{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:40:39Z","timestamp":1785404439226,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82474111"],"award-info":[{"award-number":["82474111"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81872972"],"award-info":[{"award-number":["81872972"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82474111"],"award-info":[{"award-number":["82474111"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["81872972"],"award-info":[{"award-number":["81872972"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Vertical Research Development Fund of BUCM","award":["2023-ZXFZJJ-064"],"award-info":[{"award-number":["2023-ZXFZJJ-064"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Hypertension is one major risk factor of cardiovascular diseases, and RAS plays vital role during the development of hypertension. To obtain a novel antihypertensive peptide, Coix glutelin was hydrolyzed by trypsin and further separated by Sephadex G10. Based on 751 identified sequences, pharmacophore mapping, molecular docking, and in silico proteolysis were applied to screen and optimize the candidate sequence. Finally, a novel peptide, ENWAAL, was generated with IC50 of 210.57 \u03bcM, which acted with ACE in a competitively inhibitory pattern. The in vivo antihypertensive effect was evaluated in SHRs. Significant improvements were observed in hypertension-related characteristics, including blood pressure, cardiac structure and function, and serum angiotensin II (Ang II) level. In the brain, quantitative real-time PCR analysis revealed significant downregulation of angiotensin II type 1 receptor (AT1R) mRNA expression, concomitant with upregulation of angiotensin-converting enzyme 2 (ACE2) and MAS receptor. The protein expression of ACE and AT1R in the ENWAAL group also significantly decreased. This study can provide a candidate antihypertensive drug targeting RAS.<\/jats:p>","DOI":"10.3390\/biom16060888","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"888","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antihypertensive Peptide ENWAAL Derived from Coix Glutelin and Its Effect on the Expression of SHR Renin\u2013Angiotensin System"],"prefix":"10.3390","volume":"16","author":[{"given":"Wenjing","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjie","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiping","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liansheng","family":"Qiao","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","first-page":"1099","article-title":"The WHO Global report 2023 on hypertension warning the emerging hypertension burden in globe and its treatment strategy","volume":"47","author":"Kario","year":"2024","journal-title":"JSH"},{"key":"ref_2","unstructured":"WHO (2025). Global Report on Hypertension 2025: High Stakes: Turning Evidence into Action, WHO."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"111254","DOI":"10.1016\/j.mce.2021.111254","article-title":"Renin-angiotensin system and inflammation update","volume":"529","author":"Ramos","year":"2021","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"834","DOI":"10.3181\/00379727-106-26492","article-title":"Evidence for a Central Mechanism in Angiotensin Induced Hypertension","volume":"106","author":"Bickerton","year":"1961","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1007\/s00395-013-0386-5","article-title":"CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inflammation, oxidative stress and endothelial dysfunction","volume":"108","author":"Hausding","year":"2013","journal-title":"Basic Res. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s12012-025-10016-4","article-title":"Renin\u2013Angiotensin System Role in Cardiovascular Effects of Plasticizers: A Systematic Review","volume":"25","author":"Reis","year":"2025","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sitanggang, A.B., Putri, J.E., Palupi, N.S., Hatzakis, E., Syamsir, E., and Budijanto, S. (2021). Enzymatic Preparation of Bioactive Peptides Exhibiting ACE Inhibitory Activity from Soybean and Velvet Bean: A Systematic Review. Molecules, 26.","DOI":"10.3390\/molecules26133822"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Xue, B., Zhang, Y., and Johnson, A.K. (2020). Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00650"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrn1902","article-title":"The sympathetic control of blood pressure","volume":"7","author":"Guyenet","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1469-7793.2001.0445i.x","article-title":"Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat","volume":"531","author":"Paton","year":"2001","journal-title":"J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1590\/S0100-879X2011007500088","article-title":"Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: Implications in neurogenic hypertension","volume":"44","author":"Braga","year":"2011","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xue, B., Johnson, A.K., and Bassuk, A.G. (2025). Sex differences in the sensitization of prenatally programmed hypertension. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1589615"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1016\/j.jacc.2018.01.058","article-title":"Angiotensin-Converting Enzyme Inhibitors in Hypertension: To Use or Not to Use?","volume":"71","author":"Messerli","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10193","DOI":"10.2147\/JIR.S524947","article-title":"Exploring the Potential of Coix Seeds to Mitigate High Humidity-Induced Gut Inflammation via Microbiota and Metabolite Modulation","volume":"18","author":"Zhao","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117309","DOI":"10.1016\/j.jep.2023.117309","article-title":"Research on Coix seed as a food and medicinal resource, it\u2019s chemical components and their pharmacological activities: A review","volume":"319","author":"Li","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12093","DOI":"10.1021\/acs.jafc.4c12507","article-title":"Analysis of Coix Seed Oil Biosynthesis Facilitates the Identification of Lysophosphatidic Acid Acyltransferase","volume":"73","author":"Wei","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wu, G., Wang, X., Dong, H., Yu, J., Li, T., and Wang, X. (2025). Coix Seed Oil Alleviates Hyperuricemia in Mice by Ameliorating Oxidative Stress and Intestinal Microbial Composition. Nutrients, 17.","DOI":"10.3390\/nu17101679"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"145396","DOI":"10.1016\/j.foodchem.2025.145396","article-title":"Extraction, purification, structural characterization and bioactivities of polysaccharides from coix seed: A review","volume":"492","author":"Wang","year":"2025","journal-title":"Food Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, B., Qiao, L., Li, L., Zhang, Y., Li, K., Wang, L., and Qiao, Y. (2017). A Novel Antihypertensive Peptides Derived from Adlay (Coix larchryma-jobi L. var. ma-yuen Stapf) Glutelin. Molecules, 22.","DOI":"10.3390\/molecules22010123"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1080\/87559129.2021.1936005","article-title":"Understanding the Mechanism for the Structure-Activity Relationship of Food-Derived ACEI Peptides","volume":"39","author":"Ding","year":"2023","journal-title":"Food Rev. Int."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Qiao, L., Li, B., Chen, Y., Li, L., Chen, X., Wang, L., Lu, F., Luo, G., Li, G., and Zhang, Y. (2016). Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122099"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1007\/s00217-022-04015-w","article-title":"Characterization of ACE inhibitory peptide from Cassia tora L. globulin fraction and its antihypertensive activity in SHR","volume":"248","author":"Chen","year":"2022","journal-title":"Eur. Food Res. Technol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.foodchem.2018.02.107","article-title":"Identification of a novel ACE-inhibitory peptide from casein and evaluation of the inhibitory mechanisms","volume":"256","author":"Tu","year":"2018","journal-title":"Food Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"140734","DOI":"10.1016\/j.foodchem.2024.140734","article-title":"A novel ACE inhibitory peptide from Douchi hydrolysate: Stability, inhibition mechanism, and antihypertensive potential in spontaneously hypertensive rats","volume":"460","author":"Li","year":"2024","journal-title":"Food Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"105151","DOI":"10.1016\/j.jff.2022.105151","article-title":"Isolation and identification of novel angiotensin I-converting enzyme (ACE) inhibitory peptides from Pony Seed and evaluation of the inhibitory mechanisms","volume":"95","author":"Ye","year":"2022","journal-title":"J. Funct. Foods"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Daliri, E.B., Oh, D.H., and Lee, B.H. (2017). Bioactive Peptides. Foods, 6.","DOI":"10.3390\/foods6050032"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12753","DOI":"10.1039\/D5CC02378E","article-title":"Beyond the known cuts: Trypsin specificity in native proteins","volume":"61","author":"Gaspar","year":"2025","journal-title":"Chem. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"145073","DOI":"10.1016\/j.foodchem.2025.145073","article-title":"Identification of novel ACE inhibitory peptides from Nannochloropsis oculata through peptidomics, in silico screening and molecular docking","volume":"490","author":"Lin","year":"2025","journal-title":"Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"135873","DOI":"10.1016\/j.ijbiomac.2024.135873","article-title":"Discovery of a novel nanomolar angiotensin-I converting enzyme inhibitory peptide with unusual binding mechanisms derived from Chlorella pyrenoidosa","volume":"280","author":"Suo","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.lwt.2016.08.047","article-title":"A novel antioxidant and ACE inhibitory peptide from rice bran protein: Biochemical characterization and molecular docking study","volume":"75","author":"Wang","year":"2017","journal-title":"LWT"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117564","DOI":"10.1016\/j.ejmech.2025.117564","article-title":"A highly active angiotensin I-converting enzyme inhibitory peptide KAKW designed based on the role of C-terminal residue, and its antihypertensive effects on spontaneously hypertensive rats","volume":"290","author":"Hu","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"117162","DOI":"10.1016\/j.ejmech.2024.117162","article-title":"Combined usage of ligand- and structure-based virtual screening in the artificial intelligence era","volume":"283","author":"Dai","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Su, Y., Chen, S., Shen, J., Yi, Z., Liu, S., Cai, S., Pan, N., Qiao, K., Chen, X., and Chen, B. (2022). Screening and Molecular Mechanisms of Novel ACE-Inhibitory Peptides from Gracilariopsis lemaneiformis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314850"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/jb\/mvz029","article-title":"A novel angiotensin-I converting enzyme inhibitory peptide derived from the glutelin of vinegar soaked black soybean and its antihypertensive effect in spontaneously hypertensive rats","volume":"166","author":"Zhang","year":"2019","journal-title":"J. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1038\/ng.3667","article-title":"The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals","volume":"48","author":"Ehret","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Jackson, L., Eldahshan, W., Fagan, S.C., and Ergul, A. (2018). Within the Brain: The Renin Angiotensin System. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030876"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s10571-015-0327-y","article-title":"Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer\u2019s Disease","volume":"36","author":"Saavedra","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7995","DOI":"10.1007\/s00210-024-03156-x","article-title":"Pyridostigmine attenuates hypertension by inhibiting activation of the renin-angiotensin system in the hypothalamic paraventricular nucleus","volume":"397","author":"Lu","year":"2024","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1161\/HYPERTENSIONAHA.115.06017","article-title":"Role of the Paraventricular Nucleus of the Hypothalamus in the Sympathoexcitatory Effects of Leptin","volume":"66","author":"Shi","year":"2015","journal-title":"Hypertension"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1161\/CIRCRESAHA.113.301077","article-title":"Discovery and characterization of alamandine: A novel component of the renin-angiotensin system","volume":"112","author":"Lautner","year":"2013","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Cheng, L., Shi, C., Li, X., and Matsui, T. (2024). Impact of Peptide Transport and Memory Function in the Brain. Nutrients, 16.","DOI":"10.3390\/nu16172947"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108726","DOI":"10.1016\/j.fbio.2026.108726","article-title":"New insights into the protective effects of bioactive peptides against neurodegenerative disorders and the underlying molecular mechanisms","volume":"79","author":"Madhavi","year":"2026","journal-title":"Food Biosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1042\/CS20240787","article-title":"Cross-talk between microbiota\u2013gut\u2013brain axis and blood pressure regulation","volume":"139","author":"Welathanthree","year":"2025","journal-title":"Clin. Sci."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/888\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T01:19:56Z","timestamp":1781745596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/888"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["biom16060888"],"URL":"https:\/\/doi.org\/10.3390\/biom16060888","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]}}}