Pneumonia is a highly prevalent acute respiratory infection worldwide, and Inula britannica displayed an anti-pneumonia effect. Herein, twenty compounds were isolated from I. britannica, including seven newly discovered compounds—six terpenoids named inulabritanoids P−U (1−6) and one novel lignan, inulabritanoid V (7)—along with thirteen known compounds (8−20). Their structural frameworks were clarified through 1D and 2D NMR, and HR-MS data. Effects of all the elucidated compounds for anti-pneumonia activities were assessed using the lipopolysaccharide (LPS)-induced pneumonia model in MH-S alveolar macrophages. Compounds 3, 5, 6,12, and 18 showed potent anti-pneumonia activities in LPS-exposed MH-S cells. Notably, compound 6 exhibited the most potent bioactivity: it significantly inhibited nitric oxide (NO) production and downregulated the expression levels of inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-6, and chemokine (C-C motif) ligand 5 (CCL5). Further investigations revealed that the anti-pneumonia effect of compound 6 depended on inhibiting the NF-κB and MAPK/AP-1 signaling pathways. These results indicate that compound 6 represents a viable lead molecule for combating pneumonia, laying a foundation for future studies.
Declaration of competing interest
These authors have no conflict of interest to declare.
| [1] |
Ruuskanen O, Lahti E, Jennings LC. Viral pneumonia. Lancet. 2011; 377(9773):1264-1275. https://doi.org/10.1016/S0140—6736(10)61459—6.
|
| [2] |
Mikami K, Suzuki M, Kitagawa H, et al. Efficacy of corticosteroids in the treatment of community—acquired pneumonia requiring hospitalization. Lung. 2007; 185(5):249-255. https://doi.org/10.1007/s00408—007—9020—3.
|
| [3] |
Tang Y, Shi C, Sun L, et al. Herb pair of Glycyrrhiza Radix—Platycodonis Radix alleviates respiratory syncytial virus pneumonia in mice by modulating lipid metabolism and inhibiting inflammation. World J Tradit Chin Med. 2024; 10(3):322-333. https://doi.org/10.4103/wjtcm.wjtcm_79_24.
|
| [4] |
Huang HP, Chen ZP, He XY, et al. Early continuous blood purification affects TNF—α, IL—1β, and IL—6 in patients with severe acute pancreatitis via inhibiting TLR4 signaling pathway. Kaohsiung J Med Sci. 2022; 38(5):479-485. https://doi.org/10.1002/kjm2.12497.
|
| [5] |
Meloche S, Pouysségur J. The ERK1/2 mitogen—activated protein kinase pathway as a master regulator of the G1— to S—phase transition. Oncogene. 2007; 26(22):3227-3239. https://doi.org/10.1038/sj.onc.1210414.
|
| [6] |
Zhang J, Zhang M, Zhu QM, et al. Allosteric regulation of Keap1 by 8β—hydroxy—α—cyclocostunolide for the treatment of acute lung injury. Acta Pharm Sin B. 2024; 14(9):4174-4178. https://doi.org/10.1016/j.apsb.2024.06.025.
|
| [7] |
Zhu MH, Qi DX, Chen DL, et al. Joint screening and identification of potential targets of nitazoxanide by affinity chromatography and label—free techniques. Curr Drug Targets. 2024; 25(12):819-845. https://doi.org/10.2174/0113894501297697240805103744.
|
| [8] |
Zhang J, Zhang M, Huo XK, et al. Macrophage inactivation by small molecule wedelolactone via targeting sEH for the treatment of LPS—induced acute lung injury. ACS Cent Sci. 2023; 9(3):440-456. https://doi.org/10.1021/acscentsci.2c01424.
|
| [9] |
Huang HS, Wang M, Guo ZM, et al. Rutaecarpine alleviates acute pancreatitis in mice and AR42J cells by suppressing the MAPK and NF—κB signaling pathways via calcitonin gene—related peptide. Phytother Res. 2021; 35(11):6472-6485. https://doi.org/10.1002/ptr.7301.
|
| [10] |
Wang K, Zhang P, Sun H, et al. Dual—function natural products: farnesoid X receptor agonist/inflammation inhibitor for metabolic dysfunction—associated steatotic liver disease therapy. Chin J Nat Med. 2024; 22(11):965-976. https://doi.org/10.1016/S1875—5364(24)60706—5.
|
| [11] |
Chang J, Sun CP, Wang MM, et al. Berberine inhibits phagocytosis through the TLR4—PI3K—CDC42 pathway. Acta Mater Med. 2025; 4(2):280-292. https://doi.org/10.15212/amm—2024—0074.
|
| [12] |
Zhang J, Zhang WH, Morisseau C, et al. Genetic deletion or pharmacological inhibition of soluble epoxide hydrolase attenuated particulate matter 2.5 exposure mediated lung injury. J Hazard Mater. 2023; 458:131890. https://doi.org/10.1016/j.jhazmat.2023.131890.
|
| [13] |
Zhang J, Yang XT, Zhang M, et al. Discovery of soluble epoxide hydrolase inhibitors based on the skeleton of piperine: synthesis, properties, molecular dynamics simulation, and their potentials in acute lung injury. Acupunct Herb Med. 2025; 5(2):193-204. https://doi.org/10.1016/j.ijbiomac.2025.141704.
|
| [14] |
Zhang J, Luan ZL, Huo XK, et al. Direct targeting of sEH with alisol B alleviated the apoptosis, inflammation, and oxidative stress in cisplatin—induced acute kidney injury. Int J Biol Sci. 2023; 19(1):294-310. https://doi.org/10.7150/ijbs.78097.
|
| [15] |
Zhang J, Zhang HL, Xu XR, et al. Targeting PBK with small—molecule 1—O—acetyl—4R,6S—britannilactone for the treatment of neuroinflammation. Proc Natl Acad Sci U S A. 2025; 122(29):e2502593122. https://doi.org/10.1073/pnas.2502593122.
|
| [16] |
Cao LJ, Xie HT, Chu ZX, et al. Protective effect of Shenfu Injection against sepsis—induced acute lung injury by suppressing inflammation and apoptosis through the regulation of the janus kinase 2/signal transducer and activator of transcription 3 pathway. ACS Appl Energy Mater. 2024; 10(4):528-534. https://doi.org/10.4103/wjtcm.wjtcm_76_24.
|
| [17] |
Liao Q, Wu S, Li X, et al. Danggui Niantong Decoction attenuates synovial fibrosis through regulating PI3k/AKT signaling pathway. J Ethnopharmacol. 2025; 342:119381. https://doi.org/10.1016/j.jep.2025.119381.
|
| [18] |
Yuan JQ, Li XY, Fan YN, et al. Rosmarinic acid suppresses the progression of COPD via Syk by modulating airway inflammation and epithelial apoptosis in vivo and in vitro. J Asian Nat Prod Res. 2025; 27(5):732-746. https://doi.org/10.1080/10286020.2024.2403617.
|
| [19] |
Chen Y, Zhang XW, Zhao MM, et al. Chlorogenic acid targets SLC37A2 to inhibit macrophage activation via ER—dependent NF—κB and NLRP3 signaling pathways against sepsis—induced acute lung injury.J Asian Nat Prod Res. 2026; 28(3):469-490. https://doi.org/10.1080/10286020.2025.2506181.
|
| [20] |
Sun CP, Jia ZL, Huo XK, et al. Medicinal inula species: phytochemistry, biosynthesis, and bioactivities. Am J Chin Med. 2021; 49(2):315-358. https://doi.org/10.1142/S0192415X21500166.
|
| [21] |
Yoon HJ, Park JY, Min SJ, et al. Inula britannica exerts antioxidant and anti—inflammatory effects in SH—SY5Y cells through the Nrf2—Keap1 signaling pathway.Arch Biochem Biophys. 2025; 773:110597. https://doi.org/10.1016/j.abb.2025.110597.
|
| [22] |
Meng Z, Li M, Wang X, et al. Inula britannica ameliorates alcohol—induced liver injury by modulating SIRT1—AMPK/Nrf2/NF—κB signaling pathway.Chin Herb Med. 2024; 16(4):667-678. https://doi.org/10.1016/j.chmed.2023.12.006.
|
| [23] |
Zhang HL, Wang N, Shi XL, et al. Sesquiterpenoids from Inula britannica and their potential mechanism for immunomodulation. Phytochemistry. 2025; 231:114343. https://doi.org/10.1016/j.phytochem.2024.114343.
|
| [24] |
Jin HZ, Lee D, Lee JH, et al. New sesquiterpene dimers from Inula britannica inhibit NF—κB activation and NO and TNF—α production in LPS—stimulated RAW264.7 cells. Planta Med. 2006; 72(1):40-45. https://doi.org/10.1055/s—2005—873189.
|
| [25] |
Zhang J, Yan JK, Dong HJ, et al. Dimeric sesquiterpenoids with anti—inflammatory activities from Inula britannica. Chin J Nat Med. 2025; 23(8):961-971. https://doi.org/10.1016/S1875—5364.
|
| [26] |
Guo C, Qi RY, Ren JY, et al. Inubritantrimers A−D: trimerized sesquiterpenoid [4 + 2] adducts featuring a distinctive spiro—polycyclic scaffold from Inula britannica.J Org Chem. 2024; 89(7):5029-5037. https://doi.org/10.1021/acs.joc.4c00248.
|
| [27] |
Ibadullayeva AK, Kasela M, Kozhanova KK, et al. Chemical profile and biological properties of methanolic and ethanolic extracts from the aerial parts of Inula britannica L. growing in central Asia. Molecules. 2024; 29(23):5749. https://doi.org/10.3390/molecules29235749.
|
| [28] |
Gu X, Sun W, Hu Z. Natural products from untapped sources as a potent reserve against antimicrobial resistance crisis. Chin J Nat Med. 2024; 22(7):577-579. https://doi.org/10.1016/s1875—5364(24)60610—2.
|
| [29] |
Ma Y, Liu S, Zhou Q, et al. Approved drugs and natural products at clinical stages for treating Alzheimer’s disease. Chin J Nat Med. 2024; 22(8):699-710. https://doi.org/10.1016/s1875—5364(24)60606—0.
|
| [30] |
Chen S, Dai B, Zhang D, et al. Advances in intelligent mass spectrometry data processing technology for in vivo analysis of natural medicines. Chin J Nat Med. 2024; 22(10):900-913. https://doi.org/10.1016/s1875—5364(24)60687—4.
|
| [31] |
Wu ZL, Li JY, Huang PL, et al. New ent—kaurane diterpenoid acids from Nouelia insignis Franch and their anti—inflammatory activity. RSC Adv. 2022; 12(18):11155-11163. https://doi.org/10.1039/d2ra01684b.
|
| [32] |
Cunha WR, Martins C, Ferreira DS, et al. In vitro trypanocidal activity of triterpenes from Miconia species.Planta Med. 2003; 69(5):470-472. https://doi.org/10.1055/s—2003—39719.
|
| [33] |
Zhang L, Shao YL, Hua L, et al. Guaianolides and elemanolides from Vernonia anthelmintica. Phytochem Lett. 2014; 7:14-18. https://doi.org/10.1016/j.phytol.2013.09.009.
|
| [34] |
Zhang XF, Ren J, Cheng XR, et al. One new unusual sesterterpenoid and four new sesquiterpene dimers from Inula britannica. RSC Adv. 2015; 5(3):1979-1982. https://doi.org/10.1002/chin.201522236.
|
| [35] |
Xiao L, Huang YY, Wang YH, et al. Anti—neuroinflammatory benzofurans and lignans from Praxelis clematidea. Fitoterapia. 2020; 140:104440. https://doi.org/10.1016/j.fitote.2019.104440.
|
| [36] |
Wang SJ, Yu M, Li H, et al. Structures and biological activities of polyacylated ent—kaurane diterpenoid glycosides from the aerial parts ofInula hupehensis. J Nat Prod. 2022; 85(1):185-195. https://doi.org/10.1021/acs.jnatprod.1c00947.
|
| [37] |
Monsalve LN, Rosselli S, Bruno M, et al. Enzyme—catalysed transformations of ent—kaurane diterpenoids. Eur J Org Chem. 2005; 10:2106-2115. https://doi.org/10.1002/ejoc.200400862.
|
| [38] |
Ying Q, Zhang XX, Xu YK. Chemical constituents of Alisma orientalis. Chem Nat Comp. 2014; 49(6):1143-1145. https://doi.org/10.1007/s10600—014—0844—9.
|
| [39] |
Mahato SB, Kundu AP. 13C NMR spectra of pentacyclic triterpenoids—a compilation and some salient features. Phytochemistry. 1994; 37(6):1517-1575. https://doi.org/10.1016/S0031—9422(00)89569—2.
|
| [40] |
Dai JQ, Zhao CY, Zhang Q, et al. Taraxastane—type triterpenoids from Saussurea petrovii. Phytochemistry. 2001; 58(7):1107-1111. https://doi.org/10.1016/s0031—9422(01)00397—1.
|
| [41] |
Davidyants ÉS, Putieva ZM, Bandyukova VA, et al. Triterpene glycosides of Silphium perfoliatum III. Structure of silphioside E. Chem Nat Comp. 1984; 20(6):708-710. https://doi.org/10.1007/BF00580030.
|
| [42] |
Vargas D, Dominguez XA, Acuña—Askar K, et al. Norditerpenes and norditerpene glycosides from Drymaria arenarioides. Phytochemistry. 1988; 27(5):1532-1534. https://doi.org/10.1016/0031—9422(88)80233—4.
|
| [43] |
Wu YC, Hung YC, Chang FR, et al. Identification of ent—16β,17—dihydroxykauran—19—oic acid as an anti—HIV principle and isolation of the new diterpenoids annosquamosins A and B from Annona squamosa. J Nat Prod. 1996; 59(6):635-637. https://doi.org/10.1021/np960416j.
|
| [44] |
Wang Y, Hamburger M, Gueho J, et al. Antimicrobial flavonoids from Psiadia trinervia and their methylated and acetylated derivatives. Phytochemistry. 1989; 28(9):2323-2327. https://doi.org/10.1016/S0031—9422(00)97976—7.
|
| [45] |
Ito K, Iita T. Seven sesquiterpene lactones from Inula britannica var. chinensis. Phytochemistry. 1981; 20:271-273. https://doi.org/10.1016/0031—9422(81)85105—9.
|
| [46] |
Doskotch RW, Hufford CD, EI—Feraly FS. Antitumor agents. VI. Sesquiterpene lactones tulipinolide and epitulipinolide from Liriodendron tulipifera. J Org Chem. 1972; 37(17):2740-2744. https://doi.org/10.1021/jo00982a025.
|
| [47] |
Silva J, Alves C, Martins A, et al. Loliolide, a new therapeutic option for neurological diseases? In vitro neuroprotective and anti—inflammatory activities of a monoterpenoid lactone isolated from Codium tomentosum. Int J Mol Sci. 2021; 22(4):1888. https://doi.org/10.3390/ijms22041888.
|
| [48] |
Zhao QR, Zhao RH, Geng ZH, et al. Xuanfei Baidu Granule alleviates coronavirus—induced pneumonia in low—temperature and high—humidity environments. Acupunct Herb Med. 2023;3(3):200-206. https://doi.org/10.1097/HM9.00000000000000068.
|
| [49] |
Sun CP, Zhou JJ, Yu ZL, et al. Kurarinone alleviated Parkinson’s disease via stabilization of epoxyeicosatrienoic acids in animal model.Proc Natl Acad Sci U S A. 2022; 119(9):e2118818119. https://doi.org/10.1073/pnas.2118818119.
|