Abstract
The pathogenesis of hypertension is related to many factors including active angiotensin-I-converting enzyme (ACE) and excess reactive oxygen species (ROS), the combination of ACE inhibition and antioxidant activity in one compound might be useful for the treatment of hypertension. Sipunculus nudus L contain high protein content, which can be used as a valuable raw material to prepare bio-active peptides. In this study, two novel tripeptides, LPK and PRP, with dual bioactivity of ACE inhibition and antioxidant were purified and identified from the worm. The antioxidant activities of LPK and PRP are dose-dependent, including 2,2-diphenyl-1-picrylhydrazyl (DPPH), superoxide anion and hydroxyl radical scavenging activities. Moreover, the antioxidant activity of PRP was stronger than that of LPK. In addition, LPK and PRP also show higher ACE inhibitory activity, with IC50 of 6.54 and 0.42 mM, respectively. Molecular docking simulation showed that both the peptides could interact with the active ACE sites via hydrogen bonds, which can reduce the production of Ang II, thereby; LPK and PRP treatment could decrease Ang II-triggered superoxide production, and meanwhile, the peptides treatment could directly remove excess reactive oxygen species. The above-mentioned advantageous effects appeared to involve the stress of the RAS and scavenging ROS, both were benefit to treat hypertension. This research showed that LPK and PRP had potential to be developed as antihypertension agents, which might be a new strategy for high value utilization of Sipunculus nudus L as functional food material.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Change history
18 February 2023
A Correction to this paper has been published: https://doi.org/10.1007/s10989-023-10496-4
Abbreviations
- S. nudus :
-
Sipunculus nudus L.
- ACE:
-
Angiotensin I converting enzyme
- ROS:
-
Reactive oxygen species
- RAS:
-
renin-angiotensin-aldosterone system
- RSM:
-
Response surface methodology
- DPPH:
-
1,1–Diphenyl-2-Picrylhydrazyl
- HHL:
-
Hippuryl–l– Histidyl-l-Leucine
- BBD:
-
Box–Behnken design
- MD:
-
Molecular dynamics
- Ang:
-
Angiotensin
References
Abachi S, Bazinet L, Beaulieu L (2019) Antihypertensive and angio tensin-i-converting enzyme (ACE)-inhibitory peptides from fish as potential cardioprotective compounds. Mar Drugs 17(11):613. https://doi.org/10.3390/md17110613
Abdelhedi O, Nasri R, Jridi M, Mora L, Oseguera-Toledo ME, Aristoy M-C et al (2017) In silico analysis and antihypertensive effect of ACE-inhibitory peptides from smooth-hound viscera protein hydrolysate: enzyme-peptide interaction study using molecular docking simulation. Process Biochem 58:145–159. https://doi.org/10.1016/j.procbio.2017.04.032
Abdelhedi O, Nasri R, Mora L, Jridi M, Toldrá F, Nasri M (2018) In silico analysis and molecular docking study of angiotensin I-converting enzyme inhibitory peptides from smooth-hound viscera protein hydrolysates fractionated by ultrafiltration. Food Chem 239:453–463. https://doi.org/10.1016/j.foodchem.2017.06.112
Aluko RE (2015) Antihypertensive peptides from food proteins. Annu Rev Food Sci Technol 6:235–262. https://doi.org/10.1146/annurev-food-022814-015520
Antonios TF, MacGregor GA (1995) Angiotensin converting enzyme inhibitors in hypertension: potential problems. J Hypertens Suppl. https://doi.org/10.1097/00004872-199509003-00003
Asoodeh A, Haghighi L, Chamani J, Ansari-Ogholbeyk MA, Mojallal-Tabatabaei Z, Lagzian M (2014) Potential angiotensin I converting enzyme inhibitory peptides from gluten hydrolysate: biochemical characterization and molecular docking study. J Cereal Sci 60:92–98. https://doi.org/10.1016/j.jcs.2014.01.019
Aydin F, Turkoglu V, Bas Z (2021) Purification and characterization of angiotensin-converting enzyme (ACE) from sheep lung. Mol Biol Rep 48(5):4191–4199. https://doi.org/10.1007/s11033-021-06432-8
Bhuyan BJ, Mugesh G (2011) Synthesis, characterization and antioxidant activity of angiotensin converting enzyme inhibitors. Org Biomol Chem 9(5):1356–1365. https://doi.org/10.1039/c0ob00823k
Bomback AS, Toto R (2009) Dual blockade of the renin-angiotensin-aldosterone system: beyond the ACE inhibitor and angiotensin-II receptor blocker combination. Am J Hypertens 22(10):1032–1040. https://doi.org/10.1038/ajh.2009.138
Boschin G, Scigliuolo GM, Resta D, Arnoldi A (2014) ACE-inhibitory activity of enzymatic protein hydrolysates from lupin and other legumes. Food Chem 145:34–40. https://doi.org/10.1016/j.foodchem.2013.07.076
Brands S, Schein P, Castro-Ochoa KF, Galinski EA (2019) Hydroxyl radical scavenging of the compatible solute ectoine generates two N-acetimides. Arch Biochem Biophys 674:108097. https://doi.org/10.1016/j.abb.2019.108097
Brown DI, Griendling KK (2015) Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res 116(3):531–549. https://doi.org/10.1161/circresaha.116.303584
Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87(10):840–844. https://doi.org/10.1161/01.res.87.10.840
Cao Y, Dai Y, Lu X, Li R, Zhou W, Li J et al (2021) Formation of shelf-stable pickering high internal phase emulsion stabilized by Sipunculus nudus water-soluble proteins (WSPs). Front Nutr 8:770218. https://doi.org/10.3389/fnut.2021.770218
Chi C-F, Wang B, Deng Y-Y, Wang Y-M, Deng S-G, Ma J-Y (2014) Isolation and characterization of three antioxidant pentapeptides from protein hydrolysate of monkfish (Lophius litulon) muscle. Food Res Int 55:222–228. https://doi.org/10.1016/j.foodres.2013.11.01
Cifuentes ME, Pagano PJ (2006) Targeting reactive oxygen species in hypertension. Curr Opin Nephrol Hypertens 15(2):179–1786. https://doi.org/10.1097/01.mnh.0000214776.19233.68
Cushman DW, Cheung HS (1971) Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol 20(7):1637–1648. https://doi.org/10.1016/0006-2952(71)90292-9
García MC, Puchalska P, Esteve C, Marina ML (2013) Vegetable foods: a cheap source of proteins and peptides with antihypertensive, antioxidant, and other less occurrence bioactivities. Talanta 106:328–349. https://doi.org/10.1016/j.talanta.2012.12.041
Ge YH, Chen YY, Zhou GS, Liu X, Tang YP, Liu R et al (2018) A novel antithrombotic protease from marine worm Sipunculus nudus. Int J Mol Sci 19(10):3023. https://doi.org/10.3390/ijms19103023
Gaikwad SB, More PR, Sonawane SK, Arya SS (2021) Antioxidant and anti–hypertensive bioactive peptides from Indian Mackerel fish waste. Int J Pept Res Ther 27:2671–2684. https://doi.org/10.1007/s10989-021-10282-0
Harrison DG, Widder J, Grumbach I, Chen W, Weber M, Searles C (2006) Endothelial mechanotransduction, nitric oxide and vascular inflammation. J Intern Med 259(4):351–363. https://doi.org/10.1111/j.1365-2796.2006.01621.x
Hernández-Ledesma B, del Mar Contreras M, Recio I (2011) Antihypertensive peptides: production, bioavailability and incorporation into foods. Adv Colloid Interface Sci 165(1):23–35. https://doi.org/10.1016/j.cis.2010.11.001
Ishak NH, Shaik MI, Yellapu NK, Howell NK, Sarbon NM (2021) Purification, characterization and molecular docking study of angiotensin-I converting enzyme (ACE) inhibitory peptide from shortfin scad (Decapterus macrosoma) protein hydrolysate. J Food Sci Technol 58(12):4567–4577. https://doi.org/10.1007/s13197-020-04944-y
Kheeree N, Sangtanoo P, Srimongkol P, Saisavoey T, Reamtong O, Choowongkomon K et al (2020) ACE inhibitory peptides derived from de-fatted lemon basil seeds: optimization, purification, identification, structure-activity relationship and molecular docking analysis. Food Funct 11(9):8161–8178. https://doi.org/10.1039/d0fo01240h
Kim M, Nam DG, Ju WT, Choe JS, Choi AJ (2020) Response surface methodology for optimization of process parameters and antioxidant properties of mulberry (Morus alba L.) leaves by extrusion. Molecules 25(22):5231. https://doi.org/10.3390/molecules25225231
Kim YS, Hwang JW, Jang JH, Son S, Seo IB, Jeong JH et al (2016) Trapa japonica pericarp extract reduces LPS-induced inflammation in macrophages and acute lung injury in mice. Molecules 21(3):392. https://doi.org/10.3390/molecules21030392
Kizhakekuttu TJ, Widlansky ME (2010) Natural antioxidants and hypertension: promise and challenges. Cardiovasc Ther. https://doi.org/10.1111/j.1755-5922.2010.00137.x
Lassoued I, Mora L, Barkia A, Aristoy MC, Nasri M, Toldrá F (2015) Bioactive peptides identified in thornback ray skin’s gelatin hydrolysates by proteases from Bacillus subtilis and Bacillus amyloliquefaciens. J Proteom 128:8–17. https://doi.org/10.1016/j.jprot.2015.06.016
Li L, Lai EY, Luo Z, Solis G, Mendonca M, Griendling KK et al (2018) High salt enhances reactive oxygen species and angiotensin II contractions of glomerular afferent arterioles from mice with reduced renal mass. Hypertension 72(5):1208–1216. https://doi.org/10.1161/HYPERTENSIONAHA.118.11354
Li N, Shen X, Liu Y, Zhang J, He Y, Liu Q et al (2016) Isolation, characterization, and radiation protection of Sipunculus nudus L. polysaccharide. Int J Biol Macromol 83:288–296. https://doi.org/10.1016/j.ijbiomac.2015.11.071
Li Y, Li J, Lin SJ, Yang ZS, Jin HX (2019) Preparation of antioxidant peptide by microwave-assisted hydrolysis of collagen and its protective effect against H(2)O(2)-induced damage of RAW264.7 cells. Mar Drugs 17(11):642. https://doi.org/10.3390/md17110642
Lin K, Zhang L-w, Han X, Cheng D-y (2017) Novel angiotensin I-converting enzyme inhibitory peptides from protease hydrolysates of Qula casein: Quantitative structure-activity relationship modeling and molecular docking study. J Funct Foods 32:266–277. https://doi.org/10.1016/j.jff.2017.03.008
Liu YM, Qian TT, Lin-Fang MO, Yin HE, Jiang SQ, Shen XR (2012) Study on the anti-fatigue effects of polysaccharides from Sipunculus nudus in mice. Chin J Mar Drugs 31(3):41–44. https://doi.org/10.13400/j.cnki.cjmd.2012.03.007
Luna-Vital DA, Luis Mojica G (2015) Biological potential of protein hydrolysates and peptides from common bean (Phaseolus vulgaris L.): A review. Food Res Int 76:39–50. https://doi.org/10.1016/j.foodres.2014.11.024
Luo F, Xing R, Wang X, Yang H, Li P (2018) Antioxidant activities of Rapana venosa meat and visceral mass during simulated gastrointestinal digestion and their membrane ultrafiltration fractions. J Food Sci Technol 53:395–403. https://doi.org/10.1111/ijfs.13597
Mazumdar S, Marar T, Devarajan S, Patki J (2021) Functional relevance of Gedunin as a bona fide ligand of NADPH oxidase 5 and ROS scavenger: an in silico and in vitro assessment in a hyperglycemic RBC model. Biochem Biophys Rep 25:100904. https://doi.org/10.1016/j.bbrep.2020.100904
Mirzaei M, Mirdamadi S, Safavi M, Hadizadeh M (2019) In vitro and in silico studies of novel synthetic ACE-inhibitory peptides derived from Saccharomyces cerevisiae protein hydrolysate. Bioorg Chem 87:647–654. https://doi.org/10.1016/j.bioorg.2019.03.057
Mirzapour-Kouhdasht A, Moosavi-Nasab M, Lee CW, Yun H, Eun JB (2021) Structure-function engineering of novel fish gelatin-derived multifunctional peptides using high-resolution peptidomics and bioinformatics. Sci Rep 11(1):7401. https://doi.org/10.1038/s41598-021-86808-9
Moslehishad M, Reza Ehsani M, Salami M, Mirdamadi S, Ezzatpanah H, Naslaji AN et al (2013) The comparative assessment of ACE-inhibitory and antioxidant activities of peptide fractions obtained from fermented camel and bovine milk by Lactobacillus rhamnosus PTCC 1637. Int Dairy J 29:82–87. https://doi.org/10.1016/j.idairyj.2012.10.015
Natesh R, Schwager SL, Sturrock ED, Acharya KR (2003) Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature 421(6922):551–554. https://doi.org/10.1038/nature01370
Oparil S, Acelajado M, Bakris G et al (2018) Hypertension. Nat Rev Dis Primers 4:18014. https://doi.org/10.1038/nrdp.2018.14
Qi Y, Tang X, Liu H, Lin Q, Lu Y, Luo H (2022) Identification of novel nonapeptides from Sipunculus nudus L. and comparing Its ACEI activities mechanism by molecular docking. Int J Pept Res Ther 28(1):1–12. https://doi.org/10.1007/s10989-021-10328-3
Rao S, Sun J, Liu Y, Zeng H, Su Y, Yang Y (2012) ACE inhibitory peptides and antioxidant peptides derived from in vitro digestion hydrolysate of hen egg white lysozyme. Food Chem 135(3):1245–1252. https://doi.org/10.1016/j.foodchem.2012.05.059
Schiffrin B, Radford SE, Brockwell DJ, Calabrese AN (2020) PyXlinkViewer: a flexible tool for visualization of protein chemical crosslinking data within the PyMOL molecular graphics system. Protein Sci 29(8):1851–1857. https://doi.org/10.1002/pro.3902
Sedeek M, Hébert RL, Kennedy CR, Burns KD, Touyz RM (2009) Molecular mechanisms of hypertension: role of Nox family NADPH oxidases. Curr Opin Nephrol Hypertens 18(2):122–127. https://doi.org/10.1097/MNH.0b013e32832923c3
Shang X, Dai L, He J, Yang X, Wang Y, Li B et al (2022) A high-value-added application of the stems of Rheum palmatum L. as a healthy food: the nutritional value, chemical composition, and anti-inflammatory and antioxidant activities. Food Funct 13(9):4901–4913. https://doi.org/10.1039/d1fo04214a
Sturrock ED, Natesh R, van Rooyen JM, Acharya KR (2004) Structure of angiotensin I-converting enzyme. Cell Mol Life Sci 61:2677–2686. https://doi.org/10.1007/s00018-004-4239-0
Su J, Jiang L, Wu J, Liu Z, Wu Y (2016) Anti-tumor and anti-virus activity of polysaccharides extracted from Sipunculus nudus (SNP) on Hepg2.2.15. Int J Biol Macromol 87:597–602. https://doi.org/10.1016/j.ijbiomac.2016.03.022
Touyz RM (2004) Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension 44(3):248–252. https://doi.org/10.1161/01.HYP.0000138070.47616.9d
Tu M, Feng L, Wang Z, Qiao M, Shahidi F, Lu W et al (2017) Sequence analysis and molecular docking of antithrombotic peptides from casein hydrolysate by trypsin digestion. J Funct Foods 32:313–323. https://doi.org/10.1016/j.jff.2017.03.015
van Esch JH, van Gool JM, de Bruin RJ, Payne JR, Montgomery HE, Hectors M et al (2008) Different contributions of the angiotensin-converting enzyme C-domain and N-domain in subjects with the angiotensin-converting enzyme II and DD genotype. J Hypertens 26(4):706–713. https://doi.org/10.1097/HJH.0b013e3282f465d2
Wang X, Chen H, Fu X, Li S, Wei J (2017) A novel antioxidant and ACE inhibitory peptide from rice bran protein: biochemical characterization and molecular docking study. Lwt Food Sci Technol 75:93–99. https://doi.org/10.1016/j.lwt.2016.08.047
Wolfe KL, Liu RH (2007) Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J Agric Food Chem 55(22):8896–8907. https://doi.org/10.1021/jf0715166
Wu J, Aluko RE, Muir AD (2002) Improved method for direct high-performance liquid chromatography assay of angiotensin-converting enzyme-catalyzed reactions. J Chromatogr A 950(1–2):125–130. https://doi.org/10.1016/s0021-9673(02)00052-3
Wu R, Huang J, Huan R, Chen L, Yi C, Liu D et al (2021) New insights into the structure-activity relationships of antioxidative peptide PMRGGGGYHY. Food Chem 337:127678. https://doi.org/10.1016/j.foodchem.2020.127678
Yang S, Fan W, Xu Y (2019) Melanoidins from Chinese distilled spent grain: content, preliminary structure, antioxidant, and ACE-inhibitory activities in vitro. Foods 8(10):516. https://doi.org/10.3390/foods8100516
Yu W, Gao J, Xue Z, Kou X, Wang Y, Zhai L (2013) Radical-scavenging activity, ACE-inhibiting capability and identification of rapeseed albumin hydrolysate. Food Sci Hum Wellness 2:93–98. https://doi.org/10.1016/j.fshw.2013.05.002
Zalba G, San José G, Moreno MU, Fortuño MA, Fortuño A, Beaumont FJ et al (2001) Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 38(6):1395–1399. https://doi.org/10.1161/hy1201.09961
Zhang CX, Dai ZR (2011) Anti-hypoxia activity of a polysaccharide extracted from the Sipunculus nudus L. Int J Biol Macromol 49(4):523–526. https://doi.org/10.1016/j.ijbiomac.2011.06.018
Zhang CX, Dai ZR (2011) Immunomodulatory activities on macrophage of a polysaccharide from Sipunculus nudus L. Food Chem Toxicol 49(11):2961–2967. https://doi.org/10.1016/j.fct.2011.07.044
Zhang CX, Dai ZR, Cai QX (2011) Anti-inflammatory and anti-nociceptive activities of Sipunculus nudus L. extract. J Ethnopharmacol 137(3):1177–1182. https://doi.org/10.1016/j.jep.2011.07.039
Zhao YQ, Zhang L, Tao J, Chi CF, Wang B (2019) Eight antihypertensive peptides from the protein hydrolysate of Antarctic krill (Euphausia superba): Isolation, identification, and activity evaluation on human umbilical vein endothelial cells (HUVECs). Food Res Int (Ottawa Ont) 121:197–204. https://doi.org/10.1016/j.foodres.2019.03.035
Acknowledgements
This work was supported by the Fund of Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang) (ZJW-2019-007) and the Science and Technology Program of Zhanjiang (2020A04005)].
Author information
Authors and Affiliations
Contributions
HL: performed the experiments and analyzed the data; writing-original draft; XC: complete part of the experiment; TW, MH: proofreading the manuscript; LL: partial experimental guidance; HL: project administration; YL: experimental design and guidance, revised the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original online version of this article was revised: the typo in author name Xiaoxuan Cai has been corrected.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Liu, H., Cai, X., Huang, M. et al. Dual Bioactivity of Angiotensin Converting Enzyme Inhibition and Antioxidant Novel Tripeptides from Sipunculus nudus L. and Their Related Mechanism Analysis for Antihypertention. Int J Pept Res Ther 29, 3 (2023). https://doi.org/10.1007/s10989-022-10470-6
Accepted:
Published:
DOI: https://doi.org/10.1007/s10989-022-10470-6