Anti-inflammatory Effect of a Limonin Derivative In Vivo and Its Mechanisms in RAW264.7 Cells.
Mice
Rats
Animals
NF-kappa B
/ metabolism
Limonins
/ pharmacology
Proto-Oncogene Proteins c-akt
/ metabolism
Phosphatidylinositol 3-Kinases
/ metabolism
Interleukin-6
RAW 264.7 Cells
Anti-Inflammatory Agents
/ pharmacology
Phosphatidylinositol 3-Kinase
/ metabolism
Protein Serine-Threonine Kinases
Tumor Necrosis Factor-alpha
Lipopolysaccharides
/ pharmacology
AKT
NF-κB
PI3K
anti-inflammation
immunofluorescence
limonin derivate
Journal
Inflammation
ISSN: 1573-2576
Titre abrégé: Inflammation
Pays: United States
ID NLM: 7600105
Informations de publication
Date de publication:
Feb 2023
Feb 2023
Historique:
received:
20
04
2022
accepted:
21
07
2022
revised:
14
06
2022
pubmed:
21
8
2022
medline:
3
3
2023
entrez:
20
8
2022
Statut:
ppublish
Résumé
A potential new limonoid derivative, (12S,12aS)-6,6,8a,12a-tetramethyl-12-(5-(4-(piperidin-1-yl)butanoyl)furan-3-yl)decahydro-1H,3H-oxireno[2,3-d]pyrano[4',3':3,3a]isobenzofuro[5,4-f]isochromene-3,8,10(6H,9aH)-trione (I-C-1), has been screened for its anti-inflammatory activity. This study aimed to demonstrate the anti-inflammatory activities of I-C-1 and to further explore the underlying mechanisms of these activities in RAW264.7 macrophages. We verified the anti-inflammatory activity of I-C-1 in vivo by a carrageenan-induced paw edema model in rats and cotton pellet-induced granuloma in mice. Further, we found that I-C-1 significantly inhibited levels of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-induced RAW264.7 cells. I-C-1 demonstrated strong inhibition of the NF-κB activation through repression of the IKKα and IKKβ phosphorylations, as well as a significant suppression of the phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt) pathway, an upstream of the NF-κB pathway. Additionally, we verified the inhibitory effect of I-C-1 on PI3K phosphorylation by immunofluorescence assay and compared the effects of I-C-1 with the PI3K inhibitor LY294002 in IL-1β, IL-6, and TNF-α levels. The data indicated that I-C-1 likely acts as an inhibitor of PI3K, exerting anti-inflammatory effects by inhibiting the PI3K/AKT/NF-κB signaling pathway. Based on these findings, we believe that I-C-1 has the potential to be further developed as a potential therapeutic agent for inflammatory-related diseases.
Identifiants
pubmed: 35986873
doi: 10.1007/s10753-022-01722-0
pii: 10.1007/s10753-022-01722-0
doi:
Substances chimiques
NF-kappa B
0
limonin
L0F260866S
Limonins
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Interleukin-6
0
Anti-Inflammatory Agents
0
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Protein Serine-Threonine Kinases
EC 2.7.11.1
Tumor Necrosis Factor-alpha
0
Lipopolysaccharides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
190-201Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Komatsu, K., J.Y. Lee, M. Miyata, et al. 2013. Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD. Nature Communications 4: 1684.
doi: 10.1038/ncomms2674
pubmed: 23575688
He, G.Y., M. Xie, Y. Gao, and J.G. Huang. 2015. Sodium ferulate attenuates oxidative stress induced inflammation via suppressing NALP3 and NF-kappaB signal pathway. Sichuan da xue xue bao Yi xue ban = Journal of Sichuan University Medical Science Edition 46 (3): 367–371.
Gao, Q., X. Liang, A.S. Shaikh, J. Zang, W. Xu, and Y. Zhang. 2018. JAK/STAT signal transduction: Promising attractive targets for immune, inflammatory and hematopoietic diseases. Current Drug Targets 19 (5): 487–500.
doi: 10.2174/1389450117666161207163054
pubmed: 27928945
Yang, Q., Y. Xu, G. Feng, et al. 2014. p38 MAPK signal pathway involved in anti-inflammatory effect of Chaihu-Shugan-San and Shen-ling-bai-zhu-San on hepatocyte in non-alcoholic steatohepatitis rats. African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM 11 (1): 213–221.
pubmed: 24653580
Wang, L., Y. Xu, Q. Yu, et al. 2014. H-RN, a novel antiangiogenic peptide derived from hepatocyte growth factor inhibits inflammation in vitro and in vivo through PI3K/AKT/IKK/NF-kappaB signal pathway. Biochemical Pharmacology 89 (2): 255–265.
doi: 10.1016/j.bcp.2014.02.026
pubmed: 24630926
Kunihiro, K., T.N. Huu, S. Yukihiro, S. Shigeyuki, M. Takayuki, and T. Takuji. 2012. Dietary Crocin inhibits colitis and colitis-associated colorectal carcinogenesis in male ICR mice. Evidenced-Based Complementary and Alternative Medicine 2012 (4).
Kunnumakkara, A.B., B.L. Sailo, K. Banik, et al. 2018. Chronic diseases, inflammation, and spices: How are they linked? Journal of Translational Medicine 16 (1): 14.
doi: 10.1186/s12967-018-1381-2
pubmed: 29370858
pmcid: 5785894
Ma, Z.G., H.Q. Xia, S.L. Cui. et al. 2017. Attenuation of renal ischemic reperfusion injury by salvianolic acid B via suppressing oxidative stress and inflammation through PI3K/Akt signaling pathway. Brazilian Journal of Medical & Biological Research 50 (6).
Cai, J.Y., D.Z. Chen, S.H. Luo, et al. 2014. Limonoids from Aphanamixis polystachya and their antifeedant activity. Journal of Natural Products 77 (3): 472–482.
doi: 10.1021/np400678h
pubmed: 24256462
Choodej, S., D. Sommit, and K. Pudhom. 2013. Rearranged limonoids and chromones from Harrisonia perforata and their anti-inflammatory activity. Bioorganic & Medicinal Chemistry Letters 23 (13): 3896–3900.
doi: 10.1016/j.bmcl.2013.04.064
Joray, M.B., F. Villafanez, M.L. Gonzalez, et al. 2017. P53 tumor suppressor is required for efficient execution of the death program following treatment with a cytotoxic limonoid obtained from Melia azedarach. Food and Chemical Toxicology: An international journal published for the British Industrial Biological Research Association 109 (Pt 2): 888–897.
doi: 10.1016/j.fct.2017.04.039
pubmed: 28465189
Zhu, G.Y., L.P. Bai, L. Liu, and Z.H. Jiang. 2014. Limonoids from the fruits of Melia toosendan and their NF-κB modulating activities. Phytochemistry 107: 175.
doi: 10.1016/j.phytochem.2014.08.009
pubmed: 25189120
Bao, Y., H. Li, Q.Y. Li, et al. 2018. Therapeutic effects of Smilax glabra and Bolbostemma paniculatum on rheumatoid arthritis using a rat paw edema model. Biomedicine & Pharmacotherapy 108: 309–315.
doi: 10.1016/j.biopha.2018.09.004
Qi, S., Y. Xin, Y. Guo, et al. 2012. Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-kappaB signaling pathways. International Immunopharmacology 12 (1): 278–287.
doi: 10.1016/j.intimp.2011.12.001
pubmed: 22193240
Chen, X., X. Li, X. Zhai, et al. 2018. Shikimic acid inhibits osteoclastogenesis in vivo and in vitro by blocking RANK/TRAF6 association and suppressing NF-kappaB and MAPK signaling pathways. Cellular Physiology and Biochemistry: International journal of experimental cellular physiology, biochemistry, and pharmacology 51 (6): 2858–2871.
doi: 10.1159/000496039
pubmed: 30562759
Chen, H., Y. Wu, Z. Chen, et al. 2017. Performance evaluation of a novel sample in-answer out (SIAO) system based on magnetic nanoparticles. Journal of Biomedical Nanotechnology 13 (12): 1619–1630.
doi: 10.1166/jbn.2017.2478
pubmed: 29490751
Asante, D.B., I.T. Henneh, D.O. Acheampong, et al. 2019. Anti-inflammatory, anti-nociceptive and antipyretic activity of young and old leaves of Vernonia amygdalina. Biomedicine & Pharmacotherapy 111: 1187–1203.
doi: 10.1016/j.biopha.2018.12.147
Wang, J.W., S.S. Chen, Y.M. Zhang, et al. 2019. Anti-inflammatory and analgesic activity based on polymorphism of cedrol in mice. Environmental Toxicology and Pharmacology 68: 13–18.
doi: 10.1016/j.etap.2019.02.005
pubmed: 30852303
Subash, A., G. Veeraraghavan, V.K. Sali, M. Bhardwaj, and H.R. Vasanthi. 2016. Attenuation of inflammation by marine algae Turbinaria ornata in cotton pellet induced granuloma mediated by fucoidan like sulphated polysaccharide. Carbohydrate Polymers 151: 1261–1268.
doi: 10.1016/j.carbpol.2016.06.077
pubmed: 27474679
Shin, J.S., Y. Hong, H.H. Lee, et al. 2015. Fulgidic acid isolated from the rhizomes of Cyperus rotundus suppresses LPS-induced iNOS, COX-2, TNF-alpha, and IL-6 expression by AP-1 inactivation in RAW264.7 macrophages. Biological & Pharmaceutical Bulletin 38 (7): 1081–1086.
Krishnan, S.M., C.G. Sobey, E. Latz, A. Mansell, and G.R. Drummond. 2014. IL-1β and IL-18: Inflammatory markers or mediators of hypertension? British Journal of Pharmacology 171 (24): 5589–5602.
doi: 10.1111/bph.12876
pubmed: 25117218
pmcid: 4290704
DiDonato, J.A., F. Mercurio, and M. Karin. 2012. NF-kappaB and the link between inflammation and cancer. Immunological Reviews 246 (1): 379–400.
doi: 10.1111/j.1600-065X.2012.01099.x
pubmed: 22435567
Wang, Z., H. Wesche, T. Stevens, N. Walker, and W.C. Yeh. 2009. IRAK-4 inhibitors for inflammation. Current Topics in Medicinal Chemistry 9 (8): 724–737.
doi: 10.2174/156802609789044407
pubmed: 19689377
pmcid: 3182414
Zhang, J., T. Macartney, M. Peggie, and P. Cohen. 2017. Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3. The Biochemical Journal 474 (13): 2235–2248.
doi: 10.1042/BCJ20170288
pubmed: 28507161
Huang, X.L., J. Xu, X.H. Zhang, et al. 2011. PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis. Inflammation Research 60 (8): 727–734.
doi: 10.1007/s00011-011-0325-6
pubmed: 21442372
Sun, Y., Y. Zhao, X. Wang, et al. 2016. Wogonoside prevents colitis-associated colorectal carcinogenesis and colon cancer progression in inflammation-related microenvironment via inhibiting NF-κB activation through PI3K/Akt pathway. Oncotarget 7 (23): 34300–34315.
doi: 10.18632/oncotarget.8815
pubmed: 27102438
pmcid: 5085157
Wang, Y., Y. Kuramitsu, B. Baron, et al. 2017. PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. International Journal of Oncology 50 (2): 606–612.
doi: 10.3892/ijo.2016.3804
pubmed: 28000865
Jahan, S., D. Kumar, S. Singh, et al. 2018. Resveratrol prevents the cellular damages induced by monocrotophos via PI3K signaling pathway in human cord blood mesenchymal stem cells. Molecular Neurobiology 55 (11): 8278–8292.
doi: 10.1007/s12035-018-0986-z
pubmed: 29526017
Zeinali, M., S.A. Rezaee, and H. Hosseinzadeh. 2017. An overview on immunoregulatory and anti-inflammatory properties of chrysin and flavonoids substances. Biomedicine & Pharmacotherapy = Biomedecine & pharmacotherapie 92: 998.
Decourt, B., D.K. Lahiri, and M.N. Sabbagh. 2017. Targeting tumor necrosis factor alpha for Alzheimer’s disease. Current Alzheimer Research 14 (4): 412–425.
doi: 10.2174/1567205013666160930110551
pubmed: 27697064
pmcid: 5328927
Liu, D., X. Wang, and Z. Chen. 2016. Tumor necrosis factor-alpha, a regulator and therapeutic agent on breast cancer. Current Pharmaceutical Biotechnology 17 (6): 486–494.
doi: 10.2174/1389201017666160301102713
pubmed: 26927216
Postal, M., and S. Appenzeller. 2011. The role of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of systemic lupus erythematosus. Cytokine 56 (3): 537–543.
doi: 10.1016/j.cyto.2011.08.026
pubmed: 21907587
Slevin, S.M., and L.J. Egan. 2015. New insights into the mechanisms of action of anti-tumor necrosis factor-alpha monoclonal antibodies in inflammatory bowel disease. Inflammatory Bowel Diseases 21 (12): 2909–2920.
doi: 10.1097/MIB.0000000000000533
pubmed: 26348448
Kawahara, K., H. Hohjoh, T. Inazumi, S. Tsuchiya, and Y. Sugimoto. 2015. Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors. Biochimica Et Biophysica Acta 1851 (4): 414.
doi: 10.1016/j.bbalip.2014.07.008
pubmed: 25038274
Yadav, S.K., B. Adhikary, S.K. Bandyopadhyay, and S. Chattopadhyay. 2013. Inhibition of TNF-α, and NF-κB and JNK pathways accounts for the prophylactic action of the natural phenolic, allylpyrocatechol against indomethacin gastropathy. Biochimica et Biophysica Acta 1830 (6): 3776–3786.
doi: 10.1016/j.bbagen.2013.03.013
pubmed: 23523691
Clark, K., M. Peggie, L. Plater, et al. 2011. Novel cross-talk within the IKK family controls innate immunity. Biochemical Journal 434 (1): 93–104.
doi: 10.1042/BJ20101701
pubmed: 21138416
Hinz, M., and C. Scheidereit. 2014. The IκB kinase complex in NF-κB regulation and beyond. EMBO Reports 15 (1): 46–61.
doi: 10.1002/embr.201337983
pubmed: 24375677
McKenna, S., M. Gossling, A. Bugarini, et al. 2015. Endotoxemia induces IκBβ/NF-κB-dependent endothelin-1 expression in hepatic macrophages. Journal of Immunology (Baltimore, Md: 1950) 195 (8): 3866–3879.
Rao, P., M.S. Hayden, M. Long, et al. 2010. IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response. Nature 466 (7310): 1115–1119.
doi: 10.1038/nature09283
pubmed: 20740013
pmcid: 2946371
Madianos, P.N., Y.A. Bobetsis, and D.F. Kinane. 2005. Generation of inflammatory stimuli: How bacteria set up inflammatory responses in the gingiva. Journal of Clinical Periodontology 32 Suppl 6 (s6): 57.
Seki, E., and B. Schnabl. 2012. Role of innate immunity and the microbiota in liver fibrosis: Crosstalk between the liver and gut. The Journal of Physiology 590 (3): 447–458.
doi: 10.1113/jphysiol.2011.219691
pubmed: 22124143
Xie, S., M. Chen, B. Yan, X. He, X. Chen, and D. Li. 2014. Identification of a role for the PI3K/AKT/mTOR signaling pathway in innate immune cells. 9 (4): e94496.
Tas, S.W., P.H. Remans, K.A. Reedquist, and P.P. Tak. 2005. Signal transduction pathways and transcription factors as therapeutic targets in inflammatory disease: Towards innovative antirheumatic therapy. Current Pharmaceutical Design 11 (5): 581–611.