{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T17:26:44Z","timestamp":1786296404724,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T00:00:00Z","timestamp":1612569600000},"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":["81372870"],"award-info":[{"award-number":["81372870"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["135130006, 130029804, 111498001, 131004006."],"award-info":[{"award-number":["135130006, 130029804, 111498001, 131004006."]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Foundation of Jilin Province Science &amp; Technology Committee (China)","award":["20200404124YY, 20200201135JC."],"award-info":[{"award-number":["20200404124YY, 20200201135JC."]}]},{"name":"Foundation of Jilin Province Development and Reform Commission (China)","award":["2020C015, 2018C051-1."],"award-info":[{"award-number":["2020C015, 2018C051-1."]}]},{"name":"Foundation of Changchun Science and Technology Committee (China)","award":["17YJ003-1"],"award-info":[{"award-number":["17YJ003-1"]}]},{"name":"Foundation of Ministry of Industry and Information Technology of Changchun (China)","award":["2017342"],"award-info":[{"award-number":["2017342"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Stevioside, a diterpenoid glycoside, is widely used as a natural sweetener; meanwhile, it has been proven to possess various pharmacological properties as well. However, until now there were no comprehensive evaluations focused on the anti-inflammatory activity of stevioside. Thus, the anti-inflammatory activities of stevioside, both in macrophages (RAW 264.7 cells, THP-1 cells, and mouse peritoneal macrophages) and in mice, were extensively investigated for the potential application of stevioside as a novel anti-inflammatory agent. The results showed that stevioside was capable of down-regulating lipopolysaccharide (LPS)-induced expression and production of pro-inflammatory cytokines and mediators in macrophages from different sources, such as IL-6, TNF-\u03b1, IL-1\u03b2, iNOS\/NO, COX2, and HMGB1, whereas it up-regulated the anti-inflammatory cytokines IL-10 and TGF-\u03b21. Further investigation showed that stevioside could activate the AMPK -mediated inhibition of IRF5 and NF-\u03baB pathways. Similarly, in mice with LPS-induced lethal shock, stevioside inhibited release of pro-inflammatory factors, enhanced production of IL-10, and increased the survival rate of mice. More importantly, stevioside was also shown to activate AMPK in the periphery blood mononuclear cells of mice. Together, these results indicated that stevioside could significantly attenuate LPS-induced inflammatory responses both in vitro and in vivo through regulating several signaling pathways. These findings further strengthened the evidence that stevioside may be developed into a therapeutic agent against inflammatory diseases.<\/jats:p>","DOI":"10.3390\/molecules26040858","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T02:08:12Z","timestamp":1613268492000},"page":"858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Stevioside Activates AMPK to Suppress Inflammation in Macrophages and Protects Mice from LPS-Induced Lethal Shock"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3668-7209","authenticated-orcid":false,"given":"Fuyao","family":"Wei","sequence":"first","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhu","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Yu","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenbo","family":"Song","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyue","family":"Wang","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guannan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Huang","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongli","family":"Bao","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luguo","family":"Sun","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,6]]},"reference":[{"key":"ref_1","unstructured":"Joint FAO\/WHO Expert Committee on Food Additives (2006). Safety Evaluation of Certain Food Additives\/Prepared by the Sixty-Third Meeting of the Joint FAO\/WHO Expert Committee on Food Additives (JEFCA), WHO. International Programme on Chemical Safety."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ullah, A., Munir, S., Mabkhot, Y., and Badshah, S.L. (2019). Bioactivity Profile of the Diterpene Isosteviol and its Derivatives. Molecules, 24.","DOI":"10.3390\/molecules24040678"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1039\/C8FO01883A","article-title":"Effect of dietary stevioside supplementation on growth performance, nutrient digestibility, serum parameters, and intestinal microflora in broilers","volume":"10","author":"Wu","year":"2019","journal-title":"Food Funct."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103895","DOI":"10.1016\/j.jff.2020.103895","article-title":"Stevioside improved hyperglycemia-induced cardiac dysfunction by attenuating the development of fibrosis and promoting the degradation of established fibrosis","volume":"68","author":"Zhao","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.jff.2019.04.034","article-title":"Attenuation of high-fat diet-induced fatty liver through PPAR\u03b1 activation by stevioside","volume":"57","author":"Jia","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1039\/C8FO01663A","article-title":"Stevioside attenuates isoproterenol-induced mouse myocardial fibrosis through inhibition of the myocardial NF-kappaB\/TGF-beta1\/Smad signaling pathway","volume":"10","author":"Wang","year":"2019","journal-title":"Food Funct"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00640","DOI":"10.1016\/j.heliyon.2018.e00640","article-title":"Stevioside modulates oxidative damage in the liver and kidney of high fat\/low streptozocin diabetic rats","volume":"4","author":"Rotimi","year":"2018","journal-title":"Heliyon"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.pharmthera.2008.09.007","article-title":"Stevioside and related compounds: Therapeutic benefits beyond sweetness","volume":"121","author":"Chatsudthipong","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.biopha.2017.03.045","article-title":"Insight into anti-diabetic effect of low dose of stevioside","volume":"90","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1007\/s10787-020-00736-0","article-title":"Anti-inflammatory effect of stevioside abates Freund\u2019s complete adjuvant (FCA)-induced adjuvant arthritis in rats","volume":"28","author":"Alavala","year":"2020","journal-title":"Inflammopharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1007\/s10753-012-9483-0","article-title":"Stevioside Suppressed Inflammatory Cytokine Secretion by Downregulation of NF-\u03baB and MAPK Signaling Pathways in LPS-Stimulated RAW264.7 Cells","volume":"35","author":"Fengyang","year":"2012","journal-title":"Inflammation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1007\/s10753-014-9915-0","article-title":"Stevioside Plays an Anti-inflammatory Role by Regulating the NF-\u03baB and MAPK Pathways in S. aureus-infected Mouse Mammary Glands","volume":"37","author":"Wang","year":"2014","journal-title":"Inflammation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.1002\/jsfa.6287","article-title":"Anti-inflammatory and immunomodulatory activities of stevioside and steviol on colonic epithelial cells","volume":"93","author":"Boonkaewwan","year":"2013","journal-title":"J. Sci. Food Agric."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1021\/jf0523465","article-title":"Anti-Inflammatory and Immunomodulatory Activities of Stevioside and Its Metabolite Steviol on THP-1 Cells","volume":"54","author":"Boonkaewwan","year":"2006","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"118258","DOI":"10.1016\/j.lfs.2020.118258","article-title":"The intrinsic and extrinsic elements regulating inflammation","volume":"260","author":"Mollaei","year":"2020","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sudhakaran, M., and Doseff, A.I. (2020). The Targeted Impact of Flavones on Obesity-Induced Inflammation and the Potential Synergistic Role in Cancer and the Gut Microbiota. Molecules, 25.","DOI":"10.3390\/molecules25112477"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3595","DOI":"10.1096\/fj.14-260323","article-title":"Noncoding RNAs, cytokines, and inflammation-related diseases","volume":"29","author":"Samblas","year":"2015","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/joim.12276","article-title":"High-mobility group box-1 in sterile inflammation","volume":"276","author":"Tsung","year":"2014","journal-title":"J Intern Med"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1089\/107999099313695","article-title":"The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes","volume":"19","author":"Donnelly","year":"1999","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.biomaterials.2015.11.065","article-title":"Transforming growth factor-beta 1 delivery from microporous scaffolds decreases inflammation post-implant and enhances function of transplanted islets","volume":"80","author":"Liu","year":"2016","journal-title":"Biomaterials"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, L.C., Pan, Z.H., Ning, D.S., and Fu, Y.X. (2020). Anti-Inflammatory Effect of Simonsinol on Lipopolysaccharide Stimulated RAW264.7 Cells through Inactivation of NF-\u03baB Signaling Pathway. Molecules, 25.","DOI":"10.3390\/molecules25163573"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/34956","article-title":"Crystal structure of p50\/p65 heterodimer of transcription factor NF-\u03baB bound to DNA","volume":"391","author":"Chen","year":"1998","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.clim.2014.06.001","article-title":"IRF5-mediated signaling and implications for SLE","volume":"153","author":"Lazzari","year":"2014","journal-title":"Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.biocel.2018.03.012","article-title":"Diverse mechanisms of IRF5 action in inflammatory responses","volume":"99","author":"Khoyratty","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Stempel, M., Chan, B., Jurani\u0107 Lisni\u0107, V., Krmpoti\u0107, A., Hartung, J., Paludan, S.R., F\u00fcllbrunn, N., Lemmermann, N.A., and Brinkmann, M.M. (2019). The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-\u03baB signaling and STING\u2019s dual role during MCMV infection. EMBO J., 38.","DOI":"10.15252\/embj.2018100983"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8633","DOI":"10.4049\/jimmunol.181.12.8633","article-title":"Adenosine 5 \u2018-Monophosphate-Activated Protein Kinase Promotes Macrophage Polarization to an Anti-Inflammatory Functional Phenotype","volume":"181","author":"Sag","year":"2008","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gao, X.-H., Zhang, S.-D., Wang, L.-T., Yu, L., Zhao, X.-L., Ni, H.-Y., Wang, Y.-Q., Wang, J.-D., Shan, C.-H., and Fu, Y.-J. (2020). Anti-Inflammatory Effects of Neochlorogenic Acid Extract from Mulberry Leaf (Morus alba L.) Against LPS-Stimulated Inflammatory Response through Mediating the AMPK\/Nrf2 Signaling Pathway in A549 Cells. Molecules, 25.","DOI":"10.3390\/molecules25061385"},{"key":"ref_28","unstructured":"Wei, W., Wu, X., and Li, Y. (2010). Experimental Methodology of Pharmacology. Pharmacological Experiment Design and Statistical Analysis, Peoples\u2019 Medical Publishing House."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1002\/jbm.a.35415","article-title":"Extended culture of macrophages from different sources and maturation results in a common M2 phenotype","volume":"103","author":"Chamberlain","year":"2015","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Oh, J.H., Karadeniz, F., Lee, J.I., Park, S.Y., Seo, Y., and Kong, C.S. (2020). Anticatabolic and Anti-Inflammatory Effects of Myricetin 3-O-\u03b2-d-Galactopyranoside in UVA-Irradiated Dermal Cells via Repression of MAPK\/AP-1 and Activation of TGF\u03b2\/Smad. Molecules, 25.","DOI":"10.3390\/molecules25061331"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s11892-013-0375-y","article-title":"Diabetes mellitus and inflammation","volume":"13","author":"Sobngwi","year":"2013","journal-title":"Curr. Diabetes Rep."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yang, C., Zhang, D.M., Song, Z.B., Hou, Y.Q., Bao, Y.L., Sun, L.G., Yu, C.L., and Li, Y.X. (2015). Protumoral TSP50 Regulates Macrophage Activities and Polarization via Production of TNF-\u03b1 and IL-1\u03b2, and Activation of the NF-\u03baB Signaling Pathway. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145095"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1016\/j.cellsig.2011.06.005","article-title":"CaMK IV phosphorylates prohibitin 2 and regulates prohibitin 2-mediated repression of MEF2 transcription","volume":"23","author":"Sun","year":"2011","journal-title":"Cell Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.clim.2009.11.009","article-title":"A human microsatellite DNA-mimicking oligodeoxynucleotide with CCT repeats negatively regulates TLR7\/9-mediated innate immune responses via selected TLR pathways","volume":"134","author":"Sun","year":"2010","journal-title":"Clin. Immunol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/858\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:20:27Z","timestamp":1760160027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/858"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,6]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["molecules26040858"],"URL":"https:\/\/doi.org\/10.3390\/molecules26040858","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,6]]}}}