Scutellarein regulates the PTEN/AKT/NFκB signaling pathway to reduce pirarubicin related liver inflammation

Lan,Ying; Chen,Lvlin; Zhu,Juncheng; Li,Hui; Lin,Zhimei

doi:10.3892/ijmm.2023.5258

Scutellarein regulates the PTEN/AKT/NFκB signaling pathway to reduce pirarubicin related liver inflammation

Authors:
- Ying Lan
- Lvlin Chen
- Juncheng Zhu
- Hui Li
- Zhimei Lin
View Affiliations

Affiliations: Department of Critical Care Medicine, The Affiliated Hospital of Chengdu University, Chengdu, Sichuan 610081, P.R. China, Department of Hematology, The Affiliated Hospital of Chengdu University, Chengdu, Sichuan 610081, P.R. China
Published online on: May 17, 2023 https://doi.org/10.3892/ijmm.2023.5258
Article Number: 55
Copyright: © Lan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The side effects of chemotherapy drugs have been hindering the progress of tumor treatment. The liver is the metabolic site of most drugs, which leads to the frequent occurrence of liver injury. Classical chemotherapy drugs such as pirarubicin (THP) can also cause dose‑dependent hepatotoxicity, and the related mechanism is closely related to liver inflammation. Scutellarein (Sc) is a potential Chinese herbal monomer exhibiting liver protection activity, which can effectively alleviate the liver inflammation caused by obesity. In the present study, THP was used to establish a rat model of hepatotoxicity, and Sc was used for treatment. The experimental methods used included measuring body weight, detecting serum biomarkers, observing liver morphology with H&E staining, observing cell apoptosis with TUNEL staining, and detecting the expression of PTEN/AKT/NFκB signaling pathways and inflammatory genes with PCR and western blotting. However, whether Sc can inhibit the liver inflammation induced by THP has not been reported. The experimental results showed that THP led to the upregulation of PTEN and the increase of inflammatory factors in rat liver, while Sc effectively alleviated the aforementioned changes. It was further identified in primary hepatocytes that Sc can effectively inhabited PTEN, regulate AKT/NFκB signaling pathway, inhibit liver inflammation and ultimately protect the liver.

View Figures

View References

1	Trefts E, Gannon M and Wasserman DH: The liver. Curr Biol. 27:R1147–R1151. 2017. View Article : Google Scholar : PubMed/NCBI
2	Jetter A and Kullak-Ublick GA: Drugs and hepatic transporters: A review. Pharmacol Res. 154:1042342020. View Article : Google Scholar
3	Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, Devarbhavi H, Merz M, Lucena MI, Kaplowitz N and Aithal GP: Drug-induced liver injury. Nat Rev Dis Primers. 5:582019. View Article : Google Scholar : PubMed/NCBI
4	European Association for the Study of the Liver. Electronic address easloffice@easloffice.eu; Clinical Practice Guideline Panel: Chair:; Panel members; EASL Governing Board representative: EASL Clinical practice guidelines: Drug-induced liver injury. J Hepatol. 70:1222–1261. 2019. View Article : Google Scholar : PubMed/NCBI
5	Saithanyamurthi H and Faust AJ: Drug-Induced liver disease: Clinical course. Clin Liver Dis. 21:21–34. 2017. View Article : Google Scholar
6	Luedde T, Kaplowitz N and Schwabe RF: Cell death and cell death responses in liver disease: Mechanisms and clinical relevance. Gastroenterology. 147:765–783.e4. 2014. View Article : Google Scholar : PubMed/NCBI
7	Giordano CM and Zervos XB: Clinical manifestations and treatment of drug-induced hepatotoxicity. Clin Liver Dis. 17:565–573, viii. 2013. View Article : Google Scholar : PubMed/NCBI
8	Liu Y, Zhao P, Cheng M, Yu L, Cheng Z, Fan L and Chen C: AST to ALT ratio and arterial stiffness in non-fatty liver Japanese population:a secondary analysis based on a cross-sectional study. Lipids Health Dis. 17:2752018. View Article : Google Scholar : PubMed/NCBI
9	Shi H, Yan Y, Yang H, Pu P and Tang H: Schisandrin B diet inhibits oxidative stress to reduce ferroptosis and lipid peroxidation to prevent pirarubicin-induced hepatotoxicity. Biomed Res Int. 2022:56235552022. View Article : Google Scholar : PubMed/NCBI
10	Zhang Y, Ma XY, Zhang T, Qin M, Sun B, Li Q, Hu DW and Ren LQ: Protective effects of apocynum venetum against pirarubicin-induced cardiotoxicity. Am J Chin Med. 47:1075–1097. 2019. View Article : Google Scholar : PubMed/NCBI
11	Hori H, Kudoh T, Nishimura S, Oda M, Yoshida M, Hara J, Tawa A, Usami I, Tanizawa A, Yumura-Yagi K, et al: Acute and late toxicities of pirarubicin in the treatment of childhood acute lymphoblastic leukemia: Results from a clinical trial by the Japan Association of Childhood Leukemia Study. Int J Clin Oncol. 22:387–396. 2017. View Article : Google Scholar
12	Jiménez-Castro MB, Cornide-Petronio ME, Gracia-Sancho J and Peralta C: Inflammasome-mediated inflammation in liver ischemia-reperfusion injury. Cells. 8:11312019. View Article : Google Scholar : PubMed/NCBI
13	Dai C, Xiao X, Li D, Tun S, Wang Y, Velkov T and Tang S: Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflammation and induction of apoptosis. Cell Death Dis. 9:11642018. View Article : Google Scholar : PubMed/NCBI
14	Liu YT, Qi SL and Sun KW: Traditional Chinese medicine, liver fibrosis, intestinal flora: Is there any connection?-a narrative review. Ann Palliat Med. 10:4846–4857. 2021. View Article : Google Scholar : PubMed/NCBI
15	Chen M, Xie Y, Gong S, Wang Y, Yu H, Zhou T, Huang F, Guo X, Zhang H, Huang R, et al: Traditional Chinese medicine in the treatment of nonalcoholic steatohepatitis. Pharmacol Res. 172:1058492021. View Article : Google Scholar : PubMed/NCBI
16	Serafini M, Peluso I and Raguzzini A: Flavonoids as anti-inflammatory agents. Proc Nutr Soc. 69:273–278. 2010. View Article : Google Scholar : PubMed/NCBI
17	Koirala N, Thuan NH, Ghimire GP, Thang DV and Sohng JK: Methylation of flavonoids: Chemical structures, bioactivities, progress and perspectives for biotechnological production. Enzyme Microb Technol. 86:103–116. 2016. View Article : Google Scholar : PubMed/NCBI
18	Yi YS: Regulatory roles of flavonoids on inflammasome activation during inflammatory responses. Mol Nutr Food Res. 62:e18001472018. View Article : Google Scholar : PubMed/NCBI
19	Krych-Madej J, Stawowska K and Gebicka L: Oxidation of flavonoids by hypochlorous acid: Reaction kinetics and antioxidant activity studies. Free Radic Res. 50:898–908. 2016. View Article : Google Scholar : PubMed/NCBI
20	Ha SE, Kim SM, Vetrivel P, Kim HH, Bhosale PB, Heo JD, Lee HJ and Kim GS: Inhibition of cell proliferation and metastasis by scutellarein regulating PI3K/Akt/NF-κB signaling through PTEN activation in hepatocellular carcinoma. Int J Mol Sci. 22:88412021. View Article : Google Scholar
21	Russo M, Moccia S, Spagnuolo C, Tedesco I and Russo GL: Roles of flavonoids against coronavirus infection. Chem Biol Interact. 328:1092112020. View Article : Google Scholar : PubMed/NCBI
22	Chagas MDSS, Behrens MD, Moragas-Tellis CJ, Penedo GXM, Silva AR and Gonçalves-de-Albuquerque CF: Flavonols and flavones as potential anti-inflammatory, antioxidant, and antibacterial compounds. Oxid Med Cell Longev. 2022:99667502022. View Article : Google Scholar : PubMed/NCBI
23	Lin Y, Ren N, Li S, Chen M and Pu P: Novel anti-obesity effect of scutellarein and potential underlying mechanism of actions. Biomed Pharmacother. 117:1090422019. View Article : Google Scholar : PubMed/NCBI
24	Gao L, Tang H, Zeng Q, Tang T, Chen M and Pu P: The anti-insulin resistance effect of scutellarin may be related to antioxidant stress and AMPKα activation in diabetic mice. Obes Res Clin Pract. 14:368–374. 2020. View Article : Google Scholar : PubMed/NCBI
25	Brenner C, Galluzzi L, Kepp O and Kroemer G: Decoding cell death signals in liver inflammation. J Hepatol. 59:583–594. 2013. View Article : Google Scholar : PubMed/NCBI
26	Cavalli G and Dinarello CA: Suppression of inflammation and acquired immunity by IL-37. Immunol Rev. 281:179–190. 2018. View Article : Google Scholar
27	Peyrou M, Bourgoin L and Foti M: PTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancer. Dig Dis. 28:236–246. 2010. View Article : Google Scholar : PubMed/NCBI
28	Álvarez-Garcia V, Tawil Y, Wise HM and Leslie NR: Mechanisms of PTEN loss in cancer: It's all about diversity. Semin Cancer Biol. 59:66–79. 2019. View Article : Google Scholar : PubMed/NCBI
29	Piao Y and Yin D: Mechanism underlying treatment of diabetic kidney disease using Traditional Chinese Medicine based on theory of Yin and Yang balance. J Tradit Chin Med. 38:797–802. 2018. View Article : Google Scholar : PubMed/NCBI
30	Yu G, Yu H, Yang Q, Wang J, Fan H, Liu G, Wang L, Bello BK, Zhao P, Zhang H and Dong J: Vibrio harveyi infections induce production of proinflammatory cytokines in murine peritoneal macrophages via activation of p38 MAPK and NF-κB pathways, but reversed by PI3K/AKT pathways. Dev Comp Immunol. 127:1042922022. View Article : Google Scholar
31	Pu P, Wang XA, Salim M, Zhu LH, Wang L, Chen KJ, Xiao JF, Deng W, Shi HW, Jiang H and Li HL: Baicalein, a natural product, selectively activating AMPKα(2) and ameliorates metabolic disorder in diet-induced mice. Mol Cell Endocrinol. 362:128–138. 2012. View Article : Google Scholar : PubMed/NCBI
32	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
33	Sookoian S and Pirola CJ: Liver enzymes, metabolomics and genome-wide association studies: From systems biology to the personalized medicine. World J Gastroenterol. 21:711–725. 2015. View Article : Google Scholar : PubMed/NCBI
34	Korver S, Bowen J, Pearson K, Gonzalez RJ, French N, Park K, Jenkins R and Goldring C: The application of cytokeratin-18 as a biomarker for drug-induced liver injury. Arch Toxicol. 95:3435–3448. 2021. View Article : Google Scholar : PubMed/NCBI
35	Stravitz RT and Lee WM: Acute liver failure. Lancet. 394:869–881. 2019. View Article : Google Scholar : PubMed/NCBI
36	Worby CA and Dixon JE: PTEN. Annu Rev Biochem. 83:641–669. 2014. View Article : Google Scholar : PubMed/NCBI
37	Ho J, Cruise ES, Dowling RJO and Stambolic V: PTEN nuclear functions. Cold Spring Harb Perspect Med. 10:a0360792020. View Article : Google Scholar
38	Chen J, Zhang XD and Proud C: Dissecting the signaling pathways that mediate cancer in PTEN and LKB1 double-knockout mice. Sci Signal. 8:pe12015. View Article : Google Scholar : PubMed/NCBI
39	Tang F, Wang Y, Hemmings BA, Rüegg C and Xue G: PKB/Akt-dependent regulation of inflammation in cancer. Semin Cancer Biol. 48:62–69. 2018. View Article : Google Scholar
40	Sun X, Chen L and He Z: PI3K/Akt-Nrf2 and anti-inflammation effect of macrolides in chronic obstructive pulmonary disease. Curr Drug Metab. 20:301–304. 2019. View Article : Google Scholar : PubMed/NCBI
41	Mishra V, Banga J and Silveyra P: Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets. Pharmacol Ther. 181:169–182. 2018. View Article : Google Scholar
42	Mulero MC, Huxford T and Ghosh G: NF-κB, IκB, and IKK: Integral components of immune system signaling. Adv Exp Med Biol. 1172:207–226. 2019. View Article : Google Scholar
43	Lin JK: Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. Arch Pharm Res. 25:561–571. 2002. View Article : Google Scholar : PubMed/NCBI
44	Kondylis V, Kumari S, Vlantis K and Pasparakis M: The interplay of IKK, NF-κB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation. Immunol Rev. 277:113–127. 2017. View Article : Google Scholar : PubMed/NCBI
45	Gasparini C and Feldmann M: NF-κB as a target for modulating inflammatory responses. Curr Pharm Des. 18:5735–5745. 2012. View Article : Google Scholar
46	Dumortier C, Danopoulos S, Velard F and Al Alam D: Bone cells differentiation: How CFTR mutations may rule the game of stem cells commitment? Front Cell Dev Biol. 9:6119212021. View Article : Google Scholar : PubMed/NCBI
47	Sang Eun H, Seong Min K, Ho Jeong L, Vetrivel P, Venkatarame Gowda Saralamma V, Jeong Doo H, Eun Hee K, Sang Joon L and Gon Sup K: Scutellarein induces Fas-mediated extrinsic apoptosis and G2/M cell cycle arrest in Hep3B hepatocellular carcinoma cells. Nutrients. 11:2632019. View Article : Google Scholar : PubMed/NCBI
48	Fu Y, Sun S, Sun H, Peng J, Ma X, Bao L, Ji R, Luo C, Gao C, Zhang X and Jin Y: Scutellarin exerts protective effects against atherosclerosis in rats by regulating the Hippo-FOXO3A and PI3K/AKT signaling pathways. J Cell Physiol. 234:18131–18145. 2019. View Article : Google Scholar : PubMed/NCBI
49	Nie J, Yang HM, Sun CY, Liu YL, Zhuo JY, Zhang ZB, Lai XP, Su ZR and Li YC: Scutellarin enhances antitumor effects and attenuates the toxicity of bleomycin in H22 ascites tumor-bearing mice. Front Pharmacol. 9:6152018. View Article : Google Scholar : PubMed/NCBI