Modulation of cell signaling pathways by Phyllanthus amarus and its major constituents: potential role in the prevention and treatment of inflammation and cancer

  • Hemavathy Harikrishnan
  • Ibrahim JantanEmail author
  • Akilandeshwari Alagan
  • Md. Areeful Haque


The causal and functional connection between inflammation and cancer has become a subject of much research interest. Modulation of cell signaling pathways, such as those involving mitogen activated protein kinases (MAPKs), nuclear factor kappa β (NF-κB), phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt), and Wnt, and their outcomes play a fundamental role in inflammation and cancer. Activation of these cell signaling pathways can lead to various aspects of cancer-related inflammation. Hence, compounds able to modulate inflammation-related molecular targets are sought after in anticancer drug development programs. In recent years, plant extracts and their metabolites have been documented with potential in the prevention and treatment of cancer and inflammatory ailments. Plants possessing anticancer and anti-inflammatory properties due to their bioactive constituents have been reported to modulate the molecular and cellular pathways which are related to inflammation and cancer. In this review we focus on the flavonoids (astragalin, kaempferol, quercetin, rutin), lignans (phyllanthin, hypophyllanthin, and niranthin), tannins (corilagin, geraniin, ellagic acid, gallic acid), and triterpenes (lupeol, oleanolic acid, ursolic acid) of Phyllanthus amarus, which exert various anticancer and anti-inflammatory activities via perturbation of the NF-κB, MAPKs, PI3K/Akt, and Wnt signaling networks. Understanding the underlying mechanisms involved may help future research to develop drug candidates for prevention and new treatment for cancer and inflammatory diseases.


Phyllanthus amarus Secondary metabolites Anti-inflammation Anticancer Signaling pathways 



This work was supported by the Ministry of Agriculture and Agro-based Industries, Malaysia, under the NKEA Research Grant Scheme (NRGS) Grant no. NH1015D075).

Compliance with ethical standards

Conflict of interest

All authors declare that they do not have any conflict of interest.


  1. Abhyankar G, Suprasanna P, Pandey B, Mishra K, Rao K, Reddy V (2010) Hairy root extract of Phyllanthus amarus induces apoptotic cell death in human breast cancer cells. Innov Food Sci Emerg Technol 1:526–532CrossRefGoogle Scholar
  2. Ahad A, Ganai AA, Mujeeb M, Siddiqui WA (2014) Ellagic acid, an NF-κB inhibitor, ameliorates renal function in experimental diabetic nephropathy. Chem Biol Interact 219:64–75PubMedCrossRefPubMedCentralGoogle Scholar
  3. Alagan A, Jantan I, Kumolosasi E, Ogawa S, Abdullah MA, Azmi N (2019) Protective effects of Phyllanthus amarus against lipopolysaccharide-induced neuroinflammation and cognitive impairment in rats. Front Pharmacol 10:632. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Albrecht M, Jiang W, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A et al (2004) Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7:274–283PubMedCrossRefPubMedCentralGoogle Scholar
  5. Anitha P, Priyadarsini RV, Kavitha K, Thiyagarajan P, Nagini S (2013) Ellagic acid coordinately attenuates Wnt/β-catenin and NF-κB signaling pathways to induce intrinsic apoptosis in an animal model of oral oncogenesis. Eur J Nutr 52:75–84PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bagalkotkar G, Sagineedu SR, Saad MS, Stanslas J (2006) Phytochemicals from Phyllanthus niruri Linn. and their pharmacological properties: a review. J Pharm Pharmacol 58:1559–1570PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bainey KR, Armstrong PW (2014) Clinical perspectives on reperfusion injury in acute myocardial infarction. Am Heart J 167:637–645PubMedCrossRefPubMedCentralGoogle Scholar
  8. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedCrossRefPubMedCentralGoogle Scholar
  9. Basu A, Das AS, Sharma M, Pathak MP, Chattopadhyay P, Biswas K et al (2017) STAT3 and NF-κB are common targets for kaempferol-mediated attenuation of COX-2 expression in IL-6-induced macrophages and carrageenan-induced mouse paw edema. Biochem Biophys Rep 2:54–61Google Scholar
  10. Bing SJ, Ha D, Kim MJ, Park E, Ahn G, Kim DS et al (2013) Geraniin down regulates gamma radiation-induced apoptosis by suppressing DNA damage. Food Chem Toxicol 57:147–153PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bıtıs L, Kultur S, Melıkoglu G, Ozsoy N, Can A (2010) Flavonoids and antioxidant activity of Rosa agrestis leaves. Nat Prod Res 24:580–589PubMedCrossRefPubMedCentralGoogle Scholar
  12. Burmistrova O, Quintana J, Díaz JG, Estévez F (2011) Astragalin heptaacetate-induced cell death in human leukemia cells is dependent on caspases and activates the MAPK pathway. Cancer Lett 309:71–77PubMedCrossRefPubMedCentralGoogle Scholar
  13. Calderon-Montano JM, Burgos-Moron E, Perez-Guerrero C, Lopez-Lazaro M (2011) A review on the dietary flavonoid kaempferol. Mini Rev Med Chem 11:298–344PubMedCrossRefPubMedCentralGoogle Scholar
  14. Calixto JB, Santos AR, Filho VC, Yunes RA (1998) A review of the plants of the genus Phyllanthus: their chemistry, pharmacology, and therapeutic potential. Med Res Rev 18:225–258PubMedCrossRefPubMedCentralGoogle Scholar
  15. Chen X, Yang X, Liu T, Guan M, Feng X, Dong W et al (2012) Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice. Int Immunopharmacol 14:209–216PubMedCrossRefPubMedCentralGoogle Scholar
  16. Cho I-H, Gong J-H, Kang M-K, Lee E-J, Park JHY, Park S-J et al (2014) Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling. BMC Pulm Med 14:122PubMedPubMedCentralCrossRefGoogle Scholar
  17. Choi K-C, Lee Y-H, Jung MG, Kwon SH, Kim M-J, Jun WJ et al (2009) Gallic acid suppresses lipopolysaccharide-induced nuclear factor-κB signaling by preventing RelA acetylation in A549 lung cancer cells. Mol Cancer Res 7:2011–2021PubMedCrossRefPubMedCentralGoogle Scholar
  18. Choi S, Lim T-G, Hwang MK, Kim Y-A, Kim J, Kang NJ et al (2013) Rutin inhibits B[a]PDE-induced cyclooxygenase-2 expression by targeting EGFR kinase activity. Biochem Pharmacol 86:1468–1475PubMedCrossRefPubMedCentralGoogle Scholar
  19. Choi K-S, Kundu JK, Chun K-S, Na H-K, Surh Y-J (2014) Rutin inhibits UVB radiation-induced expression of COX-2 and iNOS in hairless mouse skin: p38 MAP kinase and JNK as potential targets. Arch Biochem Biophys 559:38–45PubMedCrossRefPubMedCentralGoogle Scholar
  20. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedPubMedCentralCrossRefGoogle Scholar
  21. Deng Y, Li X, Li X, Zheng Z, Huang W, Chen L et al (2018) Corilagin induces the apoptosis of hepatocellular carcinoma cells through the mitochondrial apoptotic and death receptor pathways. Oncol Rep 39:2545–2552PubMedPubMedCentralGoogle Scholar
  22. Del Prete A, Allavena P, Santoro G, Fumarulo R, Corsi MM, Mantovani A (2011) Molecular pathways in cancer-related inflammation. Biochem Med (Zagreb) 21:264–275CrossRefGoogle Scholar
  23. Dong X-R, Luo M, Fan L, Zhang T, Liu L, Dong J-H et al (2010) Corilagin inhibits the double strand break-triggered NF-κB pathway in irradiated microglial cells. Int J Mol Med 25:531–536PubMedPubMedCentralGoogle Scholar
  24. Edderkaoui M, Odinokova I, Ohno I, Gukovsky I, Go VLW, Pandol SJ et al (2008) Ellagic acid induces apoptosis through inhibition of nuclear factor κB in pancreatic cancer cells. World J Gastroenterol 14:3672–3680PubMedPubMedCentralCrossRefGoogle Scholar
  25. Endale M, Park S-C, Kim S, Kim S-H, Yang Y, Cho JY et al (2013) Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells. Immunobiology 218:1452–1467PubMedCrossRefPubMedCentralGoogle Scholar
  26. Fang Y, Zhou H, Xia J-F, Lin J-J, Li R-Z, Yang D-Q et al (2015) Ellagic acid regulates Wnt/beta-catenin signaling pathway and CDK8 in HCT 116 and HT 29 colon cancer cells. Bangladesh J Pharmacol 10:47–56CrossRefGoogle Scholar
  27. Fernández MA, de las Heras B, Garcia MD, Sáenz MT, Villar A (2001) New insights into the mechanism of action of the anti-inflammatory triterpene lupeol. J Pharm Pharmacol 53:1533–1539PubMedCrossRefPubMedCentralGoogle Scholar
  28. Foo LY (1993) Amarulone, a novel cyclic hydrolysable tannin from Phyllanthus amarus. Nat Prod Lett 3:45–52CrossRefGoogle Scholar
  29. Foo LY, Wong H (1992) Phyllanthusiin D, an unusual hydrolysable tannin from Phyllanthus amarus. Phytochemistry 31:711–713CrossRefGoogle Scholar
  30. Fujiki H, Suganuma M, Kurusu M, Okabe S, Imayoshi Y, Taniguchi S et al (2003) New TNF-α releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with EGCG and sulindac or tamoxifen. Mutat Res Fund Mol 523:119–125CrossRefGoogle Scholar
  31. Fukuzawa J, Nishihira J, Hasebe N, Haneda T, Osaki J, Saito T et al (2002) Contribution of macrophage migration inhibitory factor to extracellular signal-regulated kinase activation by oxidative stress in cardiomyocytes. J Biol Chem 277:24889–24895PubMedCrossRefPubMedCentralGoogle Scholar
  32. Gambari R, Borgatti M, Lampronti I, Fabbri E, Brognara E, Bianchi N et al (2012) Corilagin is a potent inhibitor of NF-kappaB activity and downregulates TNF-alpha induced expression of IL-8 gene in cystic fibrosis IB3-1 cells. Int immunopharmacol 13:308–315PubMedCrossRefPubMedCentralGoogle Scholar
  33. Granado-Serrano AB, Angeles Martín M, Bravo L, Goya L, Ramos S (2008) Time-course regulation of quercetin on cell survival/proliferation pathways in human hepatoma cells. Mol Nutr Food Res 52:457–464PubMedCrossRefPubMedCentralGoogle Scholar
  34. Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S (2010) Quercetin modulates NF-κ B and AP-1/JNK pathways to induce cell death in human hepatoma cells. Nutr Cancer 62:390–401PubMedCrossRefPubMedCentralGoogle Scholar
  35. Guo Y-J, Zhao L, Li X-F, Mei Y-W, Zhang S-L, Tao J-Y et al (2010) Effect of corilagin on anti-inflammation in HSV-1 encephalitis and HSV-1 infected microglias. Eur J Pharmacol 635:79–86PubMedCrossRefGoogle Scholar
  36. Guo J, Luo T, Wu F, Liu H, Li H-R, Mei Y-W et al (2015) Corilagin protects against HSV1 encephalitis through inhibiting the TLR2 signaling pathways in vivo and in vitro. Mol Neurobiol 52:1547–1560PubMedCrossRefGoogle Scholar
  37. Guo C, Yang R-J, Jang K, Zhou X-l, Liu Y-Z (2017) Protective effects of pretreatment with quercetin against lipopolysaccharide-induced apoptosis and the inhibition of osteoblast differentiation via the MAPK and Wnt/β-catenin pathways in MC3T3-E1 cells. Cell Physiol Biochem 43:1547–1561PubMedCrossRefGoogle Scholar
  38. Handa O, Naito Y, Takagi T, Ishikawa T, Ueda M, Matsumoto N et al (2002) Inhibitory effects of catechins on neutrophil-dependent gastric inflammation. Redox Rep 7:324–328PubMedCrossRefGoogle Scholar
  39. Harikrishnan H, Jantan I, Haque MA, Kumolosasi E (2018a) Anti-inflammatory effects of Phyllanthus amarus Schum. & Thonn. through inhibition of NF-κB, MAPK, and PI3K-Akt signaling pathways in LPS-induced human macrophages. BMC Complement Altern Med 18:224PubMedPubMedCentralCrossRefGoogle Scholar
  40. Harikrishnan H, Jantan I, Haque MA, Kumolosasi E (2018b) Phyllanthin from Phyllanthus amarus inhibits LPS‐induced proinflammatory responses in U937 macrophages via downregulation of NF‐κB/MAPK/PI3K‐Akt signaling pathways. Phytother Res 32:2510–2519PubMedCrossRefPubMedCentralGoogle Scholar
  41. Harikrishnan H, Jantan I, Haque MA, Kumolosasi E (2018) Anti-inflammatory effects of hypophyllanthin and niranthin through downregulation of NF-κB/MAPKs/PI3K-Akt signaling pathways. Inflammation 41:984–995PubMedCrossRefPubMedCentralGoogle Scholar
  42. Harikumar KB, Kuttan G, Kuttan R (2009) Phyllanthus amarus inhibits cell growth and induces apoptosis in Dalton's lymphoma ascites cells through activation of caspase-3 and downregulation of Bcl-2. Integr Cancer Ther 8:190–194PubMedCrossRefPubMedCentralGoogle Scholar
  43. Ho H-H, Chang C-S, Ho W-C, Liao S-Y, Lin W-L, Wang C-J (2013) Gallic acid inhibits gastric cancer cells metastasis and invasive growth via increased expression of RhoB, downregulation of AKT/small GTPase signals and inhibition of NF-κB activity. Toxicol Appl Pharmacol 266:76–85PubMedCrossRefPubMedCentralGoogle Scholar
  44. Houghton PJ, Woldemariam TZ, O'Shea S, Thyagarajan S (1996) Two securinega-type alkaloids from Phyllanthus amarus. Phytochemistry 43:715–717CrossRefGoogle Scholar
  45. Huang RL, Huang YL, Ou JC, Chen CC, Hsu FL, Chang C (2003) Screening of 25 compounds isolated from Phyllanthus species for anti-human hepatitis B virus in vitro. Phytother Res 17:449–453PubMedCrossRefPubMedCentralGoogle Scholar
  46. Hwang MK, Song NR, Kang NJ, Lee KW, Lee HJ (2009) Activation of phosphatidylinositol 3-kinase is required for tumor necrosis factor-α-induced upregulation of matrix metalloproteinase-9: its direct inhibition by quercetin. Int J Biochem Cell Biol 41:1592–1600PubMedCrossRefPubMedCentralGoogle Scholar
  47. Ikeda Y, Murakami A, Fujimura Y, Tachibana H, Yamada K, Masuda D et al (2007) Aggregated ursolic acid, a natural triterpenoid, induces IL-1beta release from murine peritoneal macrophages: role of CD36. J Immunol 178:4854–4864PubMedCrossRefPubMedCentralGoogle Scholar
  48. Iranloye B, Owoyele V, Kelani O, Olaleye S (2011) Analgesic activity of aqueous leaf extract of Phyllanthus amarus. Afr J Med Med Sci 40:47–50PubMedPubMedCentralGoogle Scholar
  49. Javelaud D, Poupon MF, Wietzerbin J, Besançon F (2002) Inhibition of constitutive NF-κB activity suppresses tumorigenicity of Ewing sarcoma EW7 cells. Int J Cancer 98:193–198PubMedCrossRefPubMedCentralGoogle Scholar
  50. Jeena KJ, Joy K, Kuttan R (1999) Effect of Emblica officinalis, Phyllanthus amarus and Picrorrhiza kurroa on N-nitrosodiethylamine induced hepatocarcinogenesis. Cancer Lett 136:11–16PubMedCrossRefPubMedCentralGoogle Scholar
  51. Jesus JA, Lago JHG, Laurenti MD, Yamamoto ES, Passero LFD (2015) Antimicrobial activity of oleanolic and ursolic acids: an update. Evid Based Complemen Altern Med 2015:620472. CrossRefGoogle Scholar
  52. Jia L, Jin H, Zhou J, Chen L, Lu Y, Ming Y et al (2013) A potential anti-tumor herbal medicine, corilagin, inhibits ovarian cancer cell growth through blocking the TGF-β signaling pathways. BMC Complemen Altern Med 13:33CrossRefGoogle Scholar
  53. Kanakaraj P, Schafer PH, Cavender DE, Wu Y, Ngo K, Grealish PF et al (1998) Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production. J Exp Med 187:2073–2079PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kang KA, Lee IK, Zhang R, Piao MJ, Kim KC, Kim SY et al (2011) Radioprotective effect of geraniin via the inhibition of apoptosis triggered by γ-radiation-induced oxidative stress. Cell Biol Toxicol 27:83–94PubMedCrossRefPubMedCentralGoogle Scholar
  55. Kassuya CA, Silvestre AA, Rehder VLG, Calixto JB (2003) Anti-allodynic and anti-oedematogenic properties of the extract and lignans from Phyllanthus amarus in models of persistent inflammatory and neuropathic pain. Eur J Pharmacol 478:145–153PubMedCrossRefPubMedCentralGoogle Scholar
  56. Kassuya CA, Leite DF, de Melo LV, Rehder VLG, Calixto JB (2005) Anti-inflammatory properties of extracts, fractions and lignans isolated from Phyllanthus amarus. Planta Med 71:721–726PubMedCrossRefPubMedCentralGoogle Scholar
  57. Kassuya CA, Silvestre A, Menezes-de-Lima O, Marotta DM, Rehder VLG, Calixto JB (2006) Antiinflammatory and antiallodynic actions of the lignan niranthin isolated from Phyllanthus amarus: evidence for interaction with platelet activating factor receptor. Eur J Pharmacol 546:182–188PubMedCrossRefPubMedCentralGoogle Scholar
  58. Kiemer AK, Hartung T, Huber C, Vollmar AM (2003) Phyllanthus amarus has anti-inflammatory potential by inhibition of iNOS, COX-2, and cytokines via the NF-κB pathway. J Hepatol 38:289–297PubMedCrossRefPubMedCentralGoogle Scholar
  59. Kim M-S, Kim S-H (2011) Inhibitory effect of astragalin on expression of lipopolysaccharide-induced inflammatory mediators through NF-κB in macrophages. Arch Pharmacal Res 34:2101–2107CrossRefGoogle Scholar
  60. Kim S-H, Jun C-D, Suk K, Choi B-J, Lim H, Park S et al (2005) Gallic acid inhibits histamine release and pro-inflammatory cytokine production in mast cells. Toxicol Sci 91:123–131PubMedCrossRefPubMedCentralGoogle Scholar
  61. Kim JM, Lee EK, Kim DH, Yu BP, Chung HY (2010) Kaempferol modulates pro-inflammatory NF-κB activation by suppressing advanced glycation endproducts-induced NADPH oxidase. Age 32:197–208PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kim MJ, Seong AR, Yoo JY, Jin CH, Lee YH, Kim YJ et al (2011) Gallic acid, a histone acetyltransferase inhibitor, suppresses β-amyloid neurotoxicity by inhibiting microglial-mediated neuroinflammation. Mol Nutr Food Res 55:1798–1808PubMedCrossRefPubMedCentralGoogle Scholar
  63. Kim SH, Park JG, Lee J, Yang WS, Park GW, Kim HG et al (2015) The dietary flavonoid kaempferol mediates anti-inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular targets. Mediat Inflamm 2015:904142. CrossRefGoogle Scholar
  64. Kim Y-H, Choi Y-J, Kang M-K, Park S-H, Antika LD, Lee E-J et al (2017) Astragalin inhibits allergic inflammation and airway thickening in ovalbumin-challenged mice. J Agric Food Chem 65:836–845PubMedCrossRefPubMedCentralGoogle Scholar
  65. Kolodziej H, Kayser O, Kiderlen A, Ito H, Hatano T, Yoshida T et al (2001) Antileishmanial activity of hydrolyzable tannins and their modulatory effects on nitric oxide and tumour necrosis factor-α release in macrophages in vitro. Planta Med 67:825–832PubMedCrossRefPubMedCentralGoogle Scholar
  66. Kolodziej H, Burmeister A, Trun W, Radtke OA, Kiderlen AF, Ito H et al (2005) Tannins and related compounds induce nitric oxide synthase and cytokines gene expressions in Leishmania major-infected macrophage-like RAW 264.7 cells. Bioorg Med Chem 13:6470–6476PubMedCrossRefPubMedCentralGoogle Scholar
  67. Komori A, Yatsunami J, Suganuma M, Okabe S, Abe S, Sakai A et al (1993) Tumor necrosis factor acts as a tumor promoter in BALB/3T3 cell transformation. Can Res 53:1982–1985Google Scholar
  68. Krithika R, Jyothilakshmi V, Verma RJ (2016) Phyllanthin inhibits CCl4-mediated oxidative stress and hepatic fibrosis by down-regulating TNF-α/NF-κB, and pro-fibrotic factor TGF-β1 mediating inflammatory signaling. Toxicol Ind Health 32:953–960PubMedCrossRefPubMedCentralGoogle Scholar
  69. Kumar KH, Kuttan R (2004) Protective effect of an extract of Phyllanthus amarus against radiation-induced damage in mice. J Radiat Res 45:133–139PubMedCrossRefPubMedCentralGoogle Scholar
  70. Kuppan G, Balasubramanyam J, Monickaraj F, Srinivasan G, Mohan V, Balasubramanyam M (2010) Transcriptional regulation of cytokines and oxidative stress by gallic acid in human THP-1 monocytes. Cytokines 49:229–234CrossRefGoogle Scholar
  71. Kuttan R, Harikumar K (2011) Phyllanthus species: scientific evaluation and medicinal applications. CRC, Boca Raton. CrossRefGoogle Scholar
  72. Kyung T-W, Lee J-E, Shin H-H, Choi H-S (2008) Rutin inhibits osteoclast formation by decreasing reactive oxygen species and TNF-α by inhibiting activation of NF-κB. Exp Mol Med 40:52–58PubMedPubMedCentralCrossRefGoogle Scholar
  73. Lee G, Na H-J, Namkoong S, Kwon HJ, Han S, Ha K-S et al (2006) 4-O-Methylgallic acid down-regulates endothelial adhesion molecule expression by inhibiting NF-κB-DNA-binding activity. Eur J Parmacol 551:143–151CrossRefGoogle Scholar
  74. Lee TK, Poon R, Wo JY, Ma S, Guan X-Y, Myers JN et al (2007) Lupeol suppresses cisplatin-induced nuclear factor-κB activation in head and neck squamous cell carcinoma and inhibits local invasion and nodal metastasis in an orthotopic nude mouse model. Cancer Res 67:8800–8809PubMedCrossRefPubMedCentralGoogle Scholar
  75. Lee JC, Tsai CY, Kao JY, Kao MC, Tsai SC, Chang CS et al (2008) Geraniin-mediated apoptosis by cleavage of focal adhesion kinase through up-regulation of Fas ligand expression in human melanoma cells. Mol Nutr Food Res 52:655–663PubMedCrossRefPubMedCentralGoogle Scholar
  76. Lee KM, Lee KW, Jung SK, Lee EJ, Heo Y-S, Bode AM et al (2010a) Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity. Biochem Pharmacol 80:2042–2049PubMedPubMedCentralCrossRefGoogle Scholar
  77. Lee KM, Lee DE, Seo SK, Hwang MK, Heo Y-S, Lee KW et al (2010b) Phosphatidylinositol 3-kinase, a novel target molecule for the inhibitory effects of kaempferol on neoplastic cell transformation. Carcinogenesis 31:1338–1343PubMedCrossRefPubMedCentralGoogle Scholar
  78. Lee KM, Hwang MK, Lee DE, Lee KW, Lee HJ (2010c) Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells. J Agric Food Chem 58:5815–5820PubMedCrossRefPubMedCentralGoogle Scholar
  79. Lee SH, Jaganath IB, Wang SM, Sekaran SD (2011) Antimetastatic effects of Phyllanthus on human lung (A549) and breast (MCF-7) cancer cell lines. PLoS One 6:e20994PubMedPubMedCentralCrossRefGoogle Scholar
  80. Lee W, Yang EJ, Ku SK, Song KS, Bae JS (2013) Anti-inflammatory effects of oleanolic acid on LPS-induced inflammation in vitro and in vivo. Inflammation 36:94–102PubMedCrossRefPubMedCentralGoogle Scholar
  81. Lee C, Lee JW, Seo JY, Hwang SW, Im JP, Kim JS (2016) Lupeol inhibits LPS-induced NF-kappa B signaling in intestinal epithelial cells and macrophages, and attenuates acute and chronic murine colitis. Life Sci 146:100–108PubMedCrossRefPubMedCentralGoogle Scholar
  82. Li F, Liang D, Yang Z, Wang T, Wang W, Song X et al (2013a) Astragalin suppresses inflammatory responses via down-regulation of NF-κB signaling pathway in lipopolysaccharide-induced mastitis in a murine model. Int Immunopharmacol 17:478–482PubMedCrossRefPubMedCentralGoogle Scholar
  83. Li J, Wang S, Yin J, Pan L (2013b) Geraniin induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro and in vivo. Can J Physiol Pharmacol 91:1016–1024PubMedCrossRefPubMedCentralGoogle Scholar
  84. Li F, Wang W, Cao Y, Liang D, Zhang W, Zhang Z et al (2014) Inhibitory effects of astragalin on lipopolysaccharide-induced inflammatory response in mouse mammary epithelial cells. J Surg Res 192:573–581PubMedCrossRefPubMedCentralGoogle Scholar
  85. Li W, Li DY, Zhao SM, Zheng ZJ, Hu J, Li ZZ et al (2017a) Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats. Exp Ther Med 13:2056–2064PubMedPubMedCentralCrossRefGoogle Scholar
  86. Li X-H, Liu Z-Y, Gu Y, Lv Z, Chen Y, Gao H-C (2017b) Expression of NF-kappaB and p38 under intervention of rutin in lung cancer therapy. Biomed Res 28:2344–2347Google Scholar
  87. Li K, Zhang X, He B, Yang R, Zhang Y, Shen Z et al (2018) Geraniin promotes osteoblast proliferation and differentiation via the activation of Wnt/β-catenin pathway. Biomed Pharmacother 99:319–324PubMedCrossRefPubMedCentralGoogle Scholar
  88. Liao C-L, Lai K-C, Huang A-C, Yang J-S, Lin J-J, Wu S-H et al (2012) Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the matrix metalloproteinase-2/-9, protein kinase B (PKB) and PKC signaling pathways. Food Chem Toxicol 50:1734–1740PubMedCrossRefPubMedCentralGoogle Scholar
  89. Liu KC, Ho HC, Huang AC, Ji BC, Lin HY, Chueh FS et al (2013) Gallic acid provokes DNA damage and suppresses DNA repair gene expression in human prostate cancer PC-3 cells. Environ Toxicol 28:579–587PubMedCrossRefPubMedCentralGoogle Scholar
  90. Londhe JS, Devasagayam TP, Foo LY, Ghaskadbi SS (2009) Radioprotective properties of polyphenols from Phyllanthus amarus Linn. J Radiat Res 50:303–309PubMedCrossRefPubMedCentralGoogle Scholar
  91. Londhe JS, Devasagayam TP, Foo LY, Shastry P, Ghaskadbi SS (2012) Geraniin and amariin, ellagitannins from Phyllanthus amarus, protect liver cells against ethanol induced cytotoxicity. Fitoterapia 83:1562–1568PubMedCrossRefPubMedCentralGoogle Scholar
  92. Lu Y, Jiang F, Jiang H, Wu K, Zheng X, Cai Y et al (2010) Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells. Eur J Pharmacol 641:102–107PubMedPubMedCentralCrossRefGoogle Scholar
  93. Ma Z, Piao T, Wang Y, Liu J (2015) Astragalin inhibits IL-1β-induced inflammatory mediators production in human osteoarthritis chondrocyte by inhibiting NF-κB and MAPK activation. Int Immunopharmacol 25:83–87PubMedCrossRefPubMedCentralGoogle Scholar
  94. Maciel M, Cunha A, Dantas F, Kaiser C (2007) NMR characterization of bioactive lignans from Phyllanthus amarus Schum and Thonn. J Magn Reson Imaging 6:76–82Google Scholar
  95. Madlener S, Illmer C, Horvath Z, Saiko P, Losert A, Herbacek I et al (2007) Gallic acid inhibits ribonucleotide reductase and cyclooxygenases in human HL-60 promyelocytic leukemia cells. Cancer Lett 245:156–162PubMedCrossRefPubMedCentralGoogle Scholar
  96. Mahat M, Patil B (2007) Evaluation of antiinflammatory activity of methanol extract of Phyllanthus amarus in experimental animal models. Indian J Pharm Sci 69:33–36CrossRefGoogle Scholar
  97. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436PubMedCrossRefPubMedCentralGoogle Scholar
  98. Martin R, Cordova C, San Roman JA, Gutierrez B, Cachofeiro V, Nieto ML (2014) Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. J Mol Cell Cardiol 72:250–262PubMedCrossRefPubMedCentralGoogle Scholar
  99. Masamune A, Satoh M, Kikuta K, Suzuki N, Satoh K, Shimosegawa T (2005) Ellagic acid blocks activation of pancreatic stellate cells. Biochem Pharmacol 70:869–878PubMedCrossRefPubMedCentralGoogle Scholar
  100. Mattson M (2000) Emerging neuroprotective strategies for Alzheimer's disease: dietary restriction, telomerase activation, and stem cell therapy. Exp Gerontol 35:489–502PubMedCrossRefPubMedCentralGoogle Scholar
  101. Mo J, Yang R, Li F, He B, Zhang X, Zhao Y et al (2018) Geraniin promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) via activating β-catenin: a comparative study between BMSCs from normal and osteoporotic rats. J Nat Med 73:262–272PubMedCrossRefPubMedCentralGoogle Scholar
  102. Mojsin M, Topalović V, Marjanović J, Stevanović M (2013) Quercetin and lithium chloride modulate Wnt signaling in pluripotent embryonal carcinoma NT2/D1 cells. Arch Biol Sci 65:201–209CrossRefGoogle Scholar
  103. Mu DW, Guo HQ, Zhou GB, Li JY, Su B (2015) Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling. Int J Clin Exp Pathol 8:13864–13870PubMedPubMedCentralGoogle Scholar
  104. Na H-J, Lee G, Oh H-Y, Jeon K-S, Kwon H-J, Ha K-S et al (2006) 4-O-Methylgallic acid suppresses inflammation-associated gene expression by inhibition of redox-based NF-κB activation. Int Immunopharmacol 6:1597–1608PubMedCrossRefPubMedCentralGoogle Scholar
  105. Nafees S, Rashid S, Ali N, Hasan SK, Sultana S (2015) Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chem Biol Interact 231:98–107PubMedCrossRefPubMedCentralGoogle Scholar
  106. Nara TK, Glyeye J, Lavergne de Cerval E, Stanislan E (1977) Flavonoids of Phyllanthus niruri L., Phyllanthus urinaria L., Phyllanthus orbiculatus L. c. rich. Plants Med Phytother 11:82–86Google Scholar
  107. Okabe S, Suganuma M, Imayoshi Y, Taniguchi S, Yoshida T, Fujiki H (2001) New TNF-α releasing inhibitors, geraniin and corilagin, in leaves of Acer nikoense, Megusurino-ki. Biol Pharm Bull 24:1145–1148PubMedCrossRefPubMedCentralGoogle Scholar
  108. Pan M-H, Lin-Shiau S-Y, Ho C-T, Lin J-H, Lin J-K (2000) Suppression of lipopolysaccharide-induced nuclear factor-κB activity by theaflavin-3,3′-digallate from black tea and other polyphenols through down-regulation of IκB kinase activity in macrophages. Biochem Pharmacol 59:357–367PubMedCrossRefPubMedCentralGoogle Scholar
  109. Pang JL, Ricupero DA, Huang S, Fatma N, Singh DP, Romero JR et al (2006) Differential activity of kaempferol and quercetin in attenuating tumor necrosis factor receptor family signaling in bone cells. Biochem Pharmacol 71:818–826PubMedCrossRefPubMedCentralGoogle Scholar
  110. Park CH, Chang JY, Hahm ER, Park S, Kim H-K, Yang CH (2005) Quercetin, a potent inhibitor against β-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commun 328:227–234PubMedCrossRefPubMedCentralGoogle Scholar
  111. Park J-M, Kim A, Oh J-H, Chung A-S (2007a) Methylseleninic acid inhibits PMA-stimulated pro-MMP-2 activation mediated by MT1-MMP expression and further tumor invasion through suppression of NF-κB activation. Carcinogenesis 28:837–847PubMedCrossRefPubMedCentralGoogle Scholar
  112. Park S, Han SU, Lee KM, Park KH, Cho SW, Hahm KB (2007b) 5-LOX inhibitor modulates the inflammatory responses provoked by Helicobacter pylori infection. Helicobacter 12:49–58PubMedCrossRefPubMedCentralGoogle Scholar
  113. Park S, Sapkota K, Kim S, Kim H, Kim S (2011) Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br J Pharmacol 164:1008–1025PubMedPubMedCentralCrossRefGoogle Scholar
  114. Patel JR, Tripathi P, Sharma V, Chauhan NS, Dixit VK (2011) Phyllanthus amarus: ethnomedicinal uses, phytochemistry and pharmacology: a review. J Ethnopharmacol 138:286–313PubMedCrossRefPubMedCentralGoogle Scholar
  115. Prasad S, Madan E, Nigam N, Roy P, George J, Shukla Y (2009) Induction of apoptosis by lupeol in human epidermoid carcinoma A431 cells through regulation of mitochondrial, Akt/PKB and NF-kappaB signaling pathways. Cancer Bio Ther 8:1632–1639CrossRefGoogle Scholar
  116. Rajeshkumar NV, Kuttan R (2000) Phyllanthus amarus extract administration increases the life span of rats with hepatocellular carcinoma. J Ethnopharmacol 73:215–219PubMedCrossRefPubMedCentralGoogle Scholar
  117. Rajeshkumar N, Joy K, Kuttan G, Ramsewak R, Nair MG, Kuttan R (2002) Antitumour and anticarcinogenic activity of Phyllanthus amarus extract. J Ethnopharmacol 81:17–22PubMedCrossRefPubMedCentralGoogle Scholar
  118. Rakoff-Nahoum S (2006) Cancer issue: why cancer and inflammation? Yale J Biol Med 79:123–130PubMedPubMedCentralGoogle Scholar
  119. Raphael KR, Kuttan R (2003) Inhibition of experimental gastric lesion and inflammation by Phyllanthus amarus extract. J Ethnopharmacol 87:193–197PubMedCrossRefPubMedCentralGoogle Scholar
  120. Raphael KR, Sabu M, Kumar K, Kuttan R (2006) Inhibition of N-methyl N′-nitro-N-nitrosoguanidine (MNNG) induced gastric carcinogenesis by Phyllanthus amarus extract. Asian Pac J Cancer Prev 7:299–302PubMedPubMedCentralGoogle Scholar
  121. Riaz A, Rasul A, Hussain G, Zahoor MK, Jabeen F, Subhani Z et al (2018) Astragalin: a bioactive phytochemical with potential therapeutic activities. Adv Pharmacol Sci 2018:9794625. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V et al (2008) NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453:807–811PubMedPubMedCentralCrossRefGoogle Scholar
  123. Rizzo MT (2011) Cyclooxygenase-2 in oncogenesis. Clin Chim Acta 412:671–687PubMedCrossRefPubMedCentralGoogle Scholar
  124. Rogers J, Perkins I, Olphen AV, Burdash N, Klein TW, Friedman H (2005) Epigallocatechin gallate modulates cytokine production by bone marrow-derived dendritic cells stimulated with lipopolysaccharide or muramyldipeptide, or infected with Legionella pneumophila. Exp Biol Med 230:645–651CrossRefGoogle Scholar
  125. Rosillo M, Sanchez-Hidalgo M, Cárdeno A, de La Lastra CA (2011) Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn’s disease. Biochem Pharmacol 82:737–745PubMedCrossRefPubMedCentralGoogle Scholar
  126. Ryu SY, Oak MH, Yoon SK, Cho DI, Yoo GS, Kim TS et al (2000) Anti-allergic and anti-inflammatory triterpenes from the herb of Prunella vulgaris. Planta Med 66:358–360PubMedCrossRefPubMedCentralGoogle Scholar
  127. Saleem M, Afaq F, Adhami VM, Mukhtar H (2004) Lupeol modulates NF-κB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. Oncogene 23:5203–5214PubMedCrossRefPubMedCentralGoogle Scholar
  128. Saleem M, Kaur S, Kweon M-H, Adhami VM, Afaq F, Mukhtar H (2005) Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway. Carcinogenesis 26:1956–1964PubMedCrossRefPubMedCentralGoogle Scholar
  129. Shahrzad S, Aoyagi K, Winter A, Koyama A, Bitsch I (2001) Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J Nutr 131:1207–1210PubMedCrossRefPubMedCentralGoogle Scholar
  130. Shanker K, Singh M, Srivastava V, Verma R, Gupta A, Gupta M (2011) Simultaneous analysis of six bioactive lignans in Phyllanthus species by reversed phase hyphenated high performance liquid chromatographic technique. Acta Chromatogr 23:321–337CrossRefGoogle Scholar
  131. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB (2003) Ursolic acid inhibits nuclear factor-κB activation induced by carcinogenic agents through suppression of IκBα kinase and p65 phosphorylation. Cancer Res 63:4375–4383PubMedPubMedCentralGoogle Scholar
  132. Singh AK, Pandey M, Singh S, Singh AK, Singh U (2008) Antifungal activity of securinine against some plant pathogenic fungi. Mycobiology 36:99–101PubMedPubMedCentralCrossRefGoogle Scholar
  133. Song J, Wang Y, Song Y, Chan H, Bi C, Yang X et al (2014) Development and characterisation of ursolic acid nanocrystals without stabiliser having improved dissolution rate and in vitro anticancer activity. AAPS PharmSciTech 15:11–19PubMedCrossRefPubMedCentralGoogle Scholar
  134. Song H-L, Zhang X, Wang W-Z, Liu R-H, Zhao K, Liu M-Y et al (2018) Neuroprotective mechanisms of rutin for spinal cord injury through anti-oxidation and anti-inflammation and inhibition of p38 mitogen activated protein kinase pathway. Neural Regen Res 13:128–134PubMedPubMedCentralCrossRefGoogle Scholar
  135. Soromou LW, Chen N, Jiang L, Huo M, Wei M, Chu X et al (2012) Astragalin attenuates lipopolysaccharide-induced inflammatory responses by down-regulating NF-κB signaling pathway. Biochem Biophy Res Commun 419:256–261CrossRefGoogle Scholar
  136. Su S, Li X, Li S, Ming P, Huang Y, Dong Y et al (2019) Rutin protects against lipopolysaccharide-induced mastitis by inhibiting the activation of the NF-κB signaling pathway and attenuating endoplasmic reticulum stress. Inflammopharmacology 27:77–88PubMedCrossRefPubMedCentralGoogle Scholar
  137. Subbaramaiah K, Michaluart P, Sporn MB, Dannenberg AJ (2000) Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res 60:2399–2404PubMedPubMedCentralGoogle Scholar
  138. Suh N, Honda T, Finlay HJ, Barchowsky A, Williams C, Benoit NE et al (1998) Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res 58:717–723PubMedPubMedCentralGoogle Scholar
  139. Tang X, Sun YJ, Half E, Kuo MT, Sinicrope F (2002) Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells. Cancer Res 62:4903–4908PubMedPubMedCentralGoogle Scholar
  140. Tang X-L, Liu J-X, Dong W, Li P, Li L, Hou J-C et al (2015) Protective effect of kaempferol on LPS plus ATP-induced inflammatory response in cardiac fibroblasts. Inflammation 38:94–101PubMedCrossRefPubMedCentralGoogle Scholar
  141. Thyagarajan S, Jayaram S (1992) Natural history of Phyllanthus amarus in the treatment of hepatitis B. Indian J Med Microbiol 10:64–80Google Scholar
  142. Ulrich CM, Bigler J, Potter JD (2006) Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 6:130–140PubMedCrossRefPubMedCentralGoogle Scholar
  143. Umesh C, Jamsheer A, Prasad M (2018) The role of flavonoids in drug discovery—review on potential applications. Res J Life Sci Bioinform Pharm Chem Sci 4:70–77Google Scholar
  144. Ushio Y, Fang T, Okuda T, Abe H (1991) Modificational changes in function and morphology of cultured macrophages by geraniin. Jpn J Pharmacol 57:187–196PubMedCrossRefPubMedCentralGoogle Scholar
  145. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84PubMedCrossRefPubMedCentralGoogle Scholar
  146. Vasconcelos JF, Teixeira MM, Barbosa-Filho JM, Lúcio ASSC, Almeida JRGDS, De Queiroz L et al (2008) The triterpenoid lupeol attenuates allergic airway inflammation in a murine model. Int Immunopharmacol 8:1216–1221PubMedCrossRefPubMedCentralGoogle Scholar
  147. Wang X, Ye X-L, Liu R, Chen H-L, Bai H, Liang X et al (2010) Antioxidant activities of oleanolic acid in vitro: possible role of Nrf2 and MAP kinases. Chem Biol Interact 184:328–337PubMedCrossRefPubMedCentralGoogle Scholar
  148. Wang X, Bai H, Zhang X, Liu J, Cao P, Liao N et al (2013a) Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis 34:1323–1330PubMedCrossRefPubMedCentralGoogle Scholar
  149. Wang X, Liu R, Zhang W, Zhang X, Liao N, Wang Z et al (2013b) Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol Cell Endocrinol 376:70–80PubMedCrossRefPubMedCentralGoogle Scholar
  150. Wang P, Peng X, Wei Z-F, Wei F-Y, Wang W, Ma W-D et al (2015) Geraniin exerts cytoprotective effect against cellular oxidative stress by upregulation of Nrf2-mediated antioxidant enzyme expression via PI3K/AKT and ERK1/2 pathway. Biochim Biophys Acta 1850:1751–1761PubMedCrossRefPubMedCentralGoogle Scholar
  151. Ward AB, Mir H, Kapur N, Gales N, Carriere PP, Singh S (2018) Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways. World J Surg Oncol 16:108PubMedPubMedCentralCrossRefGoogle Scholar
  152. Wu CH, Wu CF, Huang HW, Jao YC, Yen GC (2009) Naturally occurring flavonoids attenuate high glucose-induced expression of proinflammatory cytokines in human monocytic THP-1 cells. Mol Nutr Food Res 53:984–995PubMedCrossRefPubMedCentralGoogle Scholar
  153. Xiao F, Zhai Z, Jiang C, Liu X, Li H, Qu X et al (2015) Geraniin suppresses RANKL-induced osteoclastogenesis in vitro and ameliorates wear particle-induced osteolysis in mouse model. Exp Cell Res 330:91–101PubMedCrossRefPubMedCentralGoogle Scholar
  154. Yang EJ, Lee W, Ku SK, Song KS, Bae JS (2012) Anti-inflammatory activities of oleanolic acid on HMGB1 activated HUVECs. Food Chem Toxicol 50:1288–1294PubMedCrossRefPubMedCentralGoogle Scholar
  155. Yeh C-H, Yang J-J, Yang M-L, Li Y-C, Kuan Y-H (2014) Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK-NF-κB pathway. Free Radic Biol Med 69:249–257PubMedCrossRefPubMedCentralGoogle Scholar
  156. Yoo H, Ku S-K, Baek Y, Bae J-S (2014) Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflamm Res 63:197–206PubMedCrossRefPubMedCentralGoogle Scholar
  157. Yoon C-H, Soo-Jin Chung S-J, Lee S-W, Park Y-B, Lee S-K, Park M-C (2013) Gallic acid, a natural polyphenolic acid, induces apoptosis and inhibits proinflammatory gene expressions in rheumatoid arthritis fibroblast-like synoviocytes. Jt Bone Spine 80:274–279CrossRefGoogle Scholar
  158. Youn K, Lee S, Jeong W-S, Ho C-T, Jun M (2016) Protective role of corilagin on Aβ25–35-induced neurotoxicity: suppression of NF-κB signaling pathway. J Med Food 19:901–911PubMedCrossRefPubMedCentralGoogle Scholar
  159. Yu JH, Lim JW, Kim H, Kim KH (2005) NADPH oxidase mediates interleukin-6 expression in cerulein-stimulated pancreatic acinar cells. Int J Biochem Cell Biol 37:1458–1469PubMedCrossRefPubMedCentralGoogle Scholar
  160. Yu Y, Wan Y, Huang C (2009) The biological functions of NF-κB1. Curr Cancer Drug Targets 9:566–571PubMedPubMedCentralCrossRefGoogle Scholar
  161. Zhang X-A, Zhang S, Yin Q, Zhang J (2015) Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor-kappa B Pathway. Pharmacogn Mag 11:404–409PubMedPubMedCentralCrossRefGoogle Scholar
  162. Zhang RX, Li Y, Tian DD, Liu Y, Nian W, Zou X et al (2016) Ursolic acid inhibits proliferation and induces apoptosis by inactivating Wnt/β-catenin signaling in human osteosarcoma cells. Int J Oncol 49:1973–1982PubMedCrossRefPubMedCentralGoogle Scholar
  163. Zhang W, Lu X, Wang W, Ding Z, Fu Y, Zhou X et al (2017) Inhibitory effects of emodin, thymol, and astragalin on leptospira interrogans-induced inflammatory response in the uterine and endometrium epithelial cells of mice. Inflammation 40:666–675PubMedCrossRefGoogle Scholar
  164. Zhao L, Zhang S-L, Tao J-Y, Pang R, Jin F, Guo YJ et al (2008) Preliminary exploration on anti-inflammatory mechanism of corilagin (beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-d-glucose) in vitro. Int Immunopharmacol 8:1059–1064PubMedCrossRefPubMedCentralGoogle Scholar
  165. Zhu YY, Huang HY, Wu YL (2015) Anticancer and apoptotic activities of oleanolic acid are mediated through cell cycle arrest and disruption of mitochondrial membrane potential in HepG2 human hepatocellular carcinoma cells. Mol Med Rep 12:5012–5018PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, School of MedicineCase Western Reserve UniversityClevelandUSA
  2. 2.School of Pharmacy, Faculty of Health and Medical SciencesTaylor’s UniversitySubang JayaMalaysia
  3. 3.Institute of Systems Biology (INBIOSIS)Universiti Kebangsaan MalaysiaBangiMalaysia
  4. 4.Crescent School of PharmacyB.S. Abdur Rahman Crescent Institute of Science and TechnologyChennaiIndia
  5. 5.Department of PharmacyInternational Islamic University ChittagongChittagongBangladesh

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