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13 pages, 1631 KiB

Open AccessArticle

Immunomodulatory Effect of Gut Microbiota-Derived Bioactive Peptides on Human Immune System from Healthy Controls and Patients with Inflammatory Bowel Disease

by Samuel Fernández-Tomé, Alicia C. Marin, Lorena Ortega Moreno, Montserrat Baldan-Martin, Irene Mora-Gutiérrez, Aitor Lanas-Gimeno, José Andrés Moreno-Monteagudo, Cecilio Santander, Borja Sánchez, María Chaparro, Javier P. Gisbert and David Bernardo

Nutrients 2019, 11(11), 2605; https://doi.org/10.3390/nu11112605 - 31 Oct 2019

Cited by 22 | Viewed by 4916

Abstract

Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells [...] Read more.

Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells (APCs) in active inflammatory bowel disease (IBD). The IBD mucosa produced higher levels of pro-inflammatory cytokines referred to healthy controls (HCs). Peptides B7 and B12, however, did not ameliorate the mucosal cytokine milieu in IBD. Human circulating APCs (B-cells, monocytes, plasmacytoid dendritic cells (pDCs), and conventional dendritic cells (cDCs)) were characterized by flow cytometry in presence/absence of the peptides. Circulating B-cells, monocytes, and cDCs from IBD patients were more activated than those from HCs. Peptide B7, but not B12, decreased CCR2 expression on all APC subsets from HC, but not IBD patients. Moreover, both peptides tend to further increase their pro-inflammatory profile in IBD. In summary, IBD patients display mucosal and circulating APC pro-inflammatory properties. Peptide B7 immunomodulatory capacity elicited over circulating APCs from HC, but not IBD patients, suggests the presence of disrupted modulatory mechanisms for this peptide in IBD. Future studies should address the effect of bacteria-derived immunomodulatory peptides in non-inflamed (quiescent) IBD patients. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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12 pages, 984 KiB

Open AccessArticle

The Lacto-Tetrapeptide Gly–Thr–Trp–Tyr, β-Lactolin, Improves Spatial Memory Functions via Dopamine Release and D1 Receptor Activation in the Hippocampus

by Tatsuhiro Ayabe, Yasuhisa Ano, Rena Ohya, Shiho Kitaoka and Tomoyuki Furuyashiki

Nutrients 2019, 11(10), 2469; https://doi.org/10.3390/nu11102469 - 15 Oct 2019

Cited by 15 | Viewed by 3336

Abstract

Scope: Peptides containing tryptophan–tyrosine sequences, including the lacto-tetrapeptide glycine–threonine–tryptophan–tyrosine (GTWY) and β-lactolin, from β-lactoglobulin in whey enzymatic digestion, enhance hippocampus-dependent memory functions, which are blocked by the systemic administration of dopamine D1-like antagonist. In this study, we investigated the role of the hippocampal [...] Read more.

Scope: Peptides containing tryptophan–tyrosine sequences, including the lacto-tetrapeptide glycine–threonine–tryptophan–tyrosine (GTWY) and β-lactolin, from β-lactoglobulin in whey enzymatic digestion, enhance hippocampus-dependent memory functions, which are blocked by the systemic administration of dopamine D1-like antagonist. In this study, we investigated the role of the hippocampal dopaminergic system in the memory-enhancing effect of β-lactolin. Methods and Results: The results of in vivo microdialysis revealed that oral administration of β-lactolin increased the extracellular concentration of dopamine in the hippocampus and enhanced both spatial working memory, as measured in the Y-maze test, and spatial reference memory, as measured in the novel object location test. These memory-enhancing effects of β-lactolin, but not the baseline memory functions, were impaired by the knockdown of the dopamine D1 receptor subtype in the hippocampus. β-Lactolin also enhanced object memory, as measured by the novel object recognition test. However, D1 knockdown in the hippocampus spared this memory function either with or without the administration of β-lactolin. Conclusions: The present results indicate that oral administration of β-lactolin increases dopamine release and D1 receptor signaling in the hippocampus, thereby enhancing spatial memory, but it may improve object memory via a separate mechanism. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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13 pages, 2232 KiB

Open AccessArticle

Egg White Ovotransferrin Attenuates RANKL-Induced Osteoclastogenesis and Bone Resorption

by Nan Shang and Jianping Wu

Nutrients 2019, 11(9), 2254; https://doi.org/10.3390/nu11092254 - 19 Sep 2019

Cited by 14 | Viewed by 5909

Abstract

Ovotransferrin, a member of the transferrin family, is the second main protein found in egg white. Ovotransferrin was reported to have antimicrobial, antioxidant, and immunomodulating activities. The aim of this work was to characterize the cellular and molecular functions of egg white ovotransferrin [...] Read more.

Ovotransferrin, a member of the transferrin family, is the second main protein found in egg white. Ovotransferrin was reported to have antimicrobial, antioxidant, and immunomodulating activities. The aim of this work was to characterize the cellular and molecular functions of egg white ovotransferrin on osteoclasts differentiation and function. Osteoclasts were prepared from mouse macrophage RAW 264.7 cells stimulated with receptor activator of nuclear factor κB ligand (RANKL). Ovotransferrin inhibited osteoclasts differentiation and the calcium–phosphate resorptive ability via the suppression of RANKL-induced nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Ovotransferrin induced apoptosis of matured osteoclasts, accompanied by increased expression of Bcl-2-like protein 11 (Bim) and Bcl-2-assoicated death promoter (Bad), but decreased expression of B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-xl). We established a novel role of egg white ovotransferrin as an inhibitor of osteoclastogenesis, which may be used for the prevention of osteoporosis. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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13 pages, 1566 KiB

Open AccessArticle

Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress

by Yasuhisa Ano, Masahiro Kita, Shiho Kitaoka and Tomoyuki Furuyashiki

Nutrients 2019, 11(9), 2161; https://doi.org/10.3390/nu11092161 - 09 Sep 2019

Cited by 17 | Viewed by 8205

Abstract

The number of patients with mental illnesses is rapidly increasing, and daily lifestyle is closely associated with the development of symptoms. It is suggested that inflammatory molecules derived from microglia play crucial roles for the pathophysiology of depression. In the present study, we [...] Read more.

The number of patients with mental illnesses is rapidly increasing, and daily lifestyle is closely associated with the development of symptoms. It is suggested that inflammatory molecules derived from microglia play crucial roles for the pathophysiology of depression. In the present study, we discovered that leucine–histidine (LH) dipeptide suppressed activation of primary microglia. The effects of LH dipeptide orally administered were measured using tail suspension test (TST) in mice injected with lipopolysaccharide and social interaction test in mice received social defeat stress. LH dipeptide reduced pro-inflammatory cytokines upon stimulation in microglia. Orally administered LH dipeptide was delivered to the brain and suppressed the production of pro-inflammatory cytokines in the brain and concomitant depression-like behavior in the TST. Moreover, oral administration of LH dipeptide suppressed the induction of depression- and anxiety-like behaviors induced by repeated social defeat stress. These results indicate that LH dipeptide suppressed the activation of microglia and ameliorated depression-associated emotional disturbances. Further, we found that LH dipeptide was abundant in various fermented products. Together with previous epidemiological reports that daily intake of these fermented foods is negatively associated with the incidence of psychiatric diseases, our findings suggest that food rich in LH dipeptide may improve mental health. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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9 pages, 1529 KiB

Open AccessArticle

Lupin Peptide T9 (GQEQSHQDEGVIVR) Modulates the Mutant PCSK9^D374Y Pathway: in vitro Characterization of its Dual Hypocholesterolemic Behavior

by Carmen Lammi, Carlotta Bollati, Davide Lecca, Maria Pia Abbracchio and Anna Arnoldi

Nutrients 2019, 11(7), 1665; https://doi.org/10.3390/nu11071665 - 20 Jul 2019

Cited by 21 | Viewed by 3436

Abstract

GQEQSHQDEGVIVR (T9) is a peptide originated by the tryptic digestion of lupin β-conglutin that is absorbed in human intestinal Caco-2 cells. A previous study has shown that T9 impairs the protein–protein interaction between mutant D374Y Proprotein Convertase Subtilisin/Kexin 9 (PCSK9^D374Y) and [...] Read more.

GQEQSHQDEGVIVR (T9) is a peptide originated by the tryptic digestion of lupin β-conglutin that is absorbed in human intestinal Caco-2 cells. A previous study has shown that T9 impairs the protein–protein interaction between mutant D374Y Proprotein Convertase Subtilisin/Kexin 9 (PCSK9^D374Y) and the low-density lipoprotein receptor (LDLR), thus exerting a hypocholesterolemic effect. Moreover, a bioinformatic study predicting that T9 may potentially act as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), has suggested a complementary cholesterol-lowering activity. The present study demonstrates that T9 inhibits in vitro the HMGCoAR functionality with an IC₅₀ value of 99.5 ± 0.56 µM. Through the inhibition of either HMGCoAR or PCSK9^D374Y activities, T9 enhances the LDLR protein levels leading to an improved ability of HepG2 cells transfected with the mutant PCSK9^D374Y-FLAG plasmid to uptake extracellular LDL with a final cholesterol-lowering effect. In addition, T9 modulates the PCSK9^D374Y signaling pathway in transfected HepG2 cells leading to a decrease of PCSK9^D374Y and HNF-1α protein levels. All these results indicate that the hypocholesterolemic effects of T9 are due to a dual mechanism of action involving either the modulation of the PCSK9^D374Y or LDLR pathways. This may represent an added value from a therapeutic point of view. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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15 pages, 905 KiB

Open AccessArticle

Preparation and Identification of Novel Antihypertensive Peptides from the In Vitro Gastrointestinal Digestion of Marine Cobia Skin Hydrolysates

by Yu-Hsin Lin, Chun-An Chen, Jenn-Shou Tsai and Guan-Wen Chen

Nutrients 2019, 11(6), 1351; https://doi.org/10.3390/nu11061351 - 15 Jun 2019

Cited by 30 | Viewed by 4022

Abstract

This research focuses on cobia skin hydrolysates and their antihypertensive effects via the inhibitory activities of angiotensin I-converting enzyme (ACE). Marine fish Cobia (Rachycentron canadum) skin was hydrolysed for 5 h using Protamex and Protease N to obtain the cobia skin [...] Read more.

This research focuses on cobia skin hydrolysates and their antihypertensive effects via the inhibitory activities of angiotensin I-converting enzyme (ACE). Marine fish Cobia (Rachycentron canadum) skin was hydrolysed for 5 h using Protamex and Protease N to obtain the cobia skin protein hydrolysates PX-5 and PN-5, respectively. The soluble protein and peptide contents of the PX-5 were 612 and 270 mg/g, respectively, and for the PN-5, 531 and 400 mg/g, respectively. The IC₅₀ of PX-5 and PN-5 on ACE was 0.221 and 0.291 mg/mL, respectively. Increasing the IC₅₀ from 0.221 to 0.044 mg/mL by simulated gastrointestinal digestion (PX-5G) reduced the ACE-inhibitory capacity of PX-5. Using gel filtration chromatography, the PX-5G was fractioned into eight fractions. The molecular weight of the fifth fraction from PX-5G was between 630 and 450 Da, and the highest inhibitory efficiency ratio on ACE was 1552.4%/mg/mL. We identified four peptide sequences: Trp-Ala-Ala, Ala-Trp-Trp, Ile-Trp-Trp, and Trp-Leu, with IC₅₀ values for ACE of 118.50, 9.40, 0.51, and 26.80 μM, respectively. At a dose of 600 mg PX-5 powder/kg body weight, in spontaneously hypertensive rats PX-5’s antihypertensive effect significantly reduced systolic and diastolic blood pressure by 21.9 and 15.5 mm Hg, respectively, after 4 h of oral gavage. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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13 pages, 2246 KiB

Open AccessArticle

Naked Oat (Avena nuda L.) Oligopeptides: Immunomodulatory Effects on Innate and Adaptive Immunity in Mice via Cytokine Secretion, Antibody Production, and Th Cells Stimulation

by Ruixue Mao, Lan Wu, Na Zhu, Xinran Liu, Rui Liu and Yong Li

Nutrients 2019, 11(4), 927; https://doi.org/10.3390/nu11040927 - 24 Apr 2019

Cited by 21 | Viewed by 4806

Abstract

The study aimed to investigate the immunomodulatory activity of oligopeptides derived from oat (Avena nuda L.) (OOPs). Healthy female BALB/c mice were randomly assigned to five groups, given deionized water (control) and 0.25, 0.5, 1.0, and 2.0 g/kg body weight (BW) of [...] Read more.

The study aimed to investigate the immunomodulatory activity of oligopeptides derived from oat (Avena nuda L.) (OOPs). Healthy female BALB/c mice were randomly assigned to five groups, given deionized water (control) and 0.25, 0.5, 1.0, and 2.0 g/kg body weight (BW) of OOPs daily by intragastric administration. Seven assays were performed to determine the immunomodulatory effects of OOPs on immune organ ratios, cellular and humoral immune responses, macrophage phagocytosis, and natural killer (NK) cell activity. Spleen T lymphocyte subpopulations (by flow cytometry), serum cytokine and immunoglobulin levels (by multiplex sandwich immunoassays) were determined to evaluate how OOPs affected the immune system. Our results showed that OOPs could significantly improve innate and adaptive immune responses in mice through the enhancement of cell-mediated and humoral immunity, macrophage phagocytosis capacity, and NK cell activity. We concluded that the immunomodulatory effects might be attributed to increased T and Th cell percentages, serum interferon (IFN)-γ, interleukin (IL)-1 α, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)- α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretions as well as immunoglobulin (Ig) A, IgG, and IgM productions. These results indicate that dietary OOPs could be considered as promising immunomodulators with dosages ranging from 0.25 to 2.0 g/kg BW. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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Review

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22 pages, 973 KiB

Open AccessReview

Improving Health-Promoting Effects of Food-Derived Bioactive Peptides through Rational Design and Oral Delivery Strategies

by Paloma Manzanares, Mónica Gandía, Sandra Garrigues and Jose F. Marcos

Nutrients 2019, 11(10), 2545; https://doi.org/10.3390/nu11102545 - 22 Oct 2019

Cited by 43 | Viewed by 5461

Abstract

Over the last few decades, scientific interest in food-derived bioactive peptides has grown as an alternative to pharmacological treatments in the control of lifestyle-associated diseases, which represent a serious health problem worldwide. Interest has been directed towards the control of hypertension, the management [...] Read more.

Over the last few decades, scientific interest in food-derived bioactive peptides has grown as an alternative to pharmacological treatments in the control of lifestyle-associated diseases, which represent a serious health problem worldwide. Interest has been directed towards the control of hypertension, the management of type 2 diabetes and oxidative stress. Many food-derived antihypertensive peptides act primarily by inhibiting angiotensin I-converting enzyme (ACE), and to a lesser extent, renin enzyme activities. Antidiabetic peptides mainly inhibit dipeptidyl peptidase-IV (DPP-IV) activity, whereas antioxidant peptides act through inactivation of reactive oxygen species, free radicals scavenging, chelation of pro-oxidative transition metals and promoting the activities of intracellular antioxidant enzymes. However, food-derived bioactive peptides have intrinsic weaknesses, including poor chemical and physical stability and a short circulating plasma half-life that must be addressed for their application as nutraceuticals or in functional foods. This review summarizes the application of common pharmaceutical approaches such as rational design and oral delivery strategies to improve the health-promoting effects of food-derived bioactive peptides. We review the structural requirements of antihypertensive, antidiabetic and antioxidant peptides established by integrated computational methods and provide relevant examples of effective oral delivery systems to enhance solubility, stability and permeability of bioactive peptides. Full article

(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)

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