Kaempferol protects rats with severe acute pancreatitis through regulating NF-κB and Keap1–Nrf2 signaling pathway

Main Article Content

Jun Cai
Suyan Yao
Hao Wang
Wei Rong


kaempferol, pancreatitis, nuclear factor kappa, inflammatory disorder


Kaempferol (KF) is an important natural anti-inflammatory flavonol. Acute pancreatitis (AP) is an inflammatory disorder, which in about 20% cases may develop into severe acute pancreatitis (SAP) with a high mortality rate. This research was to study the effects and mechanism of kaempferol on SAP. SAP was induced by sodium taurocholate. The level of cytokines was analyzed by enzyme-linked-immunosorbent serologic assay. The expression of nuclear factor kappa B (NF-κB) and Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 (Keap1–Nrf2) proteins was analyzed by Western blot assay. Pathological changes in the pancreas were evaluated by hematoxylin and eosin staining. Kaempferol attenuated pancreatic injury in SAP rats, including reduction in inflammatory infiltration and necrosis. The level of serum amylase and lipase was also decreased in kaempferol-treated SAP rats. Kaempferol inhibited the expression of inflammatory mediators (nuclear factor-α, Interlukin-1β, and Interlukin-6), and alleviated the oxidative stress characterized by the decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) levels. Kaempferol decreased the expression of cleaved caspase 3 and anti-apoptotic protein Bcl-2, which indicated that kaempferol could inhibit apoptosis of pancreatic cells in SAP rats. Kaempferol treatment could decrease the expression of p-p65 and the amount of nuclear Nrf2 (Nu-Nrf2), which demonstrated that kaempferol inhibited the NF-κB activation and enhanced the Keap1–Nrf2 pathway. Our research indicated that kaempferol could attenuate the pancreatic injury of SAP by regulating NF-κB and Keap1–Nrf2 signaling pathway. Kaempferol could serve as a natural candidate for treating SAP.

Abstract 84 | PDF Downloads 52 HTML Downloads 16 XML Downloads 105


Armstrong J.A., Cash N., Soares P.M., Souza M.H., Sutton R., and Criddle D.N., 2013. Oxidative stress in acute pancreatitis: lost in translation? Free Radic Res. 47(11):917–933. https://doi.org/10.3109/10715762.2013.835046

Baird L. and Dinkova-Kostova A.T., 2011 The cytoprotective role of the Keap1–Nrf2 pathway. Arch Toxicol. 85(4):241–272. https://doi.org/10.1007/s00204-011-0674-5

Calderón-Montaño J.M., Burgos-Morón E., Pérez-Guerrero C., and López-Lázaro M., 2011. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem. 11(4):298–344. https://doi.org/10.2174/138955711795305335

Fang D., Lin Q., Wang C., Zheng C, Li Y, Huang T, et al., 2020. Effects of sildenafil on inflammatory injury of the lung in sodium taurocholate-induced severe acute pancreatitis rats. Int Immunopharmacol. 80:106151. https://doi.org/10.1016/j. intimp.2019.106151

Fouzder C., Mukhuty A., and Kundu R., 2021. Kaempferol inhibits Nrf2 signalling pathway via downregulation of Nrf2 mRNA and induces apoptosis in NSCLC cells. Arch Biochem Biophy. 697:108700. https://doi.org/10.1016/j.abb.2020.108700

Gu H., Werner J., Bergmann F., Whitcomb D.C., Büchler M.W., and Fortunato F., 2013. Necro-inflammatory response of pancreatic acinar cells in the pathogenesis of acute alcoholic pancreatitis. Cell Death Dis. 4(10):e816. https://doi.org/10.1038/ cddis.2013.354

Habtezion A, Gukovskaya A.S., and Pandol S.J., 2019. Acute pan-creatitis: a multifaceted set of organelle and cellular interactions. Gastroenterology. 156(7):1941–1950. https://doi.org/10.1053/j. gastro.2018.11.082

Habtezion A., 2015. Inflammation in acute and chronic pancreatitis. Curr Opin Gastroenterol. 31(5):395–399. https://doi.org/10.1097/mog.0000000000000195

Hackert T. and Werner J., 2011. Antioxidant therapy in acute pancreatitis: experimental and clinical evidence. Antioxid Redox Signal. 15(10):2767–2777. https://doi.org/10.1089/ars.2011.4076

Hussain T., Tan B., Yin Y., Blachier F., Tossou M.C., and Rahu N., 2016. Oxidative stress and inflammation: what polyphenols can do for us? Oxidat Med Cell Long. 2016:7432797. https://doi.org/10.1155/2016/7432797

Jakkampudi A., Jangala R., Reddy B.R., Mitnala S., Nageshwar Reddy  D., and Talukdar R., 2016. NF-κB in acute pancreatitis: mechanisms and therapeutic potential. Pancreatology. 16(4):477–488. https://doi.org/10.1016/j.pan.2016.05.001

Kim S.H., Park J.G., Sung G.H., Yang S, Yang WS, Kim E, et al., 2015. Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain. Mol Nutr Food Res. 59(7):1400–1405. https://doi.org/10.1002/mnfr.201400820

Lankisch P.G., Apte M., and Banks P.A., 2015. Acute pancreatitis. Lancet (London). 2015;386(9988):85–96. https://doi.org/10.1016/s0140-6736(14)60649-8

Lawrence T., 2009. The nuclear factor NF-kappaB pathway in inflam-mation. Cold Spring Harbor Perspect in Biol. 1(6):a001651. https://doi.org/10.1101/cshperspect.a001651

Lee P.J. and Papachristou G.I., 2019. New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol. 16(8):479–496. https://doi.org/10.1038/s41575-019-0158-2

Liang X., Hu C., Liu C., Yu K., Zhang J. and Jia Y., 2020. Dihydrokaempferol (DHK) ameliorates severe acute pancreatitis (SAP) via Keap1/Nrf2 pathway. Life Sci. 261:118340. https://doi.org/10.1016/j.lfs.2020.118340

Liu X., Zhu Q., Zhang M., Yin T, Xu R, Xiao W, et al., 2018. Isoliquiritigenin ameliorates acute pancreatitis in mice via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway. Oxid Med Cell Longev. 2018:7161592. https://doi.org/10.1155/2018/7161592

Marek G., Ściskalska M., Grzebieniak Z., and Milnerowicz H., 2018. Decreases in Paraoxonase-1 activities promote a pro-inflammatory effect of lipids peroxidation products in non-smoking and smoking patients with acute pancreatitis. Int J Med Sci.15(14):1619–1630. https://doi.org/10.7150/ijms.27647

Montero Vega M.T. and de Andrés Martín A., 2008. Toll-like recep-tors: a family of innate sensors of danger that alert and drive immunity. Allergol Immunopathol. 36(6):347–357. https://doi.org/10.1016/s0301-0546(08)75868-3

Morgan M.J. and Liu Z.G., 2011. Crosstalk of reactive oxygen spe-cies and NF-κB signaling. Cell Res. 21(1):103–115. https://doi.org/10.1038/cr.2010.178

Oeckinghaus A., Hayden M.S., and Ghosh S., 2011. Crosstalk in NF-κB signaling pathways. Nature Immunol. 12(8):695–708. https://doi.org/10.1038/ni.2065

Ren J., Luo Z., Tian F., Wang Q., Li K., and Wang C., 2012. Hydrogen-rich saline reduces the oxidative stress and relieves the severity of trauma-induced acute pancreatitis in rats. J Trauma Acute Care Surg. 72(6):1555–1561. https://doi.org/10.1097/ TA.0b013e31824a7913

Reuter S., Gupta S.C., Chaturvedi M.M., and Aggarwal B.B., 2010. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 49(11):1603–1616. https://doi.org/10.1016/j.freeradbiomed.2010.09.006

Shi C., Hou C., Zhu X., Huang D, Peng Y, Tu M, et al., 2018. SRT1720 ameliorates sodium taurocholate-induced severe acute pancreatitis in rats by suppressing NF-κB signalling. Biomed Pharmacother. 108:50–57. https://doi.org/10.1016/j.biopha.2018.09.035

Wang H., Chen L., Zhang X., Xu L, Xie B, Shi H, 2019. Kaempferol protects mice from d-GalN/LPS-induced acute liver failure by regulating the ER stress-Grp78-CHOP signaling pathway. Biomed Pharmacotherap. 111:468–475. https://doi.org/10.1016/j.biopha.2018.12.105

Wardyn J.D., Ponsford A.H., and Sanderson C.M., 2015. Dissecting molecular crosstalk between Nrf2 and NF-κB response pathways. Biochem Soc Trans. 43(4):621–626. https://doi.org/10.1042/bst20150014

Yao H., Sun J., Wei J., Zhang X., Chen B., and Lin Y., 2020. Kaempferol protects blood vessels from damage induced by oxidative stress and inflammation in association with the Nrf2/ HO-1 signaling pathway. Front Pharmacol. 11:1118. https://doi.org/10.3389/fphar.2020.01118

Zhang L., Guo Z., Wang Y., Geng J., and Han S., 2019. The protective effect of kaempferol on heart via the regulation of Nrf2, NF-κβ, and PI3K/Akt/GSK-3β signaling pathways in isoproterenol-induced heart failure in diabetic rats. Drug Develop Res. 80(3):294–309. https://doi.org/10.1002/ddr.21495