{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:23:47Z","timestamp":1784827427736,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Jilin Provience","award":["20180101242JC"],"award-info":[{"award-number":["20180101242JC"]}]},{"name":"Scientific Research Project of Education Department of  Jilin Province","award":["JJKH20201177KJ"],"award-info":[{"award-number":["JJKH20201177KJ"]}]},{"name":"Research  Foundation of Jilin Province Science &amp; Technology Committee","award":["20200404124YY"],"award-info":[{"award-number":["20200404124YY"]}]},{"name":"Department of Human  Resources and Social Security of Jilin Province","award":["2020009"],"award-info":[{"award-number":["2020009"]}]},{"DOI":"10.13039\/100015800","name":"Jilin Province Development and Reform Commission","doi-asserted-by":"publisher","award":["2020C015"],"award-info":[{"award-number":["2020C015"]}],"id":[{"id":"10.13039\/100015800","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It seems quite necessary to obtain effective substances from natural products against inflammatory response (IR) as there are presently clinical problems regarding accompanying side effects and lowered quality of life. This work aimed to investigate the abilities of hyssopuside (HY), a novel phenolic glycoside isolated from Hyssopus cuspidatus (H. cuspidatus), against IR in lipopolysaccharide (LPS)-induced RAW 264.7 cells and mouse peritoneal macrophages. The results indicated that HY could reduce nitric oxide (NO) production and inhibit the production and secretion of pro-inflammatory mediators including tumor necrosis factor-\u03b1 (TNF-\u03b1), interleukin-6 (IL-6), and interleukin-1\u03b2 (IL-1\u03b2) in LPS-stimulated macrophages. Moreover, data from the immunofluorescence study showed that HY suppressed nuclear translocation of nuclear factor-kappa B (NF-\u03baB) upon LPS induction. The Western blot results suggested that HY reversed the LPS-induced degradation of I\u03baB (inhibitor of NF-\u03baB), which is normally required for the activation of NF-\u03baB. Meanwhile, the overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) diminished significantly with the presence of HY in response to LPS stimulation. On the other hand, HY had a negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. Moreover, an in silico study of HY against four essential proteins\/enzymes revealed that COX-2 was the most efficient enzyme for the interaction, and binding of residues Phe179, Asn351, and Ser424 with HY played crucial roles in the observed activity. The structure analysis indicated the typical characterizations with phenylethanoid glycoside contributed to the anti-inflammatory effects of HY. These results indicated that HY manipulated its anti-inflammatory effects mainly through blocking the NF-\u03baB signal transduction pathways. Collectively, we believe that HY could be a potential alternative phenolic agent for alleviating excessive inflammation in many inflammation-associated diseases.<\/jats:p>","DOI":"10.3390\/ijms222212128","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T12:46:23Z","timestamp":1636461983000},"page":"12128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Discovery of Phenolic Glycoside from Hyssopus cuspidatus Attenuates LPS-Induced Inflammatory Responses by Inhibition of iNOS and COX-2 Expression through Suppression of NF-\u03baB Activation"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9661-5995","authenticated-orcid":false,"given":"Xingyu","family":"Liu","sequence":"first","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Su","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geng","family":"Wang","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5380-2021","authenticated-orcid":false,"given":"Lihua","family":"Zheng","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guannan","family":"Wang","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, 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 130117, 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 130117, 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 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Huang","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature07205","article-title":"Cancer-related inflammation","volume":"454","author":"Mantovani","year":"2008","journal-title":"Nature"},{"key":"ref_2","first-page":"469","article-title":"Nitric oxide and superoxide in inflammation and immune regulation","volume":"54","author":"Guzik","year":"2003","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1165\/ajrcmb\/2.3.233","article-title":"Macrophages: Important Physiologic and Pathologic Sources of Polypeptide Growth Factors","volume":"2","author":"Pierce","year":"1990","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.apsb.2015.01.010","article-title":"Neocryptotanshinone inhibits lipopolysaccharide-induced inflammation in RAW264.7 macrophages by suppression of NF-\u03baB and iNOS signaling pathways","volume":"5","author":"Wu","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Li, Y., Wu, Y., Yao, X., Fang, H., Yu, C., Bao, Y., Wu, Y., Song, Z., Sun, Y., and Zheng, L. (2017). Ginkgolide A Ameliorates LPS-Induced Inflammatory Responses In Vitro and In Vivo. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040794"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev.immunol.18.1.621","article-title":"Phosporilation meets the ubiquitination: The Control of NF- kapp B Activity","volume":"18","author":"Karin","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0027-5107(01)00183-X","article-title":"Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of COX-2 and iNOS through suppression of NF-\u03baB activation","volume":"480\u2013481","author":"Surh","year":"2001","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"a000034","DOI":"10.1101\/cshperspect.a000034","article-title":"The NF-kappaB family of transcription factors and its regulation","volume":"1","author":"Oeckinghaus","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"117","DOI":"10.23736\/S0031-0808.18.03455-9","article-title":"Current therapies and targets for type 2 diabetes mellitus","volume":"60","author":"Chellappan","year":"2018","journal-title":"Panminerva Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1016\/j.phytochem.2011.07.008","article-title":"Terpenoids and phenethyl glucosides from Hyssopus cuspidatus (Labiatae)","volume":"72","author":"Furukawa","year":"2011","journal-title":"Phytochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.phymed.2018.12.043","article-title":"JAX2, an ethanol extract of Hyssopus cuspidatus Boriss, can prevent bronchial asthma by inhibiting MAPK\/NF-\u03baB inflammatory signaling","volume":"57","author":"Yuan","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1080\/14786419.2018.1488710","article-title":"Chemical components of Hyssopus cuspidatus Boriss.: Isolation and identification, characterization by HPLC-DAD-ESI-HRMS\/MS, antioxidant activity and antimicrobial activity","volume":"34","author":"Shomirzoeva","year":"2020","journal-title":"Nat. Prod. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.phytol.2021.09.007","article-title":"Phytochemistry Letters Two new phenolic acids and one new phenolic glycoside from Hyssopus cuspidatus Boriss and their anti-inflammatory activities","volume":"46","author":"Liu","year":"2021","journal-title":"Phytochem. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hankittichai, P., Buacheen, P., Pitchakarn, P., Takuathung, M.N., Wikan, N., Smith, D.R., Potikanond, S., and Nimlamool, W. (2020). Artocarpus lakoocha Extract Inhibits LPS-Induced Inflammatory Response in RAW 264.7 Macrophage cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041355"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1039\/C5NP00127G","article-title":"Strategies for target identification of antimicrobial natural products","volume":"33","author":"Farha","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s40200-020-00535-y","article-title":"Hyssopus officinalis exerts hypoglycemic effects on streptozotocin-induced diabetic rats via modulating GSK-3\u03b2, C-fos, NF-\u03baB, ABCA1 and ABGA1 gene expression","volume":"19","author":"Kadry","year":"2020","journal-title":"J. Diabetes Metab. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5490","DOI":"10.3390\/molecules19055490","article-title":"Evaluation of antioxidant and antimicrobial activities and phenolic profile for Hyssopus officinalis, Ocimum basilicum and Teucrium chamaedrys","volume":"19","author":"Vlase","year":"2014","journal-title":"Molecules"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.3892\/etm.2014.1978","article-title":"Effect of Hyssopus officinalis L. on inhibiting airway inflammation and immune regulation in a chronic asthmatic mouse model","volume":"8","author":"Ma","year":"2014","journal-title":"Exp. Ther. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.phytochem.2003.10.009","article-title":"Isolation of \u03b1-glusosidase inhibitors from hyssop (Hyssopus officinalis)","volume":"65","author":"Matsuura","year":"2004","journal-title":"Phytochemistry"},{"key":"ref_22","first-page":"1","article-title":"Differential effect of herbal tea extracts on free fatty acids-, ethanol- and acetaminophen-induced hepatotoxicity in FL83B hepatocytes","volume":"9","author":"Chen","year":"2019","journal-title":"Drug Chem. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1097\/CCM.0b013e31827c09f8","article-title":"Benchmarking the incidence and mortality of severe sepsis in the united states","volume":"41","author":"Gaieski","year":"2013","journal-title":"Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1124\/pr.114.010090","article-title":"Toll-like receptors in the vascular system: Sensing the dangers within","volume":"68","author":"Goulopoulou","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7625","DOI":"10.1096\/fj.201801982R","article-title":"Lactate-induced activation of HCA2 improves survival in mice with sepsis","volume":"33","author":"Takakura","year":"2019","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1016\/j.bcp.2005.08.021","article-title":"Inhibitory effects of dimethylacetyl-\u03b2-cyclodextrin on lipopolysaccharide-induced macrophage activation and endotoxin shock in mice","volume":"70","author":"Arima","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"106509","DOI":"10.1016\/j.intimp.2020.106509","article-title":"Therapeutic effects of IkB kinase inhibitor during systemic inflammation","volume":"84","author":"Shvachiy","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.3389\/fphys.2018.01929","article-title":"Dietary supplementation with high fiber alleviates oxidative stress and inflammatory responses caused by severe sepsis in mice without altering microbiome diversity","volume":"9","author":"Zhang","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/BF02977006","article-title":"In vitro antioxidant activity of some selected Prunus species in Korea","volume":"25","author":"Hyun","year":"2002","journal-title":"Arch. Pharm. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.fct.2013.03.039","article-title":"Anti-inflammatory effect of prunetin via the suppression of NF-\u03baB pathway","volume":"58","author":"Yang","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.2174\/1381612824666180327165604","article-title":"Signaling Pathways in Inflammation and Anti-inflammatory Therapies","volume":"24","author":"Yeung","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3322\/caac.21405","article-title":"Obesity and adverse breast cancer risk and outcome: Mechanistic insights and strategies for intervention","volume":"67","author":"Friedman","year":"2017","journal-title":"CA Cancer J. Clin."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0014-5793(03)00439-3","article-title":"Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38","volume":"546","author":"Clark","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/S0952-7915(96)80131-2","article-title":"Mitogen-activated protein kinase cascades and regulation of gene expression","volume":"8","author":"Su","year":"1996","journal-title":"Curr. Opin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.pharmthera.2016.01.010","article-title":"Target identification of natural and traditional medicines with quantitative chemical proteomics approaches","volume":"162","author":"Wang","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"828521","DOI":"10.1155\/2012\/828521","article-title":"Regulation of Proinflammatory Mediators via NF-\u03baB and p38 MAPK-Dependent Mechanisms in RAW 264.7 Macrophages by Polyphenol Components Isolated from Korea Lonicera japonica THUNB","volume":"2012","author":"Park","year":"2012","journal-title":"Evid.-Based Complementary Altern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cheng, Y., Zhang, D.M., Song, Z.B., Hou, Y.Q., Bao, Y.L., Sun, L.G., Yu, C.L., Li, Y.X., and Johnson, R. (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_38","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1002\/iub.2053","article-title":"Agathisflavone: Botanical sources, therapeutic promises, and molecular docking study","volume":"71","author":"Islam","year":"2019","journal-title":"Int. Union Biochem. Mol. Biol. Life"},{"key":"ref_39","first-page":"1","article-title":"Molecular docking study and molecular dynamic simulation of human cyclooxygenase-2 (COX-2) with selected eutypoids","volume":"15","author":"Taidi","year":"2020","journal-title":"J. Biomol. Struct. Dyn."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12128\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:28:12Z","timestamp":1760167692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,9]]},"references-count":39,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212128"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212128","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,9]]}}}