Suppression of LPS-Induced Hepato- and Cardiotoxic Effects by Pulicaria petiolaris via NF-κB Dependent Mechanism

  • Nishat Ahmed
  • Dina Saad El-Agamy
  • Gamal Abdallah Mohammed
  • Hany Abo-Haded
  • Mohamed Elkablawy
  • Sabrin Ragab Mohamed IbrahimEmail author


Recently, there is an increasing interest in searching for harmless natural products isolated from plant materials that can be used as beneficial dietary supplements and/or therapeutic drug candidates. The present study aimed to test the potential protective role of Pulicaria petiolaris (PP, Asteraceae) against hepatic and cardiotoxic effects associated with lipopolysaccharide (LPS) injection. PP was given orally for 5 days at two different doses before LPS injection. Results have shown that LPS induced remarkable hepatic and cardiac injurious effects in mice. Hepatic damage was evident through increased serum transaminases, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and activity. Estimation of high levels of serum creatine kinase-MB (CK-MB) and cardiac troponin I indicated cardiac damage. Histopathological examination of liver and heart confirmed the biochemical results. Increase in oxidative stress along with a depressed antioxidant status of liver and heart were observed in LPS-intoxicated animals. Furthermore, LPS induced activation of nuclear factor-κB (NF-κB) and subsequent elevation of inflammatory cytokines (TNF-α, IL-6). On the other hand, PP treatment successfully safeguards both organs against LPS-induced injury as indicated by the improvement of the biochemical and histopathological parameters. These results suggest that PP ameliorates LPS-induced hepatic and cardiac oxidative injurious effects via antioxidant and anti-inflammatory effects.


Pulicaria petiolaris Asteraceae Lipopolysaccharide Hepatotoxicity Cardiotoxicity NF-κB 



Alkaline phosphatase


Alanine transaminase


Aspartate aminotransferase




Creatine kinase-MB


Troponin I


Dimethyl sulfoxide


Deoxyribonucleic acid


Disulfide compound


Reduced glutathione


Hydrogen peroxide




Inducible nitric oxide synthase


Lactate dehydrogenase

IL-1, IL-6, IL-8, and IL-12

Interleukins 1, 6, 8, and 12






Reactive oxygen species


Reactive nitrogen species


Nuclear factor-κB




Superoxide dismutase


Tumor necrosis factor-α


Pulicaria petiolaris



The authors acknowledge the Deanship of Scientific Research (DSR), Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia, for assistance.

Author Contributions

GAM and SRMI were responsible for the collection of the plant and preparation of the extract. DSE, NA, GAM, HA, and SRMI conceived and designed the research. DSE, NA, HA and ME conducted the experiments and analyzed data. DSE, GAM, HA, and SRMI wrote the manuscript. All authors read and approved the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest regarding the publication of this manuscript.


  1. 1.
    Larrosa, M., Azorín-Ortuño, M., Yanez-Gascon, M., Garcia-Conesa, M., Tomás-Barberán, F., & Espin, J. (2011). Lack of effect of oral administration of resveratrol in LPS-induced systemic inflammation. European Journal of Nutrition, 50, 673–680.CrossRefGoogle Scholar
  2. 2.
    Sebai, H., Ben-Attia, M., Sani, M., Aouani, E., & Ghanem-Boughanmi, N. (2009). Protective effect of resveratrol in endotoxemia-induced acute phase response in rats. Archives of Toxicology, 8, 335–340.CrossRefGoogle Scholar
  3. 3.
    Jiang, Z., Meng, Y., Bo, L., Wang, C., Bian, J., & Deng, X. (2018). Sophocarpine attenuates LPS-induced liver injury and improves survival of mice through suppressing oxidative stress, inflammation, and apoptosis. Mediators of Inflammation, 2018, 5871431.CrossRefGoogle Scholar
  4. 4.
    Xianchu, L., Lan, Z., Ming, L., & Yanzhi, M. (2018). Protective effects of rutin on lipopolysaccharide-induced heart injury in mice. Journal of Toxicological Sciences, 43, 329–337.CrossRefGoogle Scholar
  5. 5.
    Zhang, W.-B., Zhang, H.-Y., Zhang, Q., Jiao, F.-Z., Zhang, H., Wang, L.-W., et al. (2017). Glutamine ameliorates lipopolysaccharide-induced cardiac dysfunction by regulating the toll-like receptor 4/mitogen-activated protein kinase/nuclear factor-kB signaling pathway. Experimental and Therapeutic Medicine, 14, 5825–5832.Google Scholar
  6. 6.
    Zhang, W. B., Zhang, H. Y., Zhang, Q., Jiao, F. Z., Zhang, H., Wang, L. W., et al. (2017). Glutamine ameliorates lipopolysaccharide-induced cardiac dysfunction by regulating the toll-like receptor 4/mitogen-activated protein kinase/nuclear factor-kB signaling pathway. Experimental and Therapeutic Medicine, 14, 5825–5832.Google Scholar
  7. 7.
    Sun, S., Zhang, H., Xue, B., Wu, Y., Wang, J., Yin, Z., et al. (2006). Protective effect of glutathione against lipopolysaccharide-induced inflammation and mortality in rats. Inflammation Research, 55, 504–510.CrossRefGoogle Scholar
  8. 8.
    Sebai, H., Ben-Attia, M., Sani, M., Aouani, E., & Ghanem-Boughanmi, N. (2008). Protective effect of resveratrol on acute endotoxemia-induced nephrotoxicity in rat through nitric oxide independent mechanism. Free Radical Research, 42, 913–920.CrossRefGoogle Scholar
  9. 9.
    Shaaban, A. A., El-Kashef, D. H., Hamed, M. F., & El-Agamy, D. S. (2018). Protective effect of pristimerin against LPS-induced acute lung injury in mice. International Immunopharmacology, 59, 31–39.CrossRefGoogle Scholar
  10. 10.
    Williams, C. A., Harborne, J. B., Greenham, J. R., Grayer, R. J., Kite, G. C., & Eagles, J. (2003). Variations in lipophilic and vacuolar flavonoids among European Plicaria species. Phytochemistry, 64, 275–283.CrossRefGoogle Scholar
  11. 11.
    Liu, L. L., Yang, J. L., & Shi, Y. P. (2010). Phytochemicals and biological activities of Pulicaria species. Chemistry & Biodiversity, 7, 327–349.CrossRefGoogle Scholar
  12. 12.
    Stavri, M., Mathew, K. T., Gordon, A., Shnyder, S. D., Falconer, R. A., & Gibbons, S. (2008). Guaianolide sesquiterpenes from Pulicaria crispa (Forssk.) Oliv. Phytochemistry, 69, 1915–1918.CrossRefGoogle Scholar
  13. 13.
    Ahmed, I. F., Alam, A., Soliman, G. A., Salkini, M. Y., Ahmed, E. I., & Yusufoglu, H. S. (2016). Pharmacognostical, antibacterial and antioxidant studies of aerial parts of Pulicaria somalensis (Family: Asteraceae). Asian Journal of Biological Sciences, 9, 19–26.CrossRefGoogle Scholar
  14. 14.
    Ahmed, N., Aljuhani, N., Salamah, S., Surrati, H., El-Agamy, D. S., Elkablawy, M. A., et al. (2018). Pulicaria petiolaris effectively attenuates LPS-induced acute lung injury in mice. Archives of Biological Sciences, 70, 699–706.CrossRefGoogle Scholar
  15. 15.
    Yusufoglu, H. S. (2014). Analgesic, antipyretic, anti-inflammatory, hepatoprotective and nephritic effects of the aerial parts of Pulicaria arabica (Family: Compositae) on rats. Asian Pacific Journal of Tropical Medicine, 7, 583–590.CrossRefGoogle Scholar
  16. 16.
    Yusufoglu, H. S., Foudah, A. I., Alam, A., & Soliman, G. A. (2016). Cardioprotective and nephroprotective activities of methanolic extracts from Pulicaria somalensis herbs against carbon tetrachloride induced toxicity in rats. Planta Medica, 82(S01), S1–S381.Google Scholar
  17. 17.
    Ezoubeiri, A., Gadhi, C. A., Fdil, N., Benharref, A., Jana, M., & Vanhaelen, M. (2005). Isolation and antimicrobial activity of two phenolic compounds from Pulicaria odora L. Journal of Ethnopharmacology, 99, 287–292.CrossRefGoogle Scholar
  18. 18.
    Picman, A. K. (1986). Biological activities of sesquiterpene lactones. Biochemical Systematics and Ecology, 14, 255–281.CrossRefGoogle Scholar
  19. 19.
    Rodriguez, E., Towers, G. H. N., & Mitchell, J. C. (1976). Biological activities of sesquiterpene lactones. Phytochemistry, 15, 1573–1580.CrossRefGoogle Scholar
  20. 20.
    Collenette S (1999) Wild Flowers of Saudi Arabia. National Commission for Wild life Conservation and Development (NCWCD) & Sheila Collenette, King Fahd National Library, King of Saudi Arabia, pp. 169.Google Scholar
  21. 21.
    Zhang, N., Feng, H., Liao, H. H., Chen, S., Yang, Z., Deng, W., et al. (2018). Myricetin attenuated LPS induced cardiac injury in vivo and in vitro. Phytotherapy Research, 32, 459–470.CrossRefGoogle Scholar
  22. 22.
    Ahmed, L. A. (2012). Protective effects of magnesium supplementation on metabolic energy derangements in lipopolysaccharide-induced cardiotoxicity in mice. European Journal of Pharmacology, 694, 75–81.CrossRefGoogle Scholar
  23. 23.
    Kaur, G., Tirkey, N., Bharrhan, S., Chanana, V., Rishi, P., & Chopra, K. (2006). Inhibition of oxidative stress and cytokine activity by curcumin in amelioration of endotoxin-induced experimental hepatotoxicity in rodents. Clinical and Experimental Immunology, 145, 313–321.CrossRefGoogle Scholar
  24. 24.
    Kaur, G., Tirkey, N., & Chopra, K. (2006). Beneficial effect of hesperidin on lipopolysaccharide-induced hepatotoxicity. Toxicology, 226, 52–160.CrossRefGoogle Scholar
  25. 25.
    Sebai, H., Sani, M., Aouani, E., & Ghanem-Boughanmi, N. (2011). Cardioprotective effect of resveratrol on lipopolysaccharide-induced oxidative stress in rat. Drug and Chemical Toxicology, 34, 146–150.CrossRefGoogle Scholar
  26. 26.
    Sebai, H., Sani, M., Yacoubi, M. T., Aouani, E., Ghanem-Boughanmi, N., & Ben-Attia, M. (2010). Resveratrol, a red wine polyphenol, attenuates lipopolysaccharide-induced oxidative stress in rat liver. Ecotoxicology and Environmental Safety, 73, 1078–1083.CrossRefGoogle Scholar
  27. 27.
    Li, X., Liu, J., Wang, J., & Zhang, D. (2019). Luteolin suppresses lipopolysaccharide–induced cardiomyocyte hypertrophy and autophagy in vitro. Molecular Medicine Reports, 19, 1551–1560.CrossRefGoogle Scholar
  28. 28.
    Ohno, M., Moore, R., Myers, P., & Negishi, M. (2018). Co-Chaperone-mediated suppression of LPS-induced cardiac toxicity through NFκB signaling. Shock, 50(2), 248–254.CrossRefGoogle Scholar
  29. 29.
    Ajuwon, O. R., Oguntibeju, O. O., & Marnewick, J. L. (2014). Amelioration of lipopolysaccharide-induced liver injury by aqueous rooibos (Aspalathus linearis) extract via inhibition of pro-inflammatory cytokines and oxidative stress. BMC Complementary and Alternative Medicine, 14, 392.CrossRefGoogle Scholar
  30. 30.
    Raish, M., Ahmad, A., Alkharfy, K. M., Ahamad, S. R., Mohsin, K., Al-Jenoobi, F. I., et al. (2016). Hepatoprotective activity of Lepidium sativum seeds against D-galactosamine/lipopolysaccharide induced hepatotoxicity in animal model. BMC Complementary and Alternative Medicine, 16, 501.CrossRefGoogle Scholar
  31. 31.
    Wu, H., Pang, H., Chen, Y., Huang, L., Liu, H., Zheng, Y., et al. (2018). Anti-inflammatory effect of a polyphenol-enriched fraction from Acalypha wilkesiana on lipopolysaccharide-stimulated RAW 264.7 macrophages and acetaminophen-induced liver injury in mice. Oxidative Medicine and Cellular Longevity, 2018, 17.Google Scholar
  32. 32.
    Gou, Z., Jiang, S., Zheng, C., Tian, Z., & Lin, X. (2015). Equol inhibits LPS-induced oxidative stress and enhances the immune response in chicken HD11 macrophages. Cellular Physiology and Biochemistry, 36, 611–621.CrossRefGoogle Scholar
  33. 33.
    Li, D. Y., Xue, M. Y., Geng, Z. R., & Chen, P. Y. (2012). The suppressive effects of Bursopentine (BP5) on oxidative stress and NF-ĸB activation in lipopolysaccharide-activated murine peritoneal macrophages. Cellular Physiology and Biochemistry, 29, 9–20.CrossRefGoogle Scholar
  34. 34.
    Sugimoto, K., Sakamoto, S., Nakagawa, K., Hayashi, S., Harada, N., Yamaji, R., et al. (2011). Suppression of inducible nitric oxide synthase expression and amelioration of lipopolysaccharide-induced liver injury by polyphenolic compounds in Eucalyptus globulus leaf extract. Food Chemistry, 125, 442–446.CrossRefGoogle Scholar
  35. 35.
    Bharrhan, S., Chopra, K., & Rishi, P. (2010). Vitamin E supplementation modulates endotoxin-induced liver damage in a rat model. American Journal of Biomedical Sciences, 2, 51–62.CrossRefGoogle Scholar
  36. 36.
    Kao, E. S., Hsu, J. D., Wang, C. J., Yang, S. H., Cheng, S. Y., & Lee, H. J. (2009). Polyphenols extracted from Hibiscus sabdariffa L. inhibited lipopolysaccharide-induced inflammation by improving antioxidative conditions and regulating cyclooxygenase-2 expression. Bioscience, Biotechnology, and Biochemistry, 73, 385–390.CrossRefGoogle Scholar
  37. 37.
    Lee, S., Choi, S. Y., Choo, Y. Y., Kim, O., Tran, P. T., Dao, C. T., et al. (2015). Sappanone A exhibits anti-inflammatory effects via modulation of Nrf2 and NF-κB. International Immunopharmacology, 28, 328–336.CrossRefGoogle Scholar
  38. 38.
    Chen, Z., Liu, H., Lei, S., Zhao, B., & Xia, Z. (2016). LY294002 prevents lipopolysaccharide–induced hepatitis in a murine model by suppressing IκB phosphorylation. Molecular Medicine Reports, 13, 811–818.CrossRefGoogle Scholar
  39. 39.
    Cui, X., Chen, Q., Dong, Z., Xu, L., Lu, T., Li, D., et al. (2016). Inactivation of Sirt1 in mouse livers protects against endotoxemic liver injury by acetylating and activating NF-κB. Cell Death Disease, 7, e2403.CrossRefGoogle Scholar
  40. 40.
    Zhang, J., Zhu, D., Wang, Y., & Ju, Y. (2015). Andrographolide attenuates LPS-Induced cardiac malfunctions through inhibition of IκB phosphorylation and apoptosis in mice. Cellular Physiology and Biochemistry, 37, 1619–1628.CrossRefGoogle Scholar
  41. 41.
    El-Agamy, D. S., Shebl, A. M., & Shaaban, A. A. (2018). Modulation of d-galactosamine/lipopolysacharride-induced fulminant hepatic failure by nilotinib. Human and Experimental Toxicology, 37, 51–60.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, College of PharmacyTaibah UniversityAl Madinah Al MunawwarahSaudi Arabia
  2. 2.Pharmacology and Toxicology Department, Faculty of PharmacyMansoura UniversityMansouraEgypt
  3. 3.Department of Natural Products and Alternative Medicine, Faculty of PharmacyKing Abdulaziz UniversityJeddahSaudi Arabia
  4. 4.Department of Pharmacognosy, Faculty of PharmacyAl-Azhar University, Assiut BranchAssiutEgypt
  5. 5.Cardiology Unit, College of MedicineTaibah UniversityAl Madinah Al MunawwarahSaudi Arabia
  6. 6.Department of Pathology, College of MedicineTaibah UniversityAl-Madinah Al-MunawwarahSaudi Arabia
  7. 7.Department of Pathology, Faculty of MedicineMenoufia UniversityMenoufiaEgypt
  8. 8.Department of Pharmacognosy and Pharmaceutical Chemistry, College of PharmacyTaibah UniversityAl Madinah Al MunawwarahSaudi Arabia
  9. 9.Department of Pharmacognosy, Faculty of PharmacyAssiut UniversityAssiutEgypt

Personalised recommendations