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Akebia saponin D attenuates allergic airway inflammation through AMPK activation

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Abstract

Akebia saponin D (ASD) is a bioactive triterpenoid saponin extracted from Dipsacus asper Wall. ex DC.. This study aimed to investigate the effects of ASD on allergic airway inflammation. Human lung epithelial BEAS-2B cells and bone marrow-derived mast cells (BMMCs) were pretreated with ASD (50, 100 and 200 μΜ) and AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) (1 mM), and then stimulated with lipopolysaccharide (LPS) or IL-33. Pretreatment with ASD and AICAR significantly inhibited TNF-α and IL-6 production from BEAS-2B cells, and IL-13 production from BMMCs. Moreover, pretreatment with ASD and AICAR significantly increased p-AMPK expression in BEAS-2B cells. Inhibition of AMPK by siRNA and compound C partly abrogated the suppression effect of ASD on TNF-α, IL-6, and IL-13 production. Asthma murine model was induced by ovalbumin (OVA) challenge and treated with ASD (150 and 300 mg/kg) or AICAR (100 mg/kg). Infiltration of eosinophils, neutrophils, monocytes, and lymphocytes, and production of TNF-α, IL-6, IL-4, and IL-13 were attenuated in ASD and AICAR treated mice. Lung histopathological changes were also ameliorated after ASD and AICAR treatment. Additionally, it showed that treatment with ASD and AICAR increased p-AMPK expression in the lung tissues. In conclusion, ASD exhibited protective effects on allergic airway inflammation through the induction of AMPK activation.

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The data will be provided by the corresponding author on request.

References

  1. GBD Chronic Respiratory Disease Collaborators (2020) Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med 8(6):585–596. https://doi.org/10.1016/S2213-2600(20)30105-3

    Article  Google Scholar 

  2. Kardas G, Kuna P, Panek M (2020) Biological therapies of severe asthma and their possible effects on airway remodeling. Front Immunol 11:1134. https://doi.org/10.3389/fimmu.2020.01134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Palumbo ML, Prochnik A, Wald MR, Genaro AM (2020) Chronic stress and glucocorticoid receptor resistance in asthma. Clin Ther 42(6):993–1006. https://doi.org/10.1016/j.clinthera.2020.03.002

    Article  CAS  PubMed  Google Scholar 

  4. Volmer T, Effenberger T, Trautner C, Buhl R (2018) Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature. Eur Respir J 52(4):1800703. https://doi.org/10.1183/13993003.00703-2018

    Article  CAS  PubMed  Google Scholar 

  5. He Y, Shi J, Nguyen QT, You E, Liu H, Ren X, Wu Z, Li J, Qiu W, Khoo SK, Yang T, Yi W, Sun F, Xi Z, Huang X, Melcher K, Min B, Xu HE (2019) Development of highly potent glucocorticoids for steroid-resistant severe asthma. Proc Natl Acad Sci U S A 116(14):6932–6937. https://doi.org/10.1073/pnas.1816734116

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Heidary Moghaddam R, Samimi Z, Asgary S, Mohammadi P, Hozeifi S, Hoseinzadeh-Chahkandak F, Xu S, Farzaei MH (2022) Natural AMPK activators in cardiovascular disease prevention. Front Pharmacol 12:738420. https://doi.org/10.3389/fphar.2021.738420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, Hashemi M, Hushmandi K, Ashrafizadeh M, Zarrabi A, Ertas YN, Mirzaei S, Samarghandian S (2022) AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: a pre-clinical and clinical investigation. Biomed Pharmacother 146:112563. https://doi.org/10.1016/j.biopha.2021.112563

    Article  CAS  PubMed  Google Scholar 

  8. Zhu Y, Wang C, Luo J, Hua S, Li D, Peng L, Liu H, Song L (2021) The protective role of Zingerone in a murine asthma model via activation of the AMPK/Nrf2/HO-1 pathway. Food Funct 12(7):3120–3131. https://doi.org/10.1039/d0fo01583k

    Article  CAS  PubMed  Google Scholar 

  9. Jiang QX, Chen YM, Ma JJ, Wang YP, Li P, Wen XD, Yang J (2022) Effective fraction from Simiao Wan prevents hepatic insulin resistant by inhibition of lipolysis via AMPK activation. Chin J Nat Med 20(3):161–176. https://doi.org/10.1016/S1875-5364(21)60115-2

    Article  CAS  PubMed  Google Scholar 

  10. Wu W, Wang S, Liu Q, Wang X, Shan T, Wang Y (2018) Cathelicidin-WA attenuates LPS-induced inflammation and redox imbalance through activation of AMPK signaling. Free Radic Biol Med 129:338–353. https://doi.org/10.1016/j.freeradbiomed.2018.09.045

    Article  CAS  PubMed  Google Scholar 

  11. Zheng C, Lin JF, Lin ZH, Lin WQ, Thapa S, Lin YZ, Lian H, Liu ZR, Chen JH, Li XW (2018) Sodium houttuyfonate alleviates post-infarct remodeling in rats via AMP-activated protein kinase pathway. Front Pharmacol 9:1092. https://doi.org/10.3389/fphar.2018.01092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Park CS, Bang BR, Kwon HS, Moon KA, Kim TB, Lee KY, Moon HB, Cho YS (2012) Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem Pharmacol 84(12):1660–1670. https://doi.org/10.1016/j.bcp.2012.09.025

    Article  CAS  PubMed  Google Scholar 

  13. Park SJ, Lee KS, Kim SR, Chae HJ, Yoo WH, Kim DI, Jeon MS, Lee YC (2012) AMPK activation reduces vascular permeability and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma. Inflamm Res 61(10):1069–1083. https://doi.org/10.1007/s00011-012-0499-6

    Article  CAS  PubMed  Google Scholar 

  14. Lv Y, Wu H, Hong Z, Wei F, Zhao M, Tang R, Li Y, Ge W, Li C, Du W (2023) Exploring active ingredients of anti-osteoarthritis in raw and wine-processed Dipsaci Radix based on spectrum-effect relationship combined with chemometrics. J Ethnopharmacol 309:116281. https://doi.org/10.1016/j.jep.2023.116281

    Article  CAS  PubMed  Google Scholar 

  15. Park JY, Park SD, Koh YJ, Kim DI, Lee JH (2019) Aqueous extract of Dipsacus asperoides suppresses lipopolysaccharide-stimulated inflammatory responses by inhibiting the ERK1/2 signaling pathway in RAW 264.7 macrophages. J Ethnopharmacol 231:253–261. https://doi.org/10.1016/j.jep.2018.11.010

    Article  CAS  PubMed  Google Scholar 

  16. Du W, Lv Y, Wu H, Li Y, Tang R, Zhao M, Wei F, Li C, Ge W (2023) Research on the effect of Dipsaci Radix before and after salt-processed on kidney yang deficiency syndrome rats and the preliminary mechanism study through the BMP-Smad signaling pathway. J Ethnopharmacol 312:116480. https://doi.org/10.1016/j.jep.2023.116480

    Article  CAS  PubMed  Google Scholar 

  17. Tian S, Zou Y, Wang J, Li Y, An BZ, Liu YQ (2022) Protective effect of Du-Zhong-Wan against osteoporotic fracture by targeting the osteoblastogenesis and angiogenesis couple factor SLIT3. J Ethnopharmacol 295:115399. https://doi.org/10.1016/j.jep.2022.115399

    Article  CAS  PubMed  Google Scholar 

  18. Gong LL, Yang S, Zhang W, Han FF, Lv YL, Wan ZR, Liu H, Jia YJ, Xuan LL, Liu LH (2018) Akebia saponin D alleviates hepatic steatosis through BNip3 induced mitophagy. J Pharmacol Sci 136(4):189–195. https://doi.org/10.1016/j.jphs.2017.11.007

    Article  CAS  PubMed  Google Scholar 

  19. Niu Y, Li Y, Huang H, Kong X, Zhang R, Liu L, Sun Y, Wang T, Mei Q (2011) Asperosaponin VI, a saponin component from Dipsacus asper wall, induces osteoblast differentiation through bone morphogenetic protein-2/p38 and extracellular signal-regulated kinase 1/2 pathway. Phytother Res 25(11):1700–1706. https://doi.org/10.1002/ptr.3414

    Article  CAS  PubMed  Google Scholar 

  20. Zhang J, Yi S, Li Y, Xiao C, Liu C, Jiang W, Yang C, Zhou T (2020) The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-κB-induced IDO expression. Psychopharmacology 237(8):2531–2545. https://doi.org/10.1007/s00213-020-05553-5

    Article  CAS  PubMed  Google Scholar 

  21. Zhou P, Yang X, Yang Z, Huang W, Kou J, Li F (2019) Akebia saponin D Regulates the metabolome and intestinal microbiota in high fat diet-induced hyperlipidemic rats. Molecules 24(7):1268. https://doi.org/10.3390/molecules24071268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang Y, Shen J, Yang X, Jin Y, Yang Z, Wang R, Zhang F, Linhardt RJ (2018) Akebia saponin D reverses corticosterone hypersecretion in an Alzheimer’s disease rat model. Biomed Pharmacother 107:219–225. https://doi.org/10.1016/j.biopha.2018.07.149

    Article  CAS  PubMed  Google Scholar 

  23. Gong LL, Yang S, Liu H, Zhang W, Ren LL, Han FF, Lv YL, Wan ZR, Liu LH (2019) Anti-nociceptive and anti-inflammatory potentials of Akebia saponin D. Eur J Pharmacol 845:85–90. https://doi.org/10.1016/j.ejphar.2018.11.038

    Article  CAS  PubMed  Google Scholar 

  24. Yang S, Zhang W, Xuan LL, Han FF, Lv YL, Wan ZR, Liu H, Ren LL, Gong LL, Liu LH (2019) Akebia Saponin D inhibits the formation of atherosclerosis in ApoE-/- mice by attenuating oxidative stress-induced apoptosis in endothelial cells. Atherosclerosis 285:23–30. https://doi.org/10.1016/j.atherosclerosis.2019.04.202

    Article  CAS  PubMed  Google Scholar 

  25. Cho JH, Lee JY, Sim SS, Whang WK, Kim CJ (2010) Inhibitory effects of diterpene acids from root of Aralia cordata on IgE-mediated asthma in guinea pigs. Pulm Pharmacol Ther 23(3):190–199. https://doi.org/10.1016/j.pupt.2009.12.004

    Article  CAS  PubMed  Google Scholar 

  26. Lan YY, Lei N, Zhang XF, Yang RT, Li C, Liu LH (2011) Hypolipidemic function with liver protection of extracts from Dipsacus asper on nonalcoholic fatty liver disease in mice and its activie fractions. Chin Tradit Herbal Drugs 42:2497–2501

    Google Scholar 

  27. Tsvilovskyy V, Solis-Lopez A, Almering J, Richter C, Birnbaumer L, Dietrich A, Freichel M (2020) Analysis of Mrgprb2 receptor-evoked Ca2+ signaling in bone marrow derived (BMMC) and peritoneal (PMC) mast cells of TRPC-deficient mice. Front Immunol 11:564. https://doi.org/10.3389/fimmu.2020.00564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang S, Hu T, Liu H, Lv YL, Zhang W, Li H, Xuan LL, Gong LL, Liu LH (2021) Akebia saponin D ameliorates metabolic syndrome (MetS) via remodeling gut microbiota and attenuating intestinal barrier injury. Biomed Pharmacother 138:111441. https://doi.org/10.1016/j.biopha.2021.111441

    Article  CAS  PubMed  Google Scholar 

  29. Xuan LL, Du P, Gong LL, Liu LH (2021) Protective effects of Akebia saponin D on ceramide-induced lung injury. Chin J Clin Pharmacol 37:1363–1366

    Google Scholar 

  30. Gu M, Jin J, Ren C, Chen X, Gao W, Wang X, Wu Y, Tian N, Pan Z, Wu A, Zhou Y, Zhang X (2020) Akebia saponin D suppresses inflammation in chondrocytes via the NRF2/HO-1/NF-κB axis and ameliorates osteoarthritis in mice. Food Funct 11(12):10852–10863. https://doi.org/10.1039/d0fo01909g

    Article  CAS  PubMed  Google Scholar 

  31. Lu C, Fan G, Wang D (2020) Akebia saponin D ameliorated kidney injury and exerted anti-inflammatory and anti-apoptotic effects in diabetic nephropathy by activation of NRF2/HO-1 and inhibition of NF-KB pathway. Int Immunopharmacol 84:106467. https://doi.org/10.1016/j.intimp.2020.106467

    Article  CAS  PubMed  Google Scholar 

  32. Yu X, Wang LN, Du QM, Ma L, Chen L, You R, Liu L, Ling JJ, Yang ZL, Ji H (2012) Akebia saponin D attenuates amyloid β-induced cognitive deficits and inflammatory response in rats: involvement of Akt/NF-κB pathway. Behav Brain Res 235(2):200–209. https://doi.org/10.1016/j.bbr.2012.07.045

    Article  CAS  PubMed  Google Scholar 

  33. Lambrecht BN, Hammad H (2012) The airway epithelium in asthma. Nat Med 18(5):684–692. https://doi.org/10.1038/nm.2737

    Article  CAS  PubMed  Google Scholar 

  34. Heijink IH, Kuchibhotla VNS, Roffel MP, Maes T, Knight DA, Sayers I, Nawijn MC (2020) Epithelial cell dysfunction, a major driver of asthma development. Allergy 75(8):1902–1917. https://doi.org/10.1111/all.14421

    Article  PubMed  Google Scholar 

  35. Michaeloudes C, Abubakar-Waziri H, Lakhdar R, Raby K, Dixey P, Adcock IM, Mumby S, Bhavsar PK, Chung KF (2022) Molecular mechanisms of oxidative stress in asthma. Mol Aspects Med 85:101026. https://doi.org/10.1016/j.mam.2021.101026

    Article  CAS  PubMed  Google Scholar 

  36. Lambrecht BN, Hammad H (2009) Biology of lung dendritic cells at the origin of asthma. Immunity 31(3):412–424. https://doi.org/10.1016/j.immuni.2009.08.008

    Article  CAS  PubMed  Google Scholar 

  37. Gon Y, Hashimoto S (2018) Role of airway epithelial barrier dysfunction in pathogenesis of asthma. Allergol Int 67(1):12–17. https://doi.org/10.1016/j.alit.2017.08.011

    Article  CAS  PubMed  Google Scholar 

  38. Roan F, Obata-Ninomiya K, Ziegler SF (2019) Epithelial cell-derived cytokines: more than just signaling the alarm. J Clin Invest 129(4):1441–1451. https://doi.org/10.1172/JCI124606

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kim HY, DeKruyff RH, Umetsu DT (2010) The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 11(7):577–584. https://doi.org/10.1038/ni.1892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kuruvilla ME, Lee FE, Lee GB (2019) Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol 56(2):219–233. https://doi.org/10.1007/s12016-018-8712-1

    Article  PubMed  PubMed Central  Google Scholar 

  41. Pan T, Chang Y, He M, He Z, Jiang J, Ren X, Zhang F (2022) Beta-hydroxyisovalerylshikonin regulates macrophage polarization via the AMPK/Nrf2 pathway and ameliorates sepsis in mice. Pharm Biol 60(1):729–742. https://doi.org/10.1080/13880209.2022.2046111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. He Y, Xu K, Wang Y, Chao X, Xu B, Wu J, Shen J, Ren W, Hu Y (2019) AMPK as a potential pharmacological target for alleviating LPS-induced acute lung injury partly via NLRC4 inflammasome pathway inhibition. Exp Gerontol 125:110661. https://doi.org/10.1016/j.exger.2019.110661

    Article  CAS  PubMed  Google Scholar 

  43. Nassif RM, Chalhoub E, Chedid P, Hurtado-Nedelec M, Raya E, Dang PM, Marie JC, El-Benna J (2022) Metformin inhibits ROS production by human M2 macrophages via the activation of AMPK. Biomedicines 10(2):319. https://doi.org/10.3390/biomedicines10020319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rabinovitch RC, Samborska B, Faubert B, Ma EH, Gravel SP, Andrzejewski S, Raissi TC, Pause A, St-Pierre J, Jones RG (2017) AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species. Cell Rep 21(1):1–9. https://doi.org/10.1016/j.celrep.2017.09.026

    Article  CAS  PubMed  Google Scholar 

  45. Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11(2):230–241. https://doi.org/10.1016/j.arr.2011.12.005

    Article  CAS  PubMed  Google Scholar 

  46. Liu JQ, Zhang L, Yao J, Yao S, Yuan T (2018) AMPK alleviates endoplasmic reticulum stress by inducing the ER-chaperone ORP150 via FOXO1 to protect human bronchial cells from apoptosis. Biochem Biophys Res Commun 497(2):564–570. https://doi.org/10.1016/j.bbrc.2018.02.095

    Article  CAS  PubMed  Google Scholar 

  47. Mansour HH, Omran MM, Hasan HF, El Kiki SM (2020) Modulation of bleomycin-induced oxidative stress and pulmonary fibrosis by N-acetylcysteine in rats via AMPK/SIRT1/NF-κβ. Clin Exp Pharmacol Physiol 47(12):1943–1952. https://doi.org/10.1111/1440-1681.13378

    Article  CAS  PubMed  Google Scholar 

  48. Zhu L, Chen X, Chong L, Kong L, Wen S, Zhang H, Zhang W, Li C (2019) Adiponectin alleviates exacerbation of airway inflammation and oxidative stress in obesity-related asthma mice partly through AMPK signaling pathway. Int Immunopharmacol 67:396–407. https://doi.org/10.1016/j.intimp.2018.12.030

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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Funding

This work was supported by the National Natural Science Foundation of China (81903692), Beijing Hospitals Authority Youth Programme (QML20230317), and Scientific Research Foundation of Capital Medical University (PYZ22081).

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Authors and Affiliations

  1. Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Beijing, 100020, China

    Lingling Xuan, Song Yang, Lulu Ren, He Liu, Wen Zhang, Yuan Sun, Benshan Xu, Lili Gong & Lihong Liu

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  1. Lingling Xuan
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Contributions

LX: Writing-original draft, Writing-review and editing, Performing the experiments. SY: Investigation, Methodology, Formal analysis. LR: Performing the experiments. HL: Methodology, Resources. WZ: Data curation. YS: Methodology. BX: Writing-review and editing. LG: Performing the experiments, Supervision, Writing-review and editing. LL: Supervision, Writing-original draft, Writing-review and editing, Conceptualization.

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Correspondence to Lingling Xuan, Lili Gong or Lihong Liu.

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Xuan, L., Yang, S., Ren, L. et al. Akebia saponin D attenuates allergic airway inflammation through AMPK activation. J Nat Med 78, 393–402 (2024). https://doi.org/10.1007/s11418-023-01762-2

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