{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:33Z","timestamp":1787029113710,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T00:00:00Z","timestamp":1690502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taishan Industrial Leading Talents Project-Blue Talent Special"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Clam peptides, marine-derived biological peptides, have been broadly investigated and applied as health foods, among which immunomodulation is one of their biological activities that cannot be ignored in vivo. In this study, we concentrated on exploring the effects of Ruditapes philippinarum peptides (RPPs) on immunomodulation and the balance of intestinal microbiota in hydrocortisone (HC)-induced immunosuppressed mice. The results revealed that RPPs could increase the thymus and spleen indices and number of white blood cells, promote the secretion level of cytokines (IL-2, IL-6, TNF-\u03b1, and INF-\u03b3), repair the morphology of the spleen and thymus, and enhance the proliferation of T-lymphocyte subsets in immunosuppressed mice. Moreover, RPPs improved the abundance of beneficial bacteria and preserved the ecological equilibrium of the gut microbiota. In conclusion, RPPs have significant immunomodulatory effects on immunosuppressed mice and may be developed as immunomodulators or immune adjuvants in functional foods and drugs; they are also beneficial to the utilization of the high value of marine shellfish.<\/jats:p>","DOI":"10.3390\/molecules28155709","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T07:58:52Z","timestamp":1690531132000},"page":"5709","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Immune Enhancement of Clam Peptides on Immunosuppressed Mice Induced by Hydrocortisone"],"prefix":"10.3390","volume":"28","author":[{"given":"Meibin","family":"Lv","sequence":"first","affiliation":[{"name":"College of Life Sciences, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyue","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengcan","family":"Zou","sequence":"additional","affiliation":[{"name":"Qingdao Chenlan Pharmaceutical Co., Ltd., Qingdao 266105, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongli","family":"Yin","sequence":"additional","affiliation":[{"name":"Qingdao Chenlan Pharmaceutical Co., Ltd., Qingdao 266105, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghan","family":"Lv","sequence":"additional","affiliation":[{"name":"Qingdao Chenlan Pharmaceutical Co., Ltd., Qingdao 266105, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0616-479X","authenticated-orcid":false,"given":"Yuxi","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.ijbiomac.2019.10.035","article-title":"Apios americana Medik flowers polysaccharide (AFP) alleviate Cyclophosphamide-induced immunosuppression in ICR mice","volume":"144","author":"Chu","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3109\/08820139.2015.1122613","article-title":"Short-Chain Fatty Acids Regulate Cytokines and Th17\/Treg Cells in Human Peripheral Blood Mononuclear Cells in vitro","volume":"45","author":"Asarat","year":"2016","journal-title":"Immunol. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"272","DOI":"10.2174\/1871530314666141010105540","article-title":"Disorders of innate immunity in human ageing and effects of nutraceutical administration","volume":"14","author":"Magrone","year":"2014","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1080\/08820139.2019.1588291","article-title":"The Immuno-Enhancement Effects of Tubiechong (Eupolyphaga sinensis) Lyophilized Powder in Cyclophosphamide-Induced Immunosuppressed Mice","volume":"48","author":"Liu","year":"2019","journal-title":"Immunol. Investig."},{"key":"ref_6","first-page":"147","article-title":"Mechanisms of immunity and autoimmunity in the pathogenesis of diabetes","volume":"94","author":"Lender","year":"1978","journal-title":"Harefuah"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"672853","DOI":"10.3389\/fimmu.2021.672853","article-title":"Regulation of the Immune System Development by Glucocorticoids and Sex Hormones","volume":"12","author":"Quatrini","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_8","first-page":"785","article-title":"Regulation Mechanism of Glucocorticoids to Immune System in Ruminants Stress Response","volume":"48","author":"Zhang","year":"2017","journal-title":"Acta Vet. Zootech. Sin."},{"key":"ref_9","first-page":"233","article-title":"Immune Regulation by Glucocorticoids","volume":"90","author":"Ray","year":"2018","journal-title":"Horm. Res. Paediatr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"173630","DOI":"10.1016\/j.ejphar.2020.173630","article-title":"Artesunate protects immunosuppression mice induced by glucocorticoids via enhancing pro-inflammatory cytokines release and bacterial clearance","volume":"890","author":"Wang","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.nut.2014.08.006","article-title":"Chemical composition and immunomodulatory effects of enzymatic protein hydrolysates from common carp (Cyprinus carpio) egg","volume":"31","author":"Chalamaiah","year":"2015","journal-title":"Nutrition"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104411","DOI":"10.1016\/j.jff.2021.104411","article-title":"The antihypertensive effect and mechanisms of bioactive peptides from Ruditapes philippinarum fermented with Bacillus natto in spontaneously hypertensive rats","volume":"79","author":"Song","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5571","DOI":"10.1007\/s11033-021-06576-7","article-title":"Evaluation of the in vivo antihypertensive effect and antioxidant activity of HL-7 and HL-10 peptide in mice","volume":"48","author":"Ghasemi","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_14","first-page":"1850","article-title":"Immune promotive effect of bioactive peptides may be mediated by regulating the expression of SOCS1\/miR-155","volume":"18","author":"Chen","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1021\/acs.jafc.1c08315","article-title":"Isolation, Identification, and Immunomodulatory Mechanism of Peptides from Lepidium meyenii (Maca) Protein Hydrolysate","volume":"70","author":"He","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"959726","DOI":"10.3389\/fmicb.2022.959726","article-title":"Effects of compound small peptides of Chinese medicine on intestinal immunity and cecal intestinal flora in CTX immunosuppressed mice","volume":"13","author":"Cui","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.3168\/jds.2013-6758","article-title":"Immunomodulatory and hypoallergenic properties of milk protein hydrolysates in ICR mice","volume":"96","author":"Pan","year":"2013","journal-title":"J. Dairy Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12842","DOI":"10.1021\/acs.jafc.9b08297","article-title":"Recent Progress in Enzymatic Release of Peptides in Foods of Animal Origin and Assessment of Bioactivity","volume":"68","author":"Gallego","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1007\/s13197-020-04796-6","article-title":"Evaluation indicators of Ruditapes philippinarum nutritional quality","volume":"58","author":"Chen","year":"2020","journal-title":"J. Food Sci. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wang, Q., Liu, F.-J., Wang, X.-M., Zhao, G.-H., Cai, D., Yu, J.-H., Yin, F.-W., and Zhou, D.-Y. (2022). Preparation and Hepatoprotective Activities of Peptides Derived from Mussels (Mytilus edulis) and Clams (Ruditapes philippinarum). Mar. Drugs, 20.","DOI":"10.3390\/md20110719"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sun, X., Wang, M., Xu, C., Wang, S., Li, L., Zou, S., Yu, J., and Wei, Y. (2022). Positive Effect of a Pea\u2013Clam Two-Peptide Composite on Hypertension and Organ Protection in Spontaneously Hypertensive Rats. Nutrients, 14.","DOI":"10.3390\/nu14194069"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ronchetti, S., Ricci, E., Migliorati, G., Gentili, M., and Riccardi, C. (2018). How Glucocorticoids Affect the Neutrophil Life. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19124090"},{"key":"ref_23","first-page":"42","article-title":"The Effect of Glucocorticoids on Angiogenesis in the Treatment of Solid Tumors","volume":"1","author":"Liu","year":"2020","journal-title":"J. Cell. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2020\/1603735","article-title":"Effects of Polysaccharide from Malus halliana Koehne Flowers in Cyclophosphamide-Induced Immunosuppression and Oxidative Stress on Mice","volume":"2020","author":"Niu","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"105481","DOI":"10.1016\/j.phrs.2021.105481","article-title":"Ginsenosides for cardiovascular diseases; update on pre-clinical and clinical evidence, pharmacological effects and the mechanisms of action","volume":"166","author":"Sarhene","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"916618","DOI":"10.3389\/fimmu.2022.916618","article-title":"Effects of Fucoidan Isolated From Laminaria japonica on Immune Response and Gut Microbiota in Cyclophosphamide-Treated Mice","volume":"13","author":"Tang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7064","DOI":"10.1021\/acs.jafc.1c02294","article-title":"Sodium Alginate Modulates Immunity, Intestinal Mucosal Barrier Function, and Gut Microbiota in Cyclophosphamide-Induced Immunosuppressed BALB\/c Mice","volume":"69","author":"Huang","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41538-022-00140-8","article-title":"Immunomodulatory activity of a water-soluble polysaccharide extracted from mussel on cyclophosphamide-induced immunosuppressive mice models","volume":"6","author":"Xiang","year":"2022","journal-title":"Npj Sci. Food"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1039\/C7FO01302G","article-title":"Effects of polysaccharides from purple sweet potatoes on immune response and gut microbiota composition in normal and cyclophosphamide treated mice","volume":"9","author":"Tang","year":"2017","journal-title":"Food Funct."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Khan, A.I., Rehman, A.U., Farooqui, N.A., Siddiqui, N.Z., Ayub, Q., Ramzan, M.N., Wang, L., and Xin, Y. (2022). Effects of Shrimp Peptide Hydrolysate on Intestinal Microbiota Restoration and Immune Modulation in Cyclophosphamide-Treated Mice. Molecules, 27.","DOI":"10.3390\/molecules27051720"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.intimp.2019.04.003","article-title":"Ginsenoside Rg3 improves cyclophosphamide-induced immunocompetence in Balb\/c mice","volume":"72","author":"Liu","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/978-94-017-9487-9_3","article-title":"Th1\/Th2 Cell\u2019s Function in Immune System","volume":"Volume 841","author":"Sun","year":"2014","journal-title":"T Helper Cell Differentiation and Their Function"},{"key":"ref_33","first-page":"113","article-title":"The CD4\/CD8 Lineages: Central Decisions and Peripheral Modifications for T Lymphocytes","volume":"Volume 373","author":"Boehm","year":"2014","journal-title":"Thymic Development and Selection of T Lymphocytes"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.3389\/fimmu.2020.01042","article-title":"Editorial: Follicular Helper T Cells in Immunity and Autoimmunity","volume":"11","author":"Cicalese","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"111244","DOI":"10.1016\/j.fct.2020.111244","article-title":"Ganoderma atrum polysaccharide ameliorates intestinal mucosal dysfunction associated with autophagy in immunosuppressed mice","volume":"138","author":"Ying","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.foodchem.2012.08.090","article-title":"Immunomodulatory effect of Ganoderma atrum polysaccharide on CT26 tumor-bearing mice","volume":"136","author":"Zhang","year":"2013","journal-title":"Food Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Hu, X., Lin, L., Ding, G., and Yu, F. (2019). Immunomodulatory Activity of Low Molecular-Weight Peptides from Nibea japonica in RAW264.7 Cells via NF-\u03baB Pathway. Mar. Drugs, 17.","DOI":"10.3390\/md17070404"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jep.2016.08.046","article-title":"Immuno-enhancement effects of Yifei Tongluo Granules on cyclophosphamide-induced immunosuppression in Balb\/c mice","volume":"194","author":"Wang","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ijbiomac.2018.04.178","article-title":"Ameliorative effects of Antrodia cinnamomea polysaccharides against cyclophosphamide-induced immunosuppression related to Nrf2\/HO-1 signaling in BALB\/c mice","volume":"116","author":"Liu","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_40","first-page":"15","article-title":"Effects of interleukin-2 in immunostimulation and immunosuppression","volume":"217","author":"Pol","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.foodchem.2016.12.041","article-title":"Immunomodulatory activity of protein hydrolysates derived from Virgibacillus halodenitrificans SK1-3-7 proteinase","volume":"224","author":"Toopcham","year":"2017","journal-title":"Food Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jff.2019.02.030","article-title":"In vitro fermentation of novel microwave-synthesized non-digestible oligosaccharides and their impact on the composition and metabolites of human gut microbiota","volume":"55","author":"Wang","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jff.2018.03.020","article-title":"Immunomodulatory effect of Ganoderma atrum polysaccharides on Th17\/Treg balance","volume":"45","author":"Xiang","year":"2018","journal-title":"J. Funct. Foods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.ijbiomac.2017.09.051","article-title":"Characterization and protective effect of Polygonatum sibiricum polysaccharide against cyclophosphamide-induced immunosuppression in Balb\/c mice","volume":"107","author":"Liu","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.foodchem.2017.10.087","article-title":"Immunomodulatory and anticancer protein hydrolysates (peptides) from food proteins: A review","volume":"245","author":"Chalamaiah","year":"2017","journal-title":"Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zhao, R., Jiang, S., Tang, Y., and Ding, G. (2023). Effects of Low Molecular Weight Peptides from Red Shrimp (Solenocera crassicornis) Head on Immune Response in Immunosuppressed Mice. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210297"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Xiang, X.-W., Zheng, H.-Z., Wang, R., Chen, H., Xiao, J.-X., Zheng, B., Liu, S.-L., and Ding, Y.-T. (2021). Ameliorative Effects of Peptides Derived from Oyster (Crassostrea gigas) on Immunomodulatory Function and Gut Microbiota Structure in Cyclophosphamide-Treated Mice. Mar. Drugs, 19.","DOI":"10.3390\/md19080456"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1039\/C8FO02312C","article-title":"Ovotransferrin ameliorates the dysbiosis of immunomodulatory function and intestinal microbiota induced by cyclophosphamide","volume":"10","author":"Zhu","year":"2019","journal-title":"Food Funct."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"117668","DOI":"10.1016\/j.carbpol.2021.117668","article-title":"Value added immunoregulatory polysaccharides of Hericium erinaceus and their effect on the gut microbiota","volume":"262","author":"Yang","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1039287","DOI":"10.3389\/fmicb.2023.1039287","article-title":"Compound small peptide of Chinese medicine alleviates cyclophosphamide induced immunosuppression in mice by Th17\/Treg and jejunum intestinal flora","volume":"14","author":"Cui","year":"2023","journal-title":"Front. Microbiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"103470","DOI":"10.1016\/j.jff.2019.103470","article-title":"Polysaccharides from the flowers of tea (Camellia sinensis L.) modulate gut health and ameliorate cyclophosphamide-induced immunosuppression","volume":"61","author":"Chen","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"766296","DOI":"10.3389\/fimmu.2021.766296","article-title":"Polysaccharides From the Roots of Millettia Speciosa Champ Modulate Gut Health and Ameliorate Cyclophosphamide-Induced Intestinal Injury and Immunosuppression","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhao, Q., Hou, D., Fu, Y., Xue, Y., Guan, X., and Shen, Q. (2021). Adzuki Bean Alleviates Obesity and Insulin Resistance Induced by a High-Fat Diet and Modulates Gut Microbiota in Mice. Nutrients, 13.","DOI":"10.3390\/nu13093240"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1039\/C5FO01516B","article-title":"Lactobacillus plantarum NCU116 attenuates cyclophosphamide-induced intestinal mucosal injury, metabolism and intestinal microbiota disorders in mice","volume":"7","author":"Xie","year":"2016","journal-title":"Food Funct."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7954","DOI":"10.1039\/D1FO01257F","article-title":"The immunoenhancement effects of sea buckthorn pulp oil in cyclophosphamide-induced immunosuppressed mice","volume":"12","author":"Zhang","year":"2021","journal-title":"Food Funct."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"906","DOI":"10.3389\/fimmu.2020.00906","article-title":"The Genus Alistipes: Gut Bacteria With Emerging Implications to Inflammation, Cancer, and Mental Health","volume":"11","author":"Parker","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_57","first-page":"149","article-title":"The effect of aspirin on immune function in cyclophosphamide model of mice","volume":"38","author":"Zhao","year":"2013","journal-title":"Chin. J. Antibiot."},{"key":"ref_58","first-page":"216","article-title":"Optimization of Enzymatic Hydrolysis of Hongdao Clam and Anti-hypertensive Activity of the Resulted Products","volume":"42","author":"Cao","year":"2021","journal-title":"Sci. Technol. Food Ind."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/15\/5709\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:21:17Z","timestamp":1760127677000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/15\/5709"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,28]]},"references-count":58,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["molecules28155709"],"URL":"https:\/\/doi.org\/10.3390\/molecules28155709","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,28]]}}}