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Original Research

Open Access

Icariside II regulates TLR4/NF-κB signaling pathway to improve septic lung injury

  • Yan Li1
  • Baishun Lin1,2

1Department of Respiratory Medicine, Wuhan Hankou Hospital, 430012 Wuhan, Hubei, China

2Department of Emergency, the First Affiliated Hospital of Nanhua University, 421001 Hengyang, Hunan, China

DOI: 10.22514/sv.2021.216

Submitted: 30 June 2021 Accepted: 25 August 2021

Online publish date: 11 October 2021

*Corresponding Author(s): Baishun Lin E-mail:


Sepsis is caused by the inadequate response to infection and may eventually lead to fatal organ dysfunction and a high mortality rate. Acute lung injury (ALI) caused by sepsis is an important cause of its high mortality, so effective treatment drugs are urgently needed. Icariside II (ICA II) is derived from Epimedii, a ubiquitous biological flavonoid compound. ICA II has shown multiple biological activities. ICA II alleviates LPS-induced neuroinflammation by inhibiting the TLR4 / MyD88 /NF-κB pathway, however, the possible role of icaridinin II in sepsis induced acute lung injury remains unclear. Herein, we developed a sepsis-related ALI mice model induced by LPS treatment, and found Icariside II ameliorated sepsis-related acute lung injury of mice induced by LPS. Our data further confirmed that Icariside II inhibited the inflammatory response in sepsis-related ALI mice, and ameliorated oxidative stress injury. We further revealed Icariside II inhibited the apoptosis of lung cells via TLR4-NF-κB axis. Our data therefore provided a promising therapeutic drug for the treatment of sepsis-induced ALI.


Sepsis; Acute lung injury (ALI); Icariside II (ICA II); Apoptosis; Inflammatory response; TLR4-NF-κB

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Yan Li,Baishun Lin. Icariside II regulates TLR4/NF-κB signaling pathway to improve septic lung injury. Signa Vitae. 2021.doi:10.22514/sv.2021.216.


[1] Ajith Kumar AK. Adrenomedullin in Sepsis: Finally, a Friend or an Enemy? Indian Journal of Critical Care Medicine. 2020; 24: 1151–1153.

[2] Agarwal V. Neutrophil CD64 a Diagnostic and Prognostic Marker of Sepsis in Adult Critically Ill Patients: a Brief Review. Indian Journal of Critical Care Medicine. 2020; 24: 1242–1250.

[3] Wu C, Li H, Zhang P, Tian C, Luo J, Zhang W, et al. Lymphatic Flow: a Potential Target in Sepsis-Associated Acute Lung Injury. Journal of Inflammation Research. 2020; 13: 961–968.

[4] Xue H, Li M. Protective effect of pterostilbene on sepsis-induced acute lung injury in a rat model via the JAK2/STAT3 pathway. Annals of Translational Medicine. 2020; 8: 1452–1452.

[5] Gao M, Yu T, Liu D, Shi Y, Yang P, Zhang J, et al. Sepsis plasma-derived exosomal miR-1-3p induces endothelial cell dysfunction by targeting SERP1. Clinical Science. 2021; 135: 347–365.

[6] Jiang L, Ni J, Shen G, Xia Z, Zhang L, Xia S, et al. Upregulation of endothelial cell-derived exosomal microRNA-125b-5p protects from sepsis-induced acute lung injury by inhibiting topoisomerase II alpha. Inflammation Research. 2021; 70: 205–216.

[7] Gao J, Long L, Xu F, Feng L, Liu Y, Shi J, et al. Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase-3beta-mediated activation of autophagy. British Journal of Pharmacology. 2020; 177: 1434–1452.

[8] Zhang L, Wang T, Zhao B, Zhang J, Yang S, Fan C, et al. Effect of 2″-O-Rhamnosyl Icariside II, Baohuoside i and Baohuoside II in Herba Epimedii on Cytotoxicity Indices in HL-7702 and HepG2 Cells. Molecules. 2019; 24: 1263.

[9] Chen M, Wu J, Luo Q, Mo S, Lyu Y, Wei Y, et al. The Anticancer Properties of Herba Epimedii and Its Main Bioactive Componentsicariin and Icariside II. Nutrients. 2016; 8: 563.

[10] Zhou J, Deng Y, Li F, Yin C, Shi J, Gong Q. Icariside II attenu-ates lipopolysaccharide-induced neuroinflammation through inhibiting TLR4/MyD88/NF-kappaB pathway in rats. Biomedicine & Pharma-cotherapy. 2019; 111: 315–324.

[11] Tian C, Gao F, Li X, Li Z. Icariside II attenuates eosinophils-induced airway inflammation and remodeling via inactivation of NF-kappaB and STAT3 in an asthma mouse model. Experimental and Molecular Pathology. 2020; 113: 104373.

[12] Lee K, Lee H, Ahn KS, Kim S, Nam D, Kim DK, et al. Cyclooxygenase-2/prostaglandin E2 pathway mediates icariside II induced apoptosis in human PC-3 prostate cancer cells. Cancer Letters. 2009; 280: 93–100.

[13] Wang Z, Chen W, Li Y, Zhang S, Lou H, Lu X, et al. Reduning injection and its effective constituent luteoloside protect against sepsis partly via inhibition of HMGB1/TLR4/NF-kappaB/MAPKs signaling pathways. Journal of Ethnopharmacology. 2021; 270: 113783.

[14] Zhu H, Wang Y, Sun J, Fan C, Wan J. Tomentosin Inhibits Lipopolysaccharide-Induced Acute Lung Injury and Inflammatory Re-sponse by Suppression of the NF-kappaB Pathway in a Mouse Model of Sepsis. Journal of Environmental Pathology, Toxicology and Oncology. 2020; 39: 291–298.

[15] Kim SY, Kim D, Kim S, Lee D, Mun SJ, Cho E, et al. Mycobacterium tuberculosis Rv2626c-derived peptide as a therapeutic agent for sepsis. EMBO Molecular Medicine. 2020; 12: e12497.

[16] Asfour SS, Asfour RS, Khalil TM, Al-Mouqdad MM. The Use of Daptomycin in the Treatment of Persistent Coagulase-Negative Staphylococcal Sepsis in Premature Infants: a Case Series. the Journal of Pediatric Pharmacology and Therapeutics. 2021; 26: 92–98.

[17] Liu S, Deng M, Pan P, Turnquist HR, Pitt BR, Billiar TR, et al. Mechanical Ventilation with Moderate Tidal Volume Exacerbates Extrapulmonary Sepsis-Induced Lung Injury via IL33-WISP1 Signaling Pathway. Shock. 2020. (in press)

[18] Tian Y, Qu S, Alam HB, Williams AM, Wu Z, Deng Q, et al. Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis. JCI Insight. 2020; 5: e138873.

[19] Hong EY, Kim TY, Hong GU, Kang H, Lee J, Park JY, et al. Inhibitory Effects of Roseoside and Icariside E4 Isolated from a Natural Product Mixture (no-ap) on the Expression of Angiotensin II Receptor 1 and Oxidative Stress in Angiotensin II-Stimulated H9C2 Cells. Molecules. 2019; 24: 414.

[20] Liu X, Li Z, Li M, Chai J, He S, Wu J, et al. Icariside II overcomes BRAF inhibitor resistance in melanoma by inducing ROS production and inhibiting MITF. Oncology Reports. 2020; 44: 360–370.

[21] Zhao H, Chen H, Xiaoyin M, Yang G, Hu Y, Xie K, et al. Autophagy Activation Improves Lung Injury and Inflammation in Sepsis. Inflammation. 2019; 42: 426–439.

[22] Zhang X, Dong S. Protective Effects of Erythropoietin towards Acute Lung Injuries in Rats with Sepsis and its Related Mechanisms. Annals of Clinical and Laboratory Science. 2019; 49: 257–264.

[23] Vivas MC, Villamarin-Guerrero HF, Sanchez CA. Interleukin-10 (IL-10) 1082 promoter polymorphisms and plasma IL-10 levels in patients with bacterial sepsis. Romanian Journal of Internal Medicine. 2021; 59: 50–57.

[24] Jensen IJ, McGonagill PW, Butler NS, Harty JT, Griffith TS, Badovinac VP. NK Cell–Derived IL-10 Supports Host Survival during Sepsis. The Journal of Immunology. 2021; 206: 1171–1180.

[25] Tang J, Xu L, Zeng Y, Gong F. Effect of gut microbiota on LPS-induced acute lung injury by regulating the TLR4/NF-kB signaling pathway. International Immunopharmacology. 2020; 91: 107272.

[26] Xiao K, Zhao F, Xie W, Ding J, Gong X, OuYang C, et al. Molecular mecshanism of TLR4 mediated T cell immune effect in transfusion-induced acute lung injury based on Slit2/Robo4 signaling pathway. Current Molecular Pharmacology. 2020. (in press)

[27] Peng LY, Shi HT, Yuan M, Li JH, Song K, Huang JN, et al. Madecassoside Protects Against LPS-Induced Acute Lung Injury via Inhibiting TLR4/NF-kappaB Activation and Blood-Air Barrier Perme-ability. Frontiers in Pharmacology. 2020; 11: 807.

[28] Xu Z, Zhang C, Cheng L, Hu M, Tao H, Song L. The microRNA miR-17 regulates lung FoxA1 expression during lipopolysaccharide-induced acute lung injury. Biochemical and Biophysical Research Communications. 2014; 445: 48–53.

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