Characterization of soy‐deprestatin, a novel orally active decapeptide that exerts antidepressant‐like effects
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            gut–brain communication

Mori, Yukiha; Asakura, Saho; Yamamoto, Akane; Odagiri, S; Yamada, Daisuke; Sekiguchi, Masayuki; Wada, Keiji; Satô, Masaru; Kurabayashi, Atsushi; Suzuki, Hideyuki; Kanamoto, Ryuhei; Ohinata, Kousaku

doi:10.1096/fj.201700333rr

Cited by 31 publications

(34 citation statements)

References 35 publications

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“…Mediators of YL-induced antidepressant-like effects were also investigated. We previously revealed that a novel signaling pathway with serotonin 5-HT 1A receptor activation followed by the activation of dopamine D 1 and GABA A receptors mediate antidepressant-like and anxiolytic-like activities 1,6 . We also found that this signaling pathway mediates the anxiolytic effect of YL.…”

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Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Maekawa

Uchida

Ohinata

2020

Sci Rep

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Depression is a worldwide health problem. In the present study, we found that a dipeptide, tyrosyl leucine (Tyr-Leu, YL), administered orally, intracerebroventricularly, or intraperitoneally exhibited a potent antidepressant-like activity in the forced swim and tail suspension tests in naïve mice. YL increased the amount of cells expressing c-Fos, a marker for neuronal activity, in the dentate gyrus of the hippocampus. YL increased bromo-2′-deoxyuridine-positive cells and doublecortin expression in the dentate gyrus of the hippocampus, suggesting that YL enhanced the proliferation of hippocampal progenitor cells in vivo and in vitro. YL did not affect hippocampal mRNA and protein expression of BDNF, which is a regulatory factor of both neurogenesis and depression-like behavior. Intriguingly, YL suppressed activation of the hypothalamo-pituitary-adrenal axis by forced swim stress. Moreover, other aromatic amino acid-leucines, Phe-Leu and Trp-Leu, also exhibited antidepressant-like activities, suggesting that the structure of aromatic amino acid-leucine may be important for antidepressant activity. In addition, bovine milk casein-derived peptide, Tyr-Leu-Gly (YLG), an anxiolytic peptide, exhibited an antidepressant-like activity. Our findings demonstrate that YL exhibits an antidepressantlike effect, moderates the stress response, and induces hippocampal neuronal proliferation through a signal pathway independent of BDnf.A number of bioactive peptides have been found in enzymatic digests of various food proteins, and some of these peptides are known to act on the nervous system. We also reported that bioactive peptides derived from food proteins exhibit anxiolytic-like effects 1-7 , suggesting interactions between food components and the nervous system. Clarification of these interactions is challenging, since the food components, including food protein digests, consist of numerous molecular species. On the other hand, we have found novel bioactive peptides based on the structure-activity relationships of dipeptides. Thus, the discovery of dipeptides with potent activities and the their structure-activity relationships are very important and powerful clues to find novel peptides. Indeed, we initially found that a dipeptide, tyrosyl leucine (Tyr-Leu, YL), had a potent anxiolytic-like effect, comparable to that of diazepam, one of the general anxiolytics, in mice 1 . Thereafter, based on the structure rule required for the anxiolytic activity of YL, novel food-derived peptides have been rapidly been identified. Thus, we focused on dipeptides.Major depressive disorder, one of the most common psychiatric diseases, is characterized by dysregulation of emotion and mood as well as abnormalities of cognitive function, sleep, appetite, and metabolism. It is known to be a leading cause of disability worldwide 8,9 . Anxiolytic molecules often exhibit antidepressant-like effects. Thus, in the current study, we investigated whether YL exhibits antidepressant-like activities using two behavioral tests commonly used to screen ant...

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Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Maekawa

Uchida

Ohinata

2020

Sci Rep

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“…To date, a number of bioactive peptides have been isolated from enzymatic digests of natural food proteins. We previously found that several bioactive peptides act on the nervous system and change emotional behavior (5)(6)(7). Among them, Tyr-Leu-Gly (YLG), a tripeptide efficiently released from bovine a s1 -casein, the ABBREVIATIONS: BDNF, brain-derived neurotrophic factor; BrdU, 5bromo-29-deoxyuridine; CD, control diet; CNTF, ciliary neurotrophic factor; EGF, epidermal growth factor; FGF-2, fibroblast growth factor 2; GDNF, glial cell line-derived neurotrophic factor; HFD, high-fat diet; ITT, insulin tolerance test; NEFA, nonesterified fatty acid; NGF, nerve growth factor; NT-3, neurotrophin 3; OFT, open-field test; OGTT, oral glucose tolerance test; OLT, object location test; ORT, object recognition test; p.o., per os; PBST, PBS with Triton X-100; TG, triglyceride; YLG, Tyr-Leu-Gly major protein of milk, when digested under gastrointestinal enzyme conditions, exhibits potent anxiolytic-like effects at a low dose comparable to pharmaceuticals (8).…”

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Orally administered milk‐derived tripeptide improved cognitive decline in mice fed a high‐fat diet

et al. 2019

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The functions of the brain, which is thought of as an organ highly independent from the periphery, are often affected by the peripheral environment. Indeed, epidemiologic studies demonstrated that diabetes was a risk factor for dementia. It was also reported that the intake of dairy products, such as milk, reduces the risk of developing dementia. We found that mice on a short‐term high‐fat diet (HFD) for 1 wk had reduced cognitive function. Thus, using this acute model, we investigated the effects of milk‐derived peptide on cognitive decline induced by HFD. Tyr‐Leu‐Gly (YLG), a tripeptide derived from αS1‐casein, a major bovine milk protein, is released by gastrointestinal proteases. We found that orally administered YLG improved cognitive decline induced by 1‐wk HFD intake in the object recognition test. YLG also improved cognitive decline in the object location test. Thus, we found that YLG improved cognitive decline induced by HFD. Next, we examined the effects of YLG on the hippocampus, a brain area essential for cognitive function. HFD intake decreased the number of 5‐bromo‐2'‐deoxyuridine (BrdU)‐positive cells, and this decrease was improved by YLG administration. HFD intake decreased nerve growth factor (NGF) and glial cell line‐derived neurotrophic factor, whereas YLG increased NGF and ciliary neurotrophic factor, suggesting that these neurotropic factors play a role in hippocampal neurogenesis after YLG administration. In conclusion, we demonstrated that 1‐wk HFD reduced cognitive function. Furthermore, we found that YLG, a milk‐derived tripeptide, improved cognitive decline in mice on HFD. The HFD reduced neural stem cell proliferation, and YLG improved this reduction. YLG is the first reported milk peptide to improve cognitive decline induced by HFD intake.—Nagai, A., Mizushige, T., Matsumura, S., Inoue, K., Ohinata, K. Orally administered milk‐derived tripeptide improved cognitive decline in mice fed a high‐fat diet. FASEB J. 33, 14095‐14102 (2019). http://www.fasebj.org

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“…Yamamoto et al reported that pyroglutamyl leucine and pyroglutamyl glutaminyl leucine derived from wheat glutenin and gliadin exhibit antidepressant activity and enhance hippocampal neurogenesis after intraperitoneal and intracerebroventricular administration in mice (17). Mori et al reported that soybean b-conglycinin hydrolysate with thermolysin had antidepressant activity via the vagus nerve in mice (18). Several groups reported that egg protein hydrolysate promoted mood and emotional function in humans (19)(20)(21).…”

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confidence: 99%

Ginger-Degraded Collagen Hydrolysate Exhibits Antidepressant Activity in Mice

Maekawa

Nogimura

Nagai

et al. 2019

J Nutr Sci Vitaminol

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Collagen is the most abundant protein in animals. Collagen hydrolysate has been found to have multiple functions in the skin, bones, joints, muscles, and blood vessels. Recently, it has been reported that the low molecular weight fraction of collagen hydrolysate exhibited anxiolytic activity, suggesting that collagen peptides affect brain functions. In the present study, we found that oral administration of ginger-degraded collagen hydrolysate (GDCH) significantly decreased depression-like behavior in a forced swim test, suggesting that GDCH exhibited antidepressant activity in mice. The antidepressant activity of GDCH was abolished by pre-treatment with an antagonist of the dopamine receptor, but not treatment with a serotonin receptor antagonist. GDCH significantly increased gene expression of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) in the hippocampus, molecules that affect the differentiation and survival of neurons, relative to that in the control condition. Meanwhile, there were no changes in the gene expression of brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3, major factors related to depression-like behavior. We also found that GDCH exhibited antidepressant activity in corticosterone-administered mice in a model of stress. In addition, GDCH increased GDNF and CNTF expression in the stressed condition, suggesting that mechanisms of the antidepressant activity of GDCH were the same in unstressed and stressed conditions. These results imply that GDCH exhibits antidepressant activity in unstressed and stressed conditions in mice. The upregulation of neurotrophic genes in the hippocampus may contribute to the reduction of depression-like behavior via a dopamine signal pathway modulated by GDCH.

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Characterization of soy‐deprestatin, a novel orally active decapeptide that exerts antidepressant‐like effects via gut–brain communication

Cited by 31 publications

References 35 publications

Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Orally administered milk‐derived tripeptide improved cognitive decline in mice fed a high‐fat diet

Ginger-Degraded Collagen Hydrolysate Exhibits Antidepressant Activity in Mice

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