterparts, Wistar‐Kyoto (WKY) rats, were isolated. Aortic segments exposed to the aqueous Spirulina extract (0.1 % w/v, for 3 h) and those not exposed were used to analyze the following parameters: (i) the release of NO; (ii) the NO‐dependent response to acetylcholine (ACh) and the vasodilator response to the NO donor, sodium nitroprusside (SNP); and (iii) the expression of HO‐1, p‐eNOS and p‐Akt. The results showed that Spirulina extracts increased the release of NO more in arteries from SHR than that of WKY rats. Spirulina extracts also increased the ACh‐ and SNP‐induced response in arteries from both WKY and SHR. Additionally, Spirulina increased the expression of HO‐1, p‐Akt and p‐eNOS in arteries from SHR. These results suggest that Spirulina extracts exert benefits for the treatment of hypertension by increasing the release and function of NO in which the increased levels of HO‐1, p‐eNOS and p‐Akt can be involved. Support or Funding Information Supported by Comunidad de Madrid (S2013/ABI‐2783, “INSPIRA1‐CM”) and Fondo Europeo de Desarrollo Regional. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
... Microalgae have emerged as a rich source of peptides with different properties, and, in particular, for the prevention of cardiovascular disease [7]. In this regard, we recently characterized a novel decameric peptide from the gastro-intestinal digest of Spirulina platensis, named SP6 (GIVAGDVTPI, allophycocyanin ␣-chain, f: 95-104), which showed very potent in vivo anti-hypertensive activity by exerting endothelium-dependent vasodilation via a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt) pathway, converging on nitric oxide (NO) release [8]. Bioactive peptides from natural sources are often labelled as "multifunctional", due to combined effects such as hypotensive and hypocholesterolemic, as showed by milk, soybean and lupin protein derived peptides [9]. ...
... All mice have been subjected to constant monitoring of systolic, diastolic blood pressure and heart rate during all observation period by non-invasive tail-cuff method using the BP-2000 instrument (Visitech systems, Apex, NC, U.S.A) as previously described [8]. Moreover, mice were weighed throughout the observation period using electronic veterinary weighing scale (Soehnle Industrial Solutions, Backnang, Germany). ...
... In a previous paper [8] we characterized a novel allophycocyanin derived peptide, named SP6, that at the dose of 10 mg/kg of SP6 reduced systolic blood pressure in an experimental model of arterial hypertension. Considering the important hemodynamic effect evoked by acute high-dosage treatment with SP6, here we chronically treated HFD ApoE knockout mice with a lower-dosage (5 mg/kg) of SP6, which, while is not sufficient to modulate blood pressure, is still associated with a significantly improved vascular function in mesenteric arteries [8]. ...
Article
Atherosclerosis, dyslipidemia and hypertension are comorbid diseases often found in combination. Among different pharmacological approaches the employment of natural multifunctional peptides is an attractive option as side therapy. Mass spectrometry-based metabolomics provide valuable information on metabolic changes and can be useful to elucidate peptide pharmacodynamics. In this this work we performed a preliminary investigation on the potential effect of a recently characterized Spirulina platensis peptide named SP6 (GIVAGDVTPI) on the modulation of metabolism in a high fat diet ApoE -/- mice atherosclerotic model. A direct infusion Fourier transform ion cyclotron resonance mass spectrometry (DI-FT-ICR-MS) approach was used to elucidate polar and non-polar metabolites extracted by mice plasma following four weeks SP6 treatment. The method delivered fast analysis time, repeatability, high mass accuracy and resolution for unambiguous molecular formula assignment. Multivariate statistical analysis (PLS-DA) highlighted a clear class separation, revealing the alteration of numerous metabolites levels belonging to different classes. In particular sphingolipids, glycerophospholipids, TCA cycle intermediates, and amino acids, which are key players in the atherosclerotic process and progression, were upregulated in saline alone HFD ApoE -/- group, while were sensibly decreased after treatment with SP6 peptide. These results could open the way to further, large-scale, investigation of SP6 peptide effects in the regulation of atherosclerotic disease development and progression, and show the potential of DI-FT-ICR as fast analytical tool to take snaphshots of metabolic changes before moving to targeted MS-based approaches
... The raw MS data were analyzed using Protein Discoverer™ Software version 2.5 using the Sequest search engine. The spectra were searched against the Arthrospira platensis and Arabidopsis thaliana databases from UniprotKB [39,40]. Precursor mass tolerance was set to 10 ppm. ...
... Spirulina platensis and Moringa oleifera are important protein sources due to their high nutritional value protein contents, as confirmed by Bradford assay [39] (protein content > 60% w/w). To determine the protein composition of the Arthrospira platensis and Moringa oleifera extracts, a label-free based liquid chromatography-mass spectrometry (LC-MS/MS) proteomic approach was carried out. ...
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Anthracyclines are essential adjuvant therapies for a variety of cancers, particularly breast, gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Spirulina, Reishi (Ganoderma Lucidum) and Moringa are three nutraceuticals with anti-inflammatory effects that are currently used in cancer patients as complementary and alternative medicines to improve quality of life and fatigue. We hypothesize that the nutraceutical combination of Spirulina, Reishi and Moringa (Singo) could reduce inflammation and cardiotoxicity induced by anthracyclines. Female C57Bl/6 mice were untreated (Sham, n = 6) or treated for 7 days with short-term doxorubicin (DOXO, n = 6) or Singo (Singo, n = 6), or pre-treated with Singo for 3 days and associated with DOXO for remaining 7 days (DOXO–Singo, n = 6). The ejection fraction and radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100, Fujifilm). The myocardial expressions of NLRP3, DAMPs (galectin-3 and calgranulin S100) and 13 cytokines were quantified through selective mouse ELISA methods. Myocardial fibrosis, necrosis and hypertrophy were analyzed through immunohistochemistry (IHC). Human cardiomyocytes were exposed to DOXO (200 nM) alone or in combination with Singo (at 10, 25 and 50 µg/mL) for 24 and 48 h. Cell viability and inflammation studies were also performed. In preclinical models, Singo significantly improved ejection fraction and fractional shortening. Reduced expressions of myocardial NLRP3 and NF-kB levels in cardiac tissues were seen in DOXO–Singo mice vs. DOXO (p < 0.05). The myocardial levels of calgranulin S100 and galectin-3 were strongly reduced in DOXO–Singo mice vs. DOXO (p < 0.05). Immunohistochemistry analysis indicates that Singo reduces fibrosis and hypertrophy in the myocardial tissues of mice during exposure to DOXO. In conclusion, in the preclinical model of DOXO-induced cardiotoxicity, Singo is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis.
... In an ex vivo vessel model, the peptide fraction isolated from spirulina showed direct endothelium-dependent vasodilation. This mechanism was proposed to be through a phosphoinositide-3-kinase (PI3K)/AKT (serine/threonine kinase AKT) pathway that converges on nitric oxide release [51]. The peptide induced a significant reduction in BP in vivo [51]. ...
... This mechanism was proposed to be through a phosphoinositide-3-kinase (PI3K)/AKT (serine/threonine kinase AKT) pathway that converges on nitric oxide release [51]. The peptide induced a significant reduction in BP in vivo [51]. Substances, such as the tripeptide lle-Gln-Pro (IQP) present in spirulina also showed antihypertensive activity by inhibiting angiotensin converting enzymes [52]. ...
Article
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The effects of spirulina consumption added in foods were investigated in two crossover clinical trials (n = 13 different healthy adults). In Trial-1 adults consumed cookies with-and-without spirulina (3.12 g per 100 g final product; 2.5 g spirulina per 50 g available carbohydrates) according to glycemic index (GI) methodology. In Trial-2, adults consumed 4 g, 6 g, and 8 g spirulina as beverage diluted in 50 g D-glucose vs. 50 g plain D-glucose. Capillary blood glucose samples were collected at 0, 15, 30, 45, 60, 90, and 120 min and blood pressure (BP) was measured at beginning and end of each visit in both trials. Trial-1: both cookies with and without spirulina provided medium GI values (59 and 60, respectively, on glucose-scale), but no significant differences were found for BP. Trial-2: both 4 g and 8 g spirulina lowered postprandial glucose at 120 min (95% CI: −1.64 to −16.12 and −1.23 to −15.87, respectively). The results explained 29% of variation. Only 8 g spirulina decreased significantly 90–120 min area under the curve (AUC) for glucose and systolic BP (−4%). No differences were found for fasting glucose. Adding spirulina to cookies did not affect glucose responses and BP. Only 8 g provided significantly lower 90–120 min-AUC for glucose and BP compared to 4 g, 6 g-and-D-glucose, indicating advantages to glycemic control and hypertension.
... The raw MS data were analyzed using Protein Discoverer™ Software version 2.5 using the Sequest search engine. The spectra were searched against the Arthrospira platensis and Arabidopsis thaliana databases from UniprotKB [39,40]. Precursor mass tolerance was set to 10 ppm. ...
... Spirulina platensis and Moringa oleifera are important protein sources due to their high nutritional value protein contents, as confirmed by Bradford assay [39] (protein content > 60% w/w). To determine the protein composition of the Arthrospira platensis and Moringa oleifera extracts, a label-free based liquid chromatography-mass spectrometry (LC-MS/MS) proteomic approach was carried out. ...
Article
e24056 Background: Anthracycline and trastuzumab are essential adjuvant therapies for a variety of cancers, particularly breast, and gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Cardioprotective agents used to mitigate cardiotoxicity, such as angiotensin antagonists, angiotensin receptor blockers and beta‐blockers, are often poorly tolerated in these patients due to intravascular volume fluctuations, which are further escalated by the hemodynamic side effects of these agents. Spiruline, Reishi and Moringa are nutaceuticals with anti-inflammatory effects that are currently used in cancer patients to improve quality of life and fatigue. We hypothesize that the combination of Spirulina, Reishi and Moringa could reduce inflammation and cardiotoxicity of anthracyclines and trastuzumab. Methods: Human cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (200 nM) alone or in combination with a formulation composed by Spiruline, Reishi and Moringa (at 10, 25 and 50 µg/ml) for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α were also performed. Results: Spiruline, Reishi and Moringa in combination increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. The nutraceutical formulation reduces intracellular Ca2+ overload (-48,8% vs cells treated only to anticancer drugs; p < 0,001), lipid peroxidation (- 47,2 % compared to cells exposed only to anticancer drugs; p < 0,001). The expression of MyD88 and NLRP3 inflammasome were also reduced (-36,3 and -28,58 % vs cells exposed only to anticancer drugs, respectively; p < 0.001). Notably, Spiruline, Reishi and Moringa increased of 26,3% the production of IL-10 and IL-2. Cytokines involved in cardiotoxicity and chemoresistance were reduced, such as IL-1α and IL-1β (-18,3 and -27,4 % vs DOXO-TRA group), IL-6 (-31,2 % vs DOXO-TRA group) and IL17-α (-27,3 % vs DOXO-TRA group) (p < 0.01 for all). Conclusions: During exposure to doxorubicin and trastuzumab, the combination of Spiruline, Reishi and Moringa exerts cardioprotective and anti-inflammatory effects. Their properties are mediated by the reduction of iCa2+ content that consequently reduces lipid peroxidation and the expression of NLRP3- MyD88. These results indicating the potential use of this nutraceutical formulation in preclinical models of anthracycline and anti HER2 antibodies-mediated cardiotoxicity.
... Due to this result, the effect of Spirulina incubation on the production of endothelial NO was studied. The results demonstrated that the incubation with the Spirulina extract increased the basal and the ACh-induced NO release, as reported in previous studies (Carrizzo et al. 2019;De Freitas Brito et al. 2019;Villalpando et al. 2020). In the aorta of aged rats, the increase in the NO production seems to be linked to the increase of p-eNOS as demonstrated by western blot experiments, although an increase in NO bioavailability cannot been ruled out. ...
... Taking into account that increased oxidative stress, which occurs in vascular ageing, may reduce the effectiveness of the NO/cGMP/cGK axis (Chen et al. 2000;Lin et al. 2001), the analysis of the influence of Spirulina extract on the smooth muscle sensitivity to NO is essential. The results showed that the SNP-induced relaxation was increased by the extract which is in line with studies describing an increased NO involvement in the responses induced by different compounds after Spirulina treatment (De Freitas Brito et al. 2018;Carrizzo et al. 2019). Similarly, to what was found in the aorta from hypertensive rats , the greatest increase in the SNP-induced relaxation after Spirulina incubation was observed at low concentrations of SNP indicating the physiological relevance of that effect. ...
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Context Vascular dysfunction is considered a hallmark of ageing that has been associated with altered vasomotor responses, in which nitric oxide (NO) and reactive oxygen species participate. The consumption of Spirulina extracts, with antioxidant properties, increased recently. Objective This study investigates the effect of Spirulina aqueous extract (SAE) on the vascular function of the aorta from aged rats. Materials and methods Aortic segments from aged male Sprague-Dawley rats (20–22 months old) were exposed to SAE (0.1% w/v, for 3 h) to analyse: (i) the vasodilator response induced by acetylcholine (ACh), by the NO donor sodium nitroprusside (SNP), by the carbon monoxide releasing molecule (CORM) and by the KATP channel opener, cromakalim (CK); (ii) the vasoconstrictor response induced by KCl and noradrenaline (NA); (iii) the production of NO and superoxide anion, and (iv) the expression of the p-eNOS and HO-1 proteins. Results Incubation with SAE increased the expression of p-eNOS (1.6-fold) and HO-1 (2.0-fold), enhanced NO release (1.4-fold in basal and 1.9-fold in ACh-stimulated conditions) while decreased the production of superoxide (0.7-fold). SAE also increased the sensitivity (measured as pEC50) to ACh (control: −7.06 ± 0.11; SAE: −8.16 ± 0.21), SNP (control: −7.96 ± 0.16; SAE: −9.11 ± 0.14) and CK (control: −7.05 ± 0.39; SAE: −8.29 ± 0.53), and potentiated the response to KCl (1.3-fold) and to NA (1.7-fold). Conclusion The antioxidant properties of SAE improved the vasomotor responses of aorta from aged rats. These results may support the use of Spirulina as a protection against vascular dysfunction.
... This mechanism may be through a phosphoinositide-3-kinase (PI3K)/AKT (serine/threonine kinase AKT) pathway that converges on nitric oxide (NO) release [20]. Moreover, this peptide induced a significant reduction in blood pressure in vivo [20]. ...
... This mechanism may be through a phosphoinositide-3-kinase (PI3K)/AKT (serine/threonine kinase AKT) pathway that converges on nitric oxide (NO) release [20]. Moreover, this peptide induced a significant reduction in blood pressure in vivo [20]. In a randomized, double-blind, placebo-controlled trial, treatment with S. maxima resulted in significant reductions in blood pressure in 40 Caucasian patients with hypertension (with no other CV risk factors) [21]. ...
Article
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The nutritional and health benefits of Spirulina have been known for thousands of years. Spirulina has been grown and harvested by ancient cultures since written history, and likely before. Much anecdotal evidence has been put forth, and more recently, evidence-based scientific research confirms many of Spriluina's nutritional and health benefits. However, such benefits are far-reaching (and only recently researched). In the commercial exuberance surrounding Spirulina, sparse research regarding any potential toxicity or adverse effects has been undertaken. This review-as a miscellany-highlights notable benefits, potential toxicity, and adverse effects in the human consumption of Spirulina. It is hoped that this review will provide the reader, especially those new to Spirulina, with an introduction and overview regarding the benefits and detriments of Spirulina, which will act as a springboard to more in-depth research regarding Spirulina as a vital nutritional and medicinal source for humans-needed now more than ever.
... Spirulina biomass has a high protein content, which is 60-70% (w w -1 , dry basis), depending on the species (Vo, Ngo, and Kim 2015). When protein is hydrolyzed, it can generate bioactive peptides, which bring health benefits to humans and animals, and exhibit different biological activities, such as antibacterial (Sun et al. 2016), antitumor (Wang and Zhang 2016), antioxidant (Safitri, Herawati, and Hsu 2017), anti-diabetes (Hu et al. 2019), ACE (angiotensin-converting-enzyme), inhibitory , iron chelating (Kim et al. 2014), antihypertensive (Carrizzo et al. 2019;) and immunomodulatory ones. ...
... Bioactive peptides can be generated by enzymatic hydrolysis Kim et al. 2014), by simulated gastrointestinal digestion in vitro (Carrizzo et al. 2019;Heo et al. 2017), by fermentation of Spirulina biomass with probiotics microorganisms ) and by extraction with physical methods (Hu et al. 2019). ...
Chapter
Microalgae usually called “Spirulina” in the literature and in commercial packages have been studied as potential sources of protein for food and feed supplementation. These microalgae are produced industrially worldwide, being recognized as GRAS (Generally Recognized as Safe) by the Food and Drug Administration (USA) and accepted by the European Union for human consumption. Apart from a high protein content and balanced amino acid composition, its biomass contains compounds with antioxidant, anti-inflammatory, anti-tumor, anti-viral and anti-microbial activities. Some of these compounds have been determined to boost the immune system and prevent diseases such as hyperglycemia, cancer, diabetes, hypertension, cardiovascular and respiratory disorders. It has also been suggested that the supplementation with Spirulina biomass and/or its extracts could help immune systems to fight different viral infections, including those by SARS-CoV2, the etiologic agent of COVID-19. This immunity boosting activity has been related to the presence of some polysaccharides, carotenoids, phycobiliproteins, fatty acids and biopeptides in the biomass. In this context, this chapter will address the boosting effect of the immune system by Spirulina exploring its antiviral activity and respective mechanisms. The applications of the biomass as a supplement and nutraceuticals production will be also address.
... Spirulina biomass has a high protein content, which is 60-70% (w w -1 , dry basis), depending on the species (Vo, Ngo, and Kim 2015). When protein is hydrolyzed, it can generate bioactive peptides, which bring health benefits to humans and animals, and exhibit different biological activities, such as antibacterial (Sun et al. 2016), antitumor (Wang and Zhang 2016), antioxidant (Safitri, Herawati, and Hsu 2017), anti-diabetes (Hu et al. 2019), ACE (angiotensin-converting-enzyme), inhibitory , iron chelating (Kim et al. 2014), antihypertensive (Carrizzo et al. 2019;) and immunomodulatory ones. ...
... Bioactive peptides can be generated by enzymatic hydrolysis Kim et al. 2014), by simulated gastrointestinal digestion in vitro (Carrizzo et al. 2019;Heo et al. 2017), by fermentation of Spirulina biomass with probiotics microorganisms ) and by extraction with physical methods (Hu et al. 2019). ...
... Differently from this approach, and following our previous study in which we have identified a novel bioactive pentapeptide isolated from buffalo ricotta cheese [38], we applied in vitro simulated human GID [39], using endogenous enzymes to mimic a physiological process on buffalo ice-cream matrix. This technique owns enormous advantages since it leads to the generation of resistant to digestion products after oral administration and allows identifying more-potent bioactive products [16]. We identified and characterized the most abundant peptide's vascular effect through this experimental approach, namely PG1 (αS1-casein, f146-150, QKEPM) obtained from the GID of buffalo ice-cream, which sequence, so far, has never been reported. ...
... Our results suggested a moderate intestinal absorption of peptide mainly through a passive diffusion mechanism. To assess its possible in vivo efficacy, we employed the Ang II-induced model of hypertension, which mimics the pathological characteristics of human hypertension, including vascular dysfunction [16]. As expected, while the chronic release of Ang II induced an increase in both systolic and diastolic blood pressure, daily oral administration of PG1 completely restored normal blood pressure levels. ...
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Background: Arterial hypertension is the most important risk factor for cardiovascular diseases, myocardial infarction, heart failure, renal failure and peripheral vascular disease. In the last decade, milk-derived bioactive peptides have attracted attention for their beneficial cardiovascular properties. Methods: Here, we combined in vitro chemical assay such as LC-MS/MS analysis of buffalo ice cream, ex vivo vascular studies evaluating endothelial and smooth muscle responses using pressure myograph, and translational assay testing in vivo the vascular actions of PG1 administration in murine models. Results: We demonstrate that a novel buffalo ice-cream-derived pentapeptide "QKEPM", namely PG1, is a stable peptide that can be obtained at higher concentration after gastro-intestinal digestions (GID) of buffalo ice-cream (BIC). It owns potent vascular effect in counteract the effects of angiotensin II-evoked vasoconstriction and high blood pressure levels. Its effects are mediated by the inhibitory effect on AT1 receptor leading to a downregulation of p-ERK½/Rac1-GTP and consequent reduction of oxidative stress. Conclusions: These results strongly candidate PG1, as a novel bioactive peptide for the prevention and management of hypertension, thus expanding the armamentarium of preventive strategies aimed at reducing the incidence and progression of hypertension and its related cardiovascular complications.
... It is not significantly related to the patient's sex, age, tumor diameter, smoking history, hypertension history, and blood lipid levels, but is closely related to AAA occurrence. 36 Recent studies have shown abnormal activation of the PI3K/AKT/mTOR pathway in AAA, 37 and inhibiting this pathway can suppress the occurrence and development of AAA. 38 This study showed that the PI3K/AKT/mTOR signaling pathway was activated in the aneurysm tissues of AAA rats. ...
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Objective: Abdominal aortic aneurysms (AAA) are a common critical cardiovascular disease with high morbidity and mortality rates. Quercetin, a flavonoid and a traditional Chinese medicinal ingredient commonly found in vegetables and fruits, has a favorable inhibitory effect on experimental aneurysms without side effects. This study aimed to model elastase AAA and investigate the mechanism of action of quercetin in alleviating AAA. Methods: Quercetin was administered at a dose of 60 mg/kg once daily starting on the day of AAA induction for 5 weeks. The therapeutic effect of quercetin on AAA was demonstrated using biochemical assays, observation of pathological tissue sections, Elastic Van Gieson staining, immunohistochemistry, molecular docking simulations, and Western blot protein validation. Results: Our study showed that quercetin treatment significantly alleviated abdominal aortic vessel wall dilatation, elastin degradation and adhesion to surrounding tissues caused by elastase. Additionally, quercetin significantly inhibited the mRNA and protein expression of the receptor for advanced glycation end products(RAGE)/ phosphatidylinositol 3-kinase (PI3K)/ phosphatidylinositol 3-kinase (AKT) / mammlian target of rapamycin (mTOR) pathway. Conclusion: Quercetin can alleviate abdominal aortic injury caused by elastase via RAGE/PI3K/AKT/mTOR and provide experience in clinical use.
... Recent work by our research group has demonstrated that a single decameric peptide called "SP6" (GIVAGDVTPI), derived from the gastrointestinal digestion (GID) of Spirulina, can lead to dose-dependent vasorelaxation in ex vivo mice vessels. In addition, this peptide can be effective as a blood-pressure-reducing agent by increasing PI3K/Akt/eNOS signaling, leading to the release of nitric oxide (NO), a well-known vasodilatation metabolite, whose bioavailability and signaling pathway are impaired in individuals with hypertension [53]. ...
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In recent decades, as a result of rising mortality rates due to cardiovascular diseases (CVDs), there has been a growing urgency to find alternative approaches to conventional pharmaceutical treatment to prevent the onset of chronic diseases. Arthrospira platensis, commonly known as Spirulina, is a blue-green cyanobacterium, classified as a “superfood”, used worldwide as a nutraceutical food supplement due to its remarkable nutritional value, lack of toxicity, and therapeutic effects. Several scientific studies have evaluated the cardioprotective role of Spirulina. This article presents a comprehensive review of the therapeutic benefits of Spirulina in improving cardio- and cerebrovascular health. It focuses on the latest experimental and clinical findings to evaluate its antihypertensive, antidiabetic, and antihyperlipidemic properties. The objective is to highlight its potential in preventing and managing risk factors associated with cardiovascular disease (CVD).
... In our experimental setting, an additional contribution to superoxide production came from uncoupled eNOS since pretreatment with the NOS inhibitor markedly reduced C2CD4B-induced ROS production. Although activation of the PI3K/Akt pathway is critical for maintaining vascular tone and endothelial integrity [39,40], previous studies by Sheu et al. [28] reported that, via a PI3K/Akt-dependent pathway, hyperglycemic conditions may cause ROS generation in HUVECs. ...
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High glucose–induced endothelial dysfunction is an important pathological feature of diabetic vasculopathy. While genome-wide studies have identified an association between type 2 diabetes mellitus (T2DM) and increased expression of a C2 calcium-dependent domain containing 4B (C2CD4B), no study has yet explored the possible direct effect of C2CD4B on vascular function. Vascular reactivity studies were conducted using a pressure myograph, and nitric oxide and oxidative stress were assessed through difluorofluorescein diacetate and dihydroethidium, respectively. We demonstrate that high glucose upregulated both mRNA and protein expression of C2CD4B in mice mesenteric arteries in a time-dependent manner. Notably, the inhibition of C2CD4B expression by genetic knockdown efficiently prevented hyperglycemia–induced oxidative stress, endothelial dysfunction, and loss of nitric oxide (NO) bioavailability. Recombinant C2CD4B evoked endothelial dysfunction of mice mesenteric arteries, an effect associated with increased reactive oxygen species (ROS) and decreased NO production. In isolated human umbilical vein endothelial cells (HUVECs), C2CD4B increased phosphorylation of endothelial nitric oxide synthase (eNOS) at the inhibitory site Thr495 and reduced eNOS dimerization. Pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and PKCα effectively attenuated oxidative stress, NO reduction, impairment of endothelial function, and eNOS uncoupling induced by C2CD4B. These data demonstrate, for the first time, that C2CD4B exerts a direct effect on vascular endothelium via a phosphoinositide 3-kinase (PI3K)/Akt/PKCα–signaling pathway, providing a new perspective on C2CD4B as a promising therapeutic target for the prevention of oxidative stress in diabetes–induced endothelial dysfunction.
... The dysfunction or inhibition of eNOS causes NO unavailability and impairs endothelium-dependent vascular relaxation, further exacerbating the progression of hypertension. [6][7][8][9][10][11] The major cause of eNOS dysfunction related to hypertension is uncoupling; uncoupled eNOS alternatively generates superoxide anions (O 2 À ) rather than NO. 6,12 In turn, NADPH oxidase-mediated oxidative stress is a major trigger for eNOS uncoupling and endothelial dysfunction. ...
Article
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Current antihypertensive options still incompletely control blood pressure, suggesting the existence of uncovered pathogenic mechanisms. Here, whether cytokine-like protein family with sequence similarity 3, member D (FAM3D) is involved in hypertension etiology is evaluated. A case-control study exhibits that FAM3D is elevated in patients with hypertension, with a positive association with odds of hypertension. FAM3D deficiency significantly ameliorates angiotensin II (AngII)-induced hypertension in mice. Mechanistically, FAM3D directly causes endothelial nitric oxide synthase (eNOS) uncoupling and impairs endothelium-dependent vasorelaxation, whereas 2,4-diamino-6-hydroxypyrimidine to induce eNOS uncoupling abolishes the protective effect of FAM3D deficiency against AngII-induced hypertension. Furthermore, antagonism of formyl peptide receptor 1 (FPR1) and FPR2 or the suppression of oxidative stress blunts FAM3D-induced eNOS uncoupling. Translationally, targeting endothelial FAM3D by adeno-associated virus or intraperitoneal injection of FAM3D-neutralizing antibodies markedly ameliorates AngII- or deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Conclusively, FAM3D causes eNOS uncoupling through FPR1- and FPR2-mediated oxidative stress, thereby exacerbating the development of hypertension. FAM3D may be a potential therapeutic target for hypertension.
... This can provide a better understanding of BPs role in health and disease. Although several studies including in vitro (Gomez et al., 2019), in vivo (Carrizzo et al., 2019), and meta-analysis (Liao et al., 2021) have been done to evaluate the short-term effects of BPs on human health, there are so limited studies on their long-term effects. Observational studies (cohort and case-control) are commonly used for investigation of the long-term effects of food ingredients. ...
Chapter
Food-derived peptides are digestion-resistant and released from parent proteins during the digestion process. Some of food-derived peptides called bioactive peptides have beneficial effects on human health. In this regard, this chapter is devoted to describe the available methods for identification of food-derived peptides and BPs. So, the following sections are described in this chapter: (1) methods of protein digestion, (2) methods of isolation and characterization of food-derived peptides, and (3) methods of function assessment for food-derived peptides.
... This can provide a better understanding of BPs' role in health and disease. Different types of studies including in vitro (Kwon et al., 2011), in vivo (Carrizzo et al., 2019), and meta-analysis (Fekete et al., 2015) have been conducted to evaluate the short-term effects of BPs on human health. However, there are so limited studies on the long-term effects of BPs. ...
Chapter
The in silico methods for predicting bioactive peptides are economical and time-saving. Also, in silico simulation prevents additional costs in in vitro experiments. The in silico BPs’ prediction is performed according to the quantitative structure–activity relationship principles. Selection of the appropriate enzyme(s) for digestion is the most important step in BPs’ prediction. The stages for BPs’ prediction include (1) selection of a food protein, (2) obtaining amino acid sequence of the selected protein, (3) enzymatic digestion, and (4) searching the obtaining fragments throughout the BP databases such as BIOPEP-UMW database. Bioactivity of the fragments that are not registered in the databases is predicted using molecular docking simulation.
... AKT1 is the center of the PI3K-AKt signaling pathway, and inhibition of its overactivation can alleviate high-fatdietinduced atherosclerosis in ApoE + mice [64]. It participates in various biological processes, such as cell metabolism, proliferation, and survival, by regulating various downstream signaling molecules [65]. e downstream targets of the PI3K-AKt pathway include eNOS, NF-κB, and GSK-3β. ...
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This study aimed to explore the mechanism of Yangxin Tongmai decoction (YXTMD) in the treatment of coronary heart disease (CHD) with blood stasis syndrome (BSS) using network pharmacology and molecular docking, and to verify these results through clinical trials. The active compounds of YXTMD were identified using the Traditional Chinese Medicine Systems Pharmacology database, and the targets of the active compounds were predicted using the SwissTarget Prediction database. The targets of CHD and BSS were predicted using the GeneCards, OMIM, PharmGKB, TTD, and DrugBank databases. The common targets of “herb-disease-phenotype” were obtained using a Venn diagram, then used Cytoscape software 3.8.2 and its plug-in CytoNCA and STRING database to construct the “herb active compounds-common target” and protein–protein interaction networks. R language software and bioconductor plug-in were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. AutoDock was used for the molecular docking analysis. Finally, clinical trials were conducted to confirm the results of network pharmacology. Eighty-three active components were obtained, and the core active components were 5,7,4′-trimethoxyflavone, tetramethoxyluteolin, isosinensetin, sinensetin, and 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one. A total of 140 common targets were identified, and the core targets were EGFR, VEGFA, AKT1, STAT3, TP53, ERBB2, and PIK3CA. Biological processes identified by the GO analysis primarily involved wound healing, regulation of body fluid levels, and vascular process in circulatory system. The cellular components were primarily located in the membrane raft, membrane microdomain, and plasma membrane raft. The primary molecular functions were activity of transmembrane receptor protein kinase, transmembrane receptor protein tyrosine kinase, and protein tyrosine kinase. KEGG analysis showed that the PI3K-Akt signaling pathway was closely related to the treatment of CHD with BSS by YXTMD. Molecular docking results showed that the core active components had a good binding activity with the core targets. The clinical trial results showed that YXTMD improved the BSS scores and decreased the serum levels of total cholesterol and low-density lipoprotein cholesterol. Moreover, the levels of PI3k and AKt mRNA were upregulated and the levels of GSK-3β mRNA were downregulated. YXTMD has multicomponent, multitarget, and multipathway effects in the treatment of CHD with BSS, and its mechanism of action may involve activation of the PI3K-AKt signaling pathway, downregulation of GSK-3β, and mediation of in vivo lipid metabolism-based metabolic processes.
... From their investigation, they concluded that the bioactive components responsible for this inhibitory activity were oligopeptides, FDGIP (FP-5), and AIDPVRA (AA-7). Although this is the first reported study utilising protein peptides from C. lentillifera, there are many other similar studies sourcing protein peptides from different seaweed species such as Undaria pinnatifida, Saccharina japonica, Sargassum fusiforme, S. maclurei (Ochrophyta), Gracilariopsis lemaneiformis, Mazzaella japonica, Palmaria palmata, Pyropia/Porphyra spp., Bangia fusco-purpurea (Rhodophyta), Ulva rigida, U. chlatrata, and U. intestinalis (Chlorophyta) [93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108]. ...
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Caulerpa lentillifera is a type of green seaweed widely consumed as a fresh vegetable, specifically in Southeast Asia. Interestingly, this green seaweed has recently gained popularity in the food sector. Over the last two decades, many studies have reported that C. lentillifera is rich in polyunsaturated fatty acids, minerals, vitamins, and bioactive compounds that contribute many health benefits. On the other hand, there is currently hardly any article dedicated specifically to C. lentillifera regarding nutritional composition and recent advancements in its potential health benefits. Hence, this study will summarise the findings on the nutritional content of C. lentillifera and compile recently discovered beneficial properties throughout the past decade. From the data compiled in this review paper, it can be concluded that the nutrient and phytochemical profile of C. lentillifera differs from one region to another depending on various external factors. As a result, this paper will offer researchers the groundwork to develop food products based on C. lentillifera. The authors of this paper are hopeful that a more systematic review could be done in the future as currently, existing data is still scarce.
... The results revealed that there were significant changes in lipid metabolism. It has been reported in the literature that algae extracts could modulate the gut microbiome and metabolic diseases such as diabetes [8,70], hepatic metabolism disorder [71], and hypertension [23]. These studies have shown that algae extracts were a potential therapeutic dietary supplement for metabolic disease. ...
Article
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Phycobiliproteins (derived from Arthrospira platensis) bioactive peptide extracts (PPE) possess multiple pharmacological effects in the mitigation of human metabolic disorders. The role of PPE in the treatment of diet-induced obesity and the understanding of the underlying mechanism between the gut microbiome and metabolic blood circulation for obese patients remains poorly understood. In this study, we showed that PPE attenuated obesity by reducing body weight, and ameliorated glucose and lipid indexes in serum. In particular, PPE is postulated to mitigate liver steatosis and insulin resistance. On the other hand, dietary treatment with PPE was found to “reconfigure” the gut microbiota in the way that the abundances were elevated for Akkermansia_muciniphila, beneficial Lactobacillus and Romboutsia, SCFA-producing species Faecalibacterium prausnitzii, Lachnospiraceae_bacterium, Clostridiales_bacterium, probiotics Clostridium sp., Enterococcus faecium, and Lactobacillus_johnsonii, while the abundance of Firmicutes was reduced and that of Bacteroidetes was increased to reverse the imbalance of Firmicutes/Bacteroidetes ratio. Finally, the metabolomics of circulating serum using UHPLC-MS/MS illustrated that PPE supplementation indeed promoted lipid metabolism in obese rats. As summary, it was seen that PPE reprogrammed the cell metabolism to prevent the aggravation of obesity. Our findings strongly support that PPE can be regarded as a potential therapeutic dietary supplement for obesity.
... The research group finds this as a green light for further investigation to prove it in preventing and treating multifactorial cardiovascular diseases [106]. According to Carrizzo et al. [107], 'SP6 (GIVAGDVTPI) exerted direct endothelium-dependent vasodilation of ex vivo vessels, an effect occurring via a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt) pathway converging on NO release'. ...
Article
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Arthrospira platensis (A. platensis) aqueous extract has massive amounts of natural products that can be used as future drugs, such as C-phycocyanin, allophycocyanin, etc. This extract was chosen because of its high adaptability, which reflects its resolute genetic composition. The proactive roles of cyanobacteria, particularly in the medical field, have been discussed in this review, including the history, previous food and drug administration (FDA) reports, health benefits and the various dose-dependent therapeutic functions that A. platensis possesses, including its role in fighting against lethal diseases such as cancer, SARS-CoV-2/COVID-19, etc. However, the remedy will not present its maximal effect without the proper delivery to the targeted place for deposition. The goal of this research is to maximize the bioavailability and delivery efficiency of A. platensis constituents through selected sites for effective therapeutic outcomes. The solutions reviewed are mainly on parenteral and tablet formulations. Moreover, suggested enteric polymers were discussed with minor composition variations applied for better storage in high humid countries alongside minor variations in the polymer design were suggested to enhance the premature release hindrance of basic drugs in low pH environments. In addition, it will open doors for research in delivering active pharmaceutical ingredients (APIs) in femtoscale with the use of various existing and new formulations. Abbrevations: SDGs; Sustainable Development Goals, IL-4; Interleukin-4, HDL; High-Density Lipoprotein, LDL; Low-Density Lipoprotein, VLDL; Very Low-Density Lipoprotein, C-PC; C-Phycocyanin, APC; Allophycocyanin, PE; Phycoerythrin, COX-2; Cyclooxygenase-2, RCTs; Randomized Control Trials, TNF-α; Tumour Necrosis Factor-alpha, γ-LFA; Gamma-Linolenic Fatty Acid, PGs; Polyglycans, PUFAs: Polyunsaturated Fatty Acids, NK-cell; Natural Killer Cell, FDA; Food and Drug Administration, GRAS; Generally Recognized as Safe, SD; Standard Deviation, API; Active Pharmaceutical Ingredient, DW; Dry Weight, IM; Intramuscular, IV; Intravenous, ID; Intradermal, SC; Subcutaneous, AERs; Adverse Event Reports, DSI-EC; Dietary Supplement Information Executive Committee, cGMP; Current Good Manufacturing Process, A. platensis; Arthrospira platensis, A. maxima; Arthrospira maxima, Spirulina sp.; Spirulina species, Arthrospira; Spirulina, Tecuitlatl; Spirulina, CRC; Colorectal Cancer, HDI; Human Development Index, Tf; Transferrin, TfR; Transferrin Receptor, FR; Flow Rate, CPP; Cell Penetrating Peptide, SUV; Small Unilamenar Vesicle, LUV; Large Unilamenar Vesicle, GUV; Giant Unilamenar Vesicle, MLV; Multilamenar Vesicle, COVID-19; Coronavirus-19, PEGylated; Stealth, PEG; Polyethylene Glycol, OSCEs; Objective Structured Clinical Examinations, GI; Gastrointestinal Tract, CAP; Cellulose Acetate Phthalate, HPMCP, Hydroxypropyl Methyl-Cellulose Phthalate, SR; Sustained Release, DR; Delay Release, Poly(MA-EA); Polymethyl Acrylic Co-Ethyl Acrylate, f-DR L-30 D-55; Femto-Delay Release Methyl Acrylic Acid Co-Ethyl Acrylate Polymer, MW; Molecular Weight, Tg; Glass Transition Temperature, SN2; Nucleophilic Substitution 2, EPR; Enhance Permeability and Retention, VEGF; Vascular Endothelial Growth Factor, RGD; Arginine-Glycine-Aspartic Acid, VCAM-1; Vascular Cell Adhesion Molecule-1, P; Coefficient of Permeability, PES; Polyether Sulfone, pHe; Extracellular pH, ζ-potential; Zeta potential, NTA; Nanoparticle Tracking Analysis, PB; Phosphate Buffer, DLS; Dynamic Light Scattering, AFM; Atomic Force Microscope, Log P; Partition Coefficient, MR; Molar Refractivity, tPSA; Topological Polar Surface Area, C log P; Calculated Partition Coefficient, CMR; Calculated Molar Refractivity, Log S; Solubility Coefficient, pka; Acid Dissociation Constant, DDAB; Dimethyl Dioctadecyl Ammonium Bromide, DOPE;Dioleoylphosphatidylethanolamine, GDP; Good Distribution Practice, RES; Reticuloendothelial System, PKU; Phenylketonuria, MS; Multiple Sclerosis, SLE; Systemic Lupus Erythematous, NASA; National Aeronautics and Space Administration, DOX; Doxorubicin, ADRs; Adverse Drug Reactions, SVM; Support Vector Machine, MDA; Malondialdehyde, TBARS; Thiobarbituric Acid Reactive Substances, CRP; C-Reactive Protein, CK; Creatine Kinase, LDH; Lactated Dehydrogenase, T2D; Type 2 Diabetes, PCB; Phycocyanobilin, PBP; Phycobiliproteins, PEB; Phycoerythrobilin, DPP-4; Dipeptidyl Peptidase-4, MTT; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, IL-2; Interleukin-2, IL-6; Interleukin-6, PRISMA; Preferred Reporting Items for Systematic Reviews and Meta-Analyses, STATA; Statistics, HepG2; Hepatoblastoma, HCT116; Colon Cancer Carcinoma, Kasumi-1; Acute Leukaemia, K562; Chronic Leukaemia, Se-PC; Selenium-Phycocyanin, MCF-7; Breast Cancer Adenocarcinoma, A375; Human Melanoma, RAS; Renin-Angiotensin System, IQP; Ile-Gln-Pro, VEP; Val-Glu-Pro, Mpro; Main Protease, PLpro; Papin-Like Protease, BMI; Body Mass Index, IC50; Inhibitory Concentration by 50%, LD50; Lethal Dose by 50%, PC12 Adh; Rat Pheochromocytoma Cells, RNS; Reactive Nitrogen Species, Hb1Ac; hemoglobin A1c.
... The mechanism of hypertension is not clear. One possible explanation may be involving PI3K/ AKT/eNOS-dependent pathway [41]. ...
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Background Rapid progress over the last decade has added numerous agents targeting specific cellular signaling pathways to the treatment armamentarium for advanced cancer. However, many of these agents can cause hypertension resulting in major adverse cardiovascular event. Methods and results A systematic literature search was performed on the databases PubMed and Google Scholar for papers published in English until December 2020. This review summarizes the risk, mechanism, diagnosis, and management of hypertension in cancer patients undergoing targeted therapy. The risk and pathogenesis of hypertension vary widely with different classes of targeted agents. Currently there is a paucity of data investigating optimal management of hypertension with targeted therapy. A practical approach is discussed with a focus on the goal of blood pressure control as well as drug selection based on the mechanism of hypertension in the context of advanced cancer, treatment toxicity, comorbidity, and drug-drug interactions. This review also discusses many studies that have explored hypertension as a biomarker for cancer treatment efficacy and as a pharmacodynamic biomarker to titrate drug dose. Conclusions The diversity of targeted agents has provided important insights into the pathogenesis of hypertension in cancer patients. The underlying mechanism may provide a guidance to the management of hypertension. Further studies are needed to investigate optimal treatment and hypertension as a biomarker for cancer treatment.
... This hypothesis relies on the fact that, in simulated human gastrointestinal digestion of Spirulina (with about 10% of CPC), tripeptides and decapeptides are produced with vasoactive action through the PI3K/AKT/eNOS pathway. In addition, one of the peptides (YNKFPY) with mild vasorelaxant activity from hydrolysis of Spirulina was associated with the α-chain [34][35][36]. Therefore, this hypothesis must be further studied using the simulated human gastrointestinal digestion of CPC to prove the antihypertensive effect of its hydrolyzed peptides. ...
Article
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C-phycocyanin (CPC) is an antihypertensive that is not still wholly pharmacologically described. The aim of this study was to evaluate whether CPC counteracts endothelial dysfunction as an antihypertensive mechanism in rats with 5/6 nephrectomy (NFx) as a chronic kidney disease (CKD) model. Twenty-four male Wistar rats were divided into four groups: sham control, sham-treated with CPC (100 mg/Kg/d), NFx, and NFx treated with CPC. Blood pressure was measured each week, and renal function evaluated at the end of the treatment. Afterward, animals were euthanized, and their thoracic aortas were analyzed for endothelium functional test, oxidative stress, and NO production. 5/6 Nephrectomy caused hypertension increasing lipid peroxidation and ROS production, overexpression of inducible nitric oxide synthase (iNOS), reduction in the first-line antioxidant enzymes activities, and reduced-glutathione (GSH) with a down-expression of eNOS. The vasomotor response reduced endothelium-dependent vasodilation in aorta segments exposed to acetylcholine and sodium nitroprusside. However, the treatment with CPC prevented hypertension by reducing oxidative stress, NO system disturbance, and endothelial dysfunction. The CPC treatment did not prevent CKD-caused disturbance in the antioxidant enzymes activities. Therefore, CPC exhibited an antihypertensive activity while avoiding endothelial dysfunction.
... They are absorbable via the digestive tract and induce various potential biological functions (10) such as anti-diabetic (11), anti-hypertensive (12), antimicrobial (13), anticancer (14), and cholesterol-lowering effects (15). Although several studies have investigated the short-term beneficial role of diary-originated BPs on human health, including a meta-analysis of randomized control trials (16), and various studies have been conducted in different settings such as In Vitro (17) and In Vivo (18), there is a significant gap in long-term research on the beneficial health effects of the abovementioned BPs. Researchers commonly conduct case-control and cohort studies to investigate the long-term effects of the intake of food components on health outcomes (19). ...
Article
Bioactive peptides (BPs) content of dairy products is suggested to be a significant ingredient for reducing breast cancer (BC) risk. There is no observational study regarding the correlation between BPs and the risk of chronic disease because BPs’ content of food items has not been evaluated in any study. The goal of the current study was to assess the association of dairy-originated BPs with BC risk. One hundred thirty-four women with BC and 267 cancer-free controls were selected from referral hospitals in Tehran, Iran. The development of an in-silico model for estimation of the bioactive and digestion-resistant peptides content of dairy products was done in our previous research. The risk assessment for BPs and BC association was performed across the tertiles of the peptide’s intake. Odds ratios (OR) were calculated by logistic regression. The negative association of all bioactive and digestion-resistant peptides except for peptides with high hydrophilicity and low bioactivity was seen in all models. In PR-negative subjects only the association of total dairy intake (OR: 0.61; 95% CI: 0.26-1.45; P for trend: 0.276), peptides with low bioactivity (OR: 0.40; 95% CI: 0.16-1.02; P for trend: 0.0.052), antidiabetic peptides (OR: 0.42; 95% CI: 0.17-1.05; P for trend: 0.0.062) and di-peptides (OR: 0.42; 95% CI: 0.17-1.05; P for trend: 0.0.062) were not significant in the final model. Also, no significant association between ER-negative subjects and total dairy intake (OR: 0.41; 95% CI: 0.16-1.07; P for trend: 0.0.068) was noted. Our findings deduced that milk-derived BPs negatively associate with the risk of ER/PR/HER2 negative BC among Iranian women. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.2009884
... In mouse experiments, VHW can reduce the systolic blood pressure of 28 spontaneously hypertensive rats (5 mg/kg) to 50 mmHg (p < 0.05). Carrizzo et al. (2019) reported that, in an experimental model of arterial hypertension, peptide SP6 from Spirulina platensis exerted an antihypertensive effect, improving endothelial vasorelaxation associated with enhanced serum nitrite levels. It may cause via a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt) pathway converging on nitric oxide release. ...
Article
Microalgae is an autotrophic organism with fast growth, short reproduction cycle, and strong environmental adaptability. In recent years, microalgae and the bioactive ingredients extracted from microalgae are regarded as potential substitutes for raw materials in the pharmaceutical and the cosmetics industry. In this review, the characteristics and efficacy of the high-value components of microalgae are discussed in detail, along with the sources and extraction technologies of algae used to obtain high-value ingredients are reviewed. Moreover, it also includes the latest trends in biotherapy based on high-value algae extracts as materials. In addition, the excellent antioxidant properties of microalgae derivatives are regarded as potential substitutes for safe and environmentally friendly cosmetic production. Only by further studying the mechanism of microalgae bioactive compounds and conducting reasonable clinical trials can safe and compliant microalgae-derived drugs or cosmetics be marketed.
... Oxidative stress connected to endothelial damage, contributing to a decrease in nitric oxide synthase (NOs), and decreased vasoconstriction has been reported in hypertension [15]. In mice, the decameric peptide of Spirulina platensis decreases blood pressure levels through a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt)/eNOS (endothelial NO synthase) -dependent mechanism [33]. Martínez-Sámano et al. proved the antioxidative properties of Spirulina in SBP-they observed an increase in glutathione peroxidase (GPx) activity and oxidized glutathione (GSSG) concentrations (p < 0.05) [15]. ...
Article
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Spirulina is a microalga that presents various important pro-health properties, for instance lowering blood pressure in the research. The study aims to appraise the efficacy of Spirulina administration on systolic (SBP) and diastolic blood pressure (DBP). Randomized controlled trials (RCTs) were retrieved by a systematic search of PubMed, Web of Science, and the Cochrane Library databases from inception to June 2021 according to a standardized protocol. The effect size of each study was counted from mean and standard deviation before and after the intervention and shown as Un-standardized mean difference and 95% confidence interval. Sensitivity analyses were performed. Meta-analysis on 5 RCTs with 230 subjects was eligible. The amount of Spirulina ranged from 1 to 8 g per day, and intervention durations ranged from 2 to 12 weeks. Data analysis indicated that Spirulina supplementation led to a significant lowering of SBP (Mean Difference (MD): −4.59 mmHg, 95% Confidence Interval (CI): −8.20 to −0.99, I square statistic (I2) = 65%) and significant lowering of DBP (MD: −7.02 mmHg, CI: −8.86 to −5.18, I2 = 11%), particularly in a subgroup of hypertensive patients. Spirulina administration might have a supportive effect on the prevention and treatment of hypertension. More exact randomized controlled trials are needed to clarify the effect of Spirulina supplementation on blood pressure.
... In recent years, epidemiological studies have identified a relationship between diet and CVD; though there is still considerable scientific uncertainty about the relationship between specific dietary components and cardiovascular risk [5,6]. One promising dietary group for cardiovascular protection are polyphenols, especially flavonoids, as they are inversely associated with blood pressure and a lower risk of hypertension [7]. ...
Article
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In recent years, epidemiological studies have identified a relationship between diet and cerebro–cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865® and constituent single anthocyanins to characterize vasomotor responses; immunofluorescence analysis with dichlorofluorescein diacetate and dihydroethidium were used to evaluate nitric oxide and oxidative stress; lucigenin assay was used to measure NADPH oxidase activity; and gel electrophoresis and immunoblotting were used to dissect the molecular mechanisms involved. We demonstrated that Healthberry 865® exerts an important vasorelaxant effect of resistance artery functions in mice. Its action is mediated by nitric oxide release through the intracellular signaling PI3K/Akt. Moreover, behind its capability of modulating vascular tone, it also exerts an important antioxidant effect though the modulation of the NADPH oxidase enzyme. Interestingly, its cardiovascular properties are mediated by the selective action of different anthocyanins. Finally, the exposure of human dysfunctional vessels to Healthberry 865® significantly reduces oxidative stress and improves NO bioavailability. Although further investigations are needed, our data demonstrate the direct role of Healthberry 865® on the modulation of vasculature, both on the vasorelaxation and on oxidative stress; thus, supporting the concept that a pure mixture of anthocyanins could be helpful in preventing the onset of vascular dysfunction associated with the development of CVD.
... Carrizzo y otros, (45) demostraron que la matriz de Spirulina platensis procesada in vitro por digestión gastrointestinal simulada induce vaso relajación mediada por óxido nítrico endotelial directo en los vasos de resistencia en ratones. En un modelo experimental de HTA, el péptido SP6 aislado de la espirulina ejerció un efecto antihipertensivo, al mejorar la relajación endotelial del vaso asociada con niveles elevados de nitrito en suero. ...
Article
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Introducción: La Spirulina platensis es una cianobacteria planctónica filamentosa, que contiene un espectro natural de mezclas de pigmentos de caroteno, xantofila y ficocianina, con actividad antioxidante y la posibilidad de inducir un mejor control de la glucemia en las personas con diabetes mellitus. Objetivo: Describir los efectos del uso del producto logrado a partir de la bacteria Spirulina platensis en el paciente con diabetes mellitus. Método: Se utilizaron como buscadores de información científica a PubMed, SciELO, Google y Google Académico. Las palabras claves utilizadas fueron: espirulina, Spirulina platensis, Arthrospira platensis, diabetes mellitus y control metabólico. Se evaluaron artículos de revisión, de investigación y páginas web que, en general, tenían menos de 10 años de publicados en idioma español, portugués e inglés, cuyos títulos estaban relacionados con el tema de estudio. Se obtuvieron 70 referencias bibliográficas, de las cuales 49 se citaron en el presente artículo. Conclusiones: La espirulina tiene varios efectos benéficos que permiten su uso como coadyuvante en la prevención y tratamiento de la diabetes mellitus. Es un nutriente con bondades nutraceúticas y funcionales, con potente actividad antioxidante, que incide en un mejor control glucémico y puede ser útil en el manejo de las posibles complicaciones y comorbilidades que acompañan a la diabetes mellitus. Su uso conlleva la posibilidad de algunas reacciones adversas, sobre todo de tipo digestivas, aunque no son frecuentes si se emplean las dosis recomendadas; en general, es considerada un producto seguro.
... Furthermore, the results were influenced by the type of spirulina supplements, their bioactive ingredients content, and geographical spirulina's origin 44 . A number of in vitro and in vivo studies were conducted to understand the underlying mechanisms of action for spirulina's anti-inflammatory and antioxidant activities 45,46 . ...
Article
Studies investigating the effects of spirulina on inflammation and oxidative stress status are controversial. Therefore, the current systematic review and meta-analysis aimed to evaluate the impacts of spirulina supplementation on oxidative stress indicators and inflammatory markers. PubMed-Medline, SCOPUS, Web of Science and Embase databases and Google Scholar were searched up to 1 October 2020. Random-effect analysis was applied to perform meta-analysis. Subgroup analyses and multivariate meta-regression were performed to find heterogeneity sources. Quality assessment was conducted using Cochrane Collaboration's tool. A total of 11 studies that enrolled 465 subjects were included in our meta-analysis. Pooled results demonstrated a significant increase in IL-2 concentrations (SMD= 2.69 pg/ml; 95% CI: 0.26, 5.11; P=0.03), however this result changed to insignificant (SMD= 0.54 pg/ml; 95% CI: -1.29, 2.27; P> 0.05) when sensitivity analysis performed. A marginal decreasing effect were also found on IL-6 (SMD= -0.72 mg/dl; 95% CI: -1.50, 0.07; P=0.073) and TBARS levels (SMD= -0.65; 95% CI: -1.37, 0.08; P=0.08). In addition, results of subgroup analysis revealed a significant reduction in IL-6 and TBARS concentrations when the baseline BMI of participants was lower than 25 kg/m2 . Moreover, spirulina had no significant effect on TNF-α (SMD= -0.07 mg/dl; 95% CI: -0.33, 0.18; P=0.56) and MDA concentrations (SMD= -0.42; 95% CI: -0.98, 0.14; P=0.14). Spirulina consumption contributed to a significant increase in IL-2 concentrations changing to insignificant after sensitivity analysis and marginal decreasing effects on IL-6 and TBARS levels. No considerable impacts were observed on TNF-α and MDA concentrations.
... So it is vital to include phycocyanin as a functional food ingredient to fight or prevent cancer and as an antioxidant-enriched supplement. Recently it was reported that a peptide of Arthrospira platensis reduced blood pressure levels through a PI3K/AKT/eNOS-dependent mechanism [11]. ...
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... This antihypertensive effect of peptidic fractions (200 mg/kg body weight) in spontaneously hypertensive rats has been attributed to the active peptides in A. platensis: Ile-Ala-Glu (IC 50 34.7 µM), Phe-Ala-Leu, Ala-Glu-Leu, Ile-Ala-Pro-Gly (11.4 µM), and Val-Ala-Phe (35.8 µM) [52]. Furthermore, the decapeptide Gly-Ile-Val-Ala-Gly-Asp-Val-Thr-Pro-Ile from A. platensis has been found to exert direct endothelium-dependent vasodilation ex vivo via a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt) pathway, resulting in NO release [53]. ...
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... Carrizzo et al. [168] described the fractionation of Spirulina lysates by a treatment that simulates gastrointestinal digestion (GID). From these extracts, four peptides were obtained and characterized by mass spectrometry (SP(3-6)). ...
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Spirulina, a filamentous cyanobacterium, possesses diverse biological activities and nutritional significance due to high concentration of natural nutrients, having bio-modulatory and immuno-modulatory functions. Different Spirulina preparations influence immune system viz. increase phagocytic activity of macrophages, stimulating the production of antibodies and cytokines, increase accumulation of NK cells into tissue and activation and mobilization of T and B cells. Spirulina have also shown to perform regulatory role on lipid and carbohydrate metabolism by exhibiting glucose and lipid profile correcting activity in experimental animals and in diabetic patients. Preparations have been found to be active against several enveloped viruses including herpes virus, cytomegalovirus, influenza virus and HIV. They are capable to inhibit carcinogenesis due to anti-oxidant properties that protect tissues and also reduce toxicity of liver, kidney and testes.
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Stracchino is a typical Italian soft cheese, widely consumed and appreciated for its flavour and freshness. With the aim to follow the release of health-promoting peptides, an in vitro gastro-intestinal digestion of Stracchino was carried out. The digest was fractionated by semi-preparative RPLC and tested for its antioxidant properties in H2O2-treated intestinal epithelial cell line (IEC-6). The most active fraction was characterized by UHPLC-MS/MS, showing the presence of two abundant β-casein hexapeptides: EAMAPK (f: 115–120) and AVPYPQ (f: 192–197), which were synthesized and tested, showing antioxidant activities in a wide concentration range (5–150 µg/mL), involving ROS reduction, SOD expression increase and Nrf2 antioxidant response activation. Hence, bioavailability studies were carried out through Caco-2 monolayers cells on the two hexapeptides, which revealed a significative concentration in the basolateral side. The results highlight the potential of Stracchino as health promoting food, and the possible employment of casein peptides in nutraceutical formulations.
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AbstractBioactive peptides represent specific sequences of amino acids that have biological activity with several health effects and potential applications, which can be obtained from diverse protein sources. Spirulina, the cyanobacterium known for its high protein content and therapeutic properties, has been investigated as a potential source of bioactive peptides. Some bioactive peptides derived from Spirulina are under study for their ability to offer specific health benefits, such as antimicrobial, anti-allergic, anti-hypertensive, anti-tumor and immunomodulatory. Bioactive peptides fractions from Spirulina biomass can be obtained through a series of operations, including cell lysis and protein extraction, enzymatic hydrolysis, potential bioactivity screening, fractionation and purification. Potentially, Spirulina-derived peptides fractions can be applied as nutraceutical ingredients of foods and pharmaceuticals. This paper reviews the functional properties and health benefits of bioactive peptides
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This study investigated the long-term (8 weeks) antihypertensive effects of 10 mg/kg tripeptides isolated from Spirulina platensis: Ile-Gln-Pro (IQP), Val-Glu-Pro (VEP), and Spirulina platensis hydrolysates (SH) on spontaneously hypertensive rats. The treatment period was 6 weeks, and observation continued for another 2 weeks. After treatment, weighted systolic blood pressure and weighted diastolic blood pressure of groups treated with IQP, VEP and SH were significantly lower than the group treated with distilled water, even when the treatments had been withdrawn for 2 weeks. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay and western blotting showed the mRNA expression levels and protein concentrations of the main components of the renin angiotensin system in myocardium were significantly affected by treatment: angiotensin converting enzyme, angiotensin II, and angiotensin type 1 receptor were downregulated while angiotensin type 2 receptor, angiotensin converting enzyme 2, angiotensin-(1-7), and Mas receptor were upregulated.
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Seafood processing by-product, Pacific cod (Gadus macrocephalus) skin, was utilised to purify an active peptide with ACE inhibitory and antioxidant activities. Gelatin was extracted from the skin and it was hydrolysed with gastrointestinal endopeptidases (pepsin, trypsin and α-chymotrypsin). Assay-guided purification of the hydrolysate resulted in an active peptide, Leu-Leu-Met-Leu-Asp-Asn-Asp-Leu-Pro-Pro (1301 Da). The peptide showed potent non-competitive ACE inhibition (IC50 = 35.7 μM) and effectively protects cellular macromolecules from reactive oxygen species (ROS) mediated damage. The peptide significantly reduced the oxidation levels of membrane lipids, proteins and DNA in RAW264.7 cells by effectively scavenging the intracellular ROS. Moreover, it was found that the peptide treatment upregulated the m-RNA expression of cellular antioxidative enzymes (superoxide dismutase, glutathione and catalase) and thereby enhanced the intracellular antioxidant mechanisms. These findings suggest that Pacific cod skin could be effectively bioconverted to produce a bioactive peptide, which could be used as a functional food ingredient to control ACE activity and oxidative stress.
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Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertensive dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5' adenosine monophosphate-activated protein kinase-mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid-derived 2-like 2-dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines.
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Oxidative stress plays a pivotal role during the islet transplantation procedure, and antioxidant supplementation may protect grafts against oxidative injury. Chinese bayberry is one of six Myrica species native to China, and we demonstrated here that anthocyanins from Chinese bayberry extract (CBE) protect pancreatic β cells (INS-1) against hydrogen peroxide (H(2)O(2))-induced necrosis and apoptosis. Anthocyanins time- and dose-dependently upregulated heme oxygenase-1 (HO-1) gene expression in β cells and primary islets. HO-1 knockdown increased H(2)O(2)-induced cell death and attenuated the cytoprotective effect of anthocyanins. Anthocyanin treatment activated ERK1/2 and PI3K/Akt signaling, and ERK1/2 and PI3K inhibitors partially attenuated anthocyanin-mediated induction of HO-1. Additionally, β cells pretreated with anthocyanins displayed a decreased extent of apoptosis after transplantation. In summary, these results suggest that anthocyanins in CBE protect β cells from H(2)O(2)-induced cell injury via ERK1/2- and PI3K/Akt-mediated HO-1 upregulation.
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An angiotensin I-converting enzyme (ACE) inhibitory peptide Ile-Gln-Pro with an IC(50) value of 5.77 +/- 0.09 microM was purified from the alcalase digests of Spirulina platensis by gel filtration chromatography and two steps of reverse-phase high-performance liquid chromatography (RP-HPLC). The peptide was synthesized and showed resistance to in vitro digestion by gastrointestinal proteases. Kinetics studies indicated that the peptide was a noncompetitive inhibitor and that the K(i) value was 7.61 +/- 0.16 microM. Oral administration of Ile-Gln-Pro at a dosage of 10 mg/kg showed significant decreases of the weighted systolic blood pressure (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHR) at 4, 6, and 8 h after treatment. The results showed that the ACE inhibitory peptide from Spirulina platensis may have potential for use in the prevention and treatment of hypertension.
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Resistance to proteases throughout the gastrointestinal (GI) tract is a prerequisite for milk-derived peptides to exert biological activities. In this work an in vitro multi-step static model to simulate complete digestion of the bovine milk proteins has been developed. The experimental set-up involved the sequential use of: (i) pepsin, (ii) pancreatic proteases, and (iii) extracts of human intestinal brush border membranes, in simulated gastric, duodenal and jejuneal environments, respectively. Enzymatic concentrations and reaction times were selected in order to closely reproduce the in vivo conditions. The aim was to identify the peptide candidates able to exhibit significant bioactive effects. Casein and whey protein peptides which survived the in vitro GI digestion have been identified by the combined application of HPLC and mass spectrometry techniques. While the permanence of the main potentially bioactive peptides from both casein and whey proteins was found of limited physiological relevance, the high resistance to proteolysis of specific regions of beta-lactoglobulin (beta-Lg), and especially that of the peptide beta-Lg f125-135, could have implications for the immunogenic action of beta-Lg in the insurgence of cow's milk allergy.
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The peptidic fractions that inhibited angiotensin I-converting enzyme (ACE) were separated from the peptic digests of 2 microalgae, Chlorella vulgaris and Spirulina platensis, by ion exchange chromatography and gel filtration. Oral administration of peptidic fractions into spontaneously hypertensive rats at 200 mg/kg of body weight resulted in marked antihypertensive effects. Further separation of the peptidic fractions by ODS high-performance liquid chromatography furnished the following active peptides: Ile-Val-Val-Glu (inhibitory against ACE with an IC(50) of 315.3 microM), Ala-Phe-Leu (63.8 microM), Phe-Ala-Leu (26.3 microM), Ala-Glu-Leu (57.1 microM), and Val-Val-Pro-Pro-Ala (79.5 microM) from C. vulgaris; Ile-Ala-Glu (34.7 microM), Phe-Ala-Leu, Ala-Glu-Leu, Ile-Ala-Pro-Gly (11.4 microM), and Val-Ala-Phe (35.8 microM) from S. platensis.
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It was mainly the advances in understanding the relationship between nutrition and health that resulted in the development of the concept of functional foods, which means a practical and new approach to achieve optimal health status by promoting the state of well-being and possibly reducing the risk of disease. Functional foods are found virtually in all food categories, however products are not homogeneously scattered over all segments of the growing market. The development and commerce of these products is rather complex, expensive and risky, as special requirements should be answered. Besides potential technological obstacles, legislative aspects, as well as consumer demands need to be taken into consideration when developing functional food. In particular, consumer acceptance has been recognized as a key factor to successfully negotiate market opportunities. This paper offers a brief overview of the current functional food market situation in USA, Japan and some European countries completed with some comments on functional food future potential. It explores the main challenges of such product development focusing on the different factors determining the acceptance of functional food. Furthermore it discusses some prominent types of these food products currently on the market.
Functional properties and health benefits of bioactive peptides derived from spirulina: a review
  • C A Ovando
  • J C De Carvalho
  • Gvd Pereira
  • P Jacques
  • V T Soccol
  • C R Soccol
Ovando CA, de Carvalho JC, Pereira GVD, Jacques P, Soccol VT, Soccol CR. Functional properties and health benefits of bioactive peptides derived from spirulina: a review. Food Rev Int. 2018;34:34-51.