Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies

In this study, kaempferol (KFL) shows hepatoprotective activity against zearalenone (ZEA)-induced oxidative stress and its underlying mechanisms in in vitro and in vivo models were investigated. Oxidative stress plays a critical role in the pathophysiology of various hepatic ailments and is normally regulated by reactive oxygen species (ROS). ZEA is a mycotoxin known to exert toxicity via inflammation and ROS accumulation. This study aims to explore the protective role of KFL against ZEA-triggered hepatic injury via the PI3K/Akt-regulated Nrf2 pathway. KFL augmented the phosphorylation of PI3K and Akt, which may stimulate antioxidative and antiapoptotic signaling in hepatic cells. KFL upregulated Nrf2 phosphorylation and the expression of antioxidant genes HO-1 and NQO-1 in a dose-dependent manner under ZEA-induced oxidative stress. Nrf2 knockdown via small-interfering RNA (siRNA) inhibited the KFL-mediated defence against ZEA-induced hepatotoxicity. In vivo studies showed that KFL decreased inflammation and lipid peroxidation and increased H2O2 scavenging and biochemical marker enzyme expression. KFL was able to normalize the expression of liver antioxidant enzymes SOD, CAT and GSH and showed a protective effect against ZEA-induced pathophysiology in the livers of mice. These outcomes demonstrate that KFL possesses notable hepatoprotective roles against ZEA-induced damage in vivo and in vitro. These protective properties of KFL may occur through the stimulation of Nrf2/HO-1 cascades and PI3K/Akt signaling.

[1]  Jie Wei,et al.  Kaempferol Protects Blood Vessels From Damage Induced by Oxidative Stress and Inflammation in Association With the Nrf2/HO-1 Signaling Pathway , 2020, Frontiers in Pharmacology.

[2]  B. Lewczuk,et al.  Effects of Deoxynivalenol and Zearalenone on the Histology and Ultrastructure of Pig Liver , 2020, Toxins.

[3]  Y. Hseu,et al.  Suppression of LPS-Induced Inflammation by Chalcone Flavokawain A through Activation of Nrf2/ARE-Mediated Antioxidant Genes and Inhibition of ROS/NFκB Signaling Pathways in Primary Splenocytes , 2020, Oxidative medicine and cellular longevity.

[4]  Se-Young Oh,et al.  Zearalenone-Induced Interaction between PXR and Sp1 Increases Binding of Sp1 to a Promoter Site of the eNOS, Decreasing Its Transcription and NO Production in BAECs , 2020, Toxins.

[5]  Xianjun Meng,et al.  Lonicera caerulea L. Polyphenols Alleviate Oxidative Stress-induced Intestinal environment Imbalance and Lipopolysaccharide-induced Liver Injury in HFD-fed Rats by Regulating the Nrf2/HO-1/NQO1 and MAPK Pathways. , 2020, Molecular nutrition & food research.

[6]  Jia Hua Cheng,et al.  Chlorogenic acid rescues zearalenone induced injury to mouse ovarian granulosa cells. , 2020, Ecotoxicology and environmental safety.

[7]  Kai Sun,et al.  The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. , 2020, Osteoarthritis and cartilage.

[8]  S. Han,et al.  Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells , 2019, Toxins.

[9]  Yulong Yin,et al.  Resveratrol Attenuates Oxidative Stress-Induced Intestinal Barrier Injury through PI3K/Akt-Mediated Nrf2 Signaling Pathway , 2019, Oxidative medicine and cellular longevity.

[10]  Shuxiang Wu,et al.  PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury. , 2019, Toxicology and applied pharmacology.

[11]  B. Salehi,et al.  Kaempferol: A Key Emphasis to Its Anticancer Potential , 2019, Molecules.

[12]  Ray-Jade Chen,et al.  Protective effect of Fisetin against angiotensin II-induced apoptosis by activation of IGF-IR-PI3K-Akt signaling in H9c2 cells and spontaneous hypertension rats. , 2019, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[13]  M. Ramesh,et al.  RETRACTED ARTICLE: Sulforaphane potentially attenuates arsenic-induced nephrotoxicity via the PI3K/Akt/Nrf2 pathway in albino Wistar rats , 2019, Environmental Science and Pollution Research.

[14]  X. Jia,et al.  Zearalenone causes embryotoxicity and induces oxidative stress and apoptosis in differentiated human embryonic stem cells. , 2019, Toxicology in vitro : an international journal published in association with BIBRA.

[15]  F. Khan,et al.  Grape Seed Proanthocyanidin Extract Alleviates AflatoxinB1-Induced Immunotoxicity and Oxidative Stress via Modulation of NF-κB and Nrf2 Signaling Pathways in Broilers , 2019, Toxins.

[16]  Y. Hseu,et al.  Chalcone flavokawain A attenuates TGF‐β1‐induced fibrotic pathology via inhibition of ROS/Smad3 signaling pathways and induction of Nrf2/ARE‐mediated antioxidant genes in vascular smooth muscle cells , 2018, Journal of cellular and molecular medicine.

[17]  M. Ramesh,et al.  Sulforaphane Potentially Ameliorates Arsenic Induced Hepatotoxicity in Albino Wistar Rats: Implication of PI3K/Akt/Nrf2 Signaling Pathway. , 2019, Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology.

[18]  Wei He,et al.  Protection of Kaempferol on Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage , 2018, Oxidative medicine and cellular longevity.

[19]  Shiwen Xu,et al.  Protective effects of selenium against zearalenone-induced apoptosis in chicken spleen lymphocyte via an endoplasmic reticulum stress signaling pathway , 2018, Cell Stress and Chaperones.

[20]  Lvhui Sun,et al.  Dietary Silymarin Supplementation Alleviates Zearalenone-Induced Hepatotoxicity and Reproductive Toxicity in Rats. , 2018, The Journal of nutrition.

[21]  P. Li,et al.  Proanthocyanidins Protect Epithelial Cells from Zearalenone-Induced Apoptosis via Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis Pathways in Mouse Small Intestines , 2018, Molecules.

[22]  J. Ko,et al.  Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice. , 2018, Toxicology letters.

[23]  L. Yin,et al.  Ganglioside GM1 protects against high altitude cerebral edema in rats by suppressing the oxidative stress and inflammatory response via the PI3K/AKT‐Nrf2 pathway , 2018, Molecular immunology.

[24]  I. Oswald,et al.  Mycotoxins and oxidative stress: where are we? , 2018 .

[25]  Mallikarjuna Korivi,et al.  Zerumbone protects human skin keratinocytes against UVA‐irradiated damages through Nrf2 induction , 2018, Biochemical pharmacology.

[26]  A. Shan,et al.  Toxicity of zearalenone on the intestines of pregnant sows and their offspring and alleviation with modified halloysite nanotubes. , 2018, Journal of the science of food and agriculture.

[27]  M. Kim,et al.  Natural Dietary Supplementation of Anthocyanins via PI3K/Akt/Nrf2/HO-1 Pathways Mitigate Oxidative Stress, Neurodegeneration, and Memory Impairment in a Mouse Model of Alzheimer’s Disease , 2017, Molecular Neurobiology.

[28]  Yuan Ding,et al.  Protective effects of ellagic acid against tetrachloride-induced cirrhosis in mice through the inhibition of reactive oxygen species formation and angiogenesis , 2017, Experimental and therapeutic medicine.

[29]  J. Spangle,et al.  The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. , 2017, Biochimica et biophysica acta. Reviews on cancer.

[30]  S. Nammi,et al.  Oxidative Stress in Liver Diseases: Pathogenesis, Prevention, and Therapeutics , 2017, Oxidative medicine and cellular longevity.

[31]  G. Font,et al.  Cytotoxic effects of zearalenone and its metabolites and antioxidant cell defense in CHO-K1 cells. , 2016, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[32]  Feng Zhang,et al.  Nrf2 knockdown attenuates the ameliorative effects of ligustrazine on hepatic fibrosis by targeting hepatic stellate cell transdifferentiation. , 2016, Toxicology.

[33]  K. Rayaguru,et al.  Physio-Chemical Changes During Repeated Frying of Cooked Oil: A Review , 2016 .

[34]  G. Sethi,et al.  Abrogation of STAT3 signaling cascade by zerumbone inhibits proliferation and induces apoptosis in renal cell carcinoma xenograft mouse model , 2015, Molecular carcinogenesis.

[35]  A. C. Ziegler,et al.  Biological and physiological role of reactive oxygen species – the good, the bad and the ugly , 2015, Acta physiologica.

[36]  I. Nishigaki,et al.  Kaempferol, a Potential Cytostatic and Cure for Inflammatory Disorders , 2014 .

[37]  Min Fang,et al.  Zearalenone induces oxidative damage involving Keap1/Nrf2/HO-1 pathway in hepatic L02 cells , 2014, Molecular & Cellular Toxicology.

[38]  Hsin-Yueh Liang,et al.  Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. , 2013, International journal of cardiology.

[39]  D. Marin,et al.  Effects of zearalenone on oxidative stress and inflammation in weanling piglets. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[40]  L. Singh,et al.  Hepatic hyperplasia and damages induces by zearalenone Fusarium mycotoxins in BALB/c mice. , 2012, Arquivos de gastroenterologia.

[41]  A. Pyle,et al.  Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. , 2011, Cell stem cell.

[42]  B. Aggarwal,et al.  Oxidative stress, inflammation, and cancer: how are they linked? , 2010, Free radical biology & medicine.

[43]  R. Burlacu,et al.  Effects of zearalenone and its derivatives on the innate immune response of swine. , 2010, Toxicon : official journal of the International Society on Toxinology.

[44]  Y. Shukla,et al.  Genotoxic and carcinogenic risks associated with the consumption of repeatedly boiled sunflower oil. , 2010, Journal of agricultural and food chemistry.

[45]  María Luisa Fernández-Cruz,et al.  Mycotoxins in fruits and their processed products: Analysis, occurrence and health implications , 2010 .

[46]  Kyeong-Man Kim,et al.  Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: novel cytoprotective mechanism against oxidative damage. , 2008, Pharmacological research.

[47]  P. Muriel,et al.  Curcumin protects against acute liver damage in the rat by inhibiting NF-kappaB, proinflammatory cytokines production and oxidative stress. , 2007, Biochimica et biophysica acta.