Abstract
Hepatitis has become a major social, health, and economic problem worldwide. Herein, we tested the beneficial influence of baicalin, a flavonoid extracted from the roots of Scutellaria baicalensis, on human normal liver L-02 and THLE2 cell apoptosis and inflammatory reaction stimulated by lipopolysaccharide (LPS) and possible molecular mechanisms. L-02 and THLE2 cell viability and apoptosis after LPS and/or baicalin treatment were tested using CCK-8 assay and Annexin V-FITC/PI apoptosis kit, respectively. qRT-PCR was used to measure the MCP-1, IL-6, TNF-α, and lncRNA taurine upregulated gene 1 (TUG1) expressions in L-02 and THLE2 cells. sh-TUG1 was transfected to knockdown TUG1. SB203580 was used as inhibitor of p38MAPK pathway, while SP600125 was used as inhibitor of JNK pathway. We discovered that LPS stimulation caused L-02 and THLE2 cell apoptosis and inflammatory reaction. Baicalin relieved the L-02 and THLE2 cell apoptosis and inflammatory reaction stimulated by LPS. Moreover, LPS lowered the TUG1 expression in L-02 cells, while baicalin promoted the TUG1 expression in L-02 and L-02 and THLE2 cells, as well as inactivated p38MAPK and JNK pathways in LPS-stimulated L-02 cells. Besides, knockdown of TUG1 activated p38MAPK and JNK pathways and promoted inflammatory cytokine expression in L-02 cells. In conclusion, this study further affirmed the beneficial influences of baicalin on LPS-stimulated human normal liver cell apoptosis and inflammatory reaction. Baicalin relived liver cell inflammation stimulated by LPS might be via upregulating TUG1 and then inactivating p38MAPK and JNK pathways.
Similar content being viewed by others
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Change history
30 September 2020
An Editorial Expression of Concern on this article has now been published: https://doi.org/10.1007/s13105-021-00803-2
23 February 2023
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s13105-023-00951-7
17 March 2021
An Editorial Expression of Concern to this paper has been published: https://doi.org/10.1007/s13105-021-00803-2
References
Aday AW, Mitchell MC, Casey LC (2017) Alcoholic hepatitis: current trends in management. Curr Opin Gastroenterol 33:142–148. https://doi.org/10.1097/mog.0000000000000359
Amako Y, Igloi Z, Mankouri J, Kazlauskas A, Saksela K, Dallas M, Peers C, Harris M (2013) Hepatitis C virus NS5A inhibits mixed lineage kinase 3 to block apoptosis. J Biol Chem 288:24753–24763. https://doi.org/10.1074/jbc.M113.491985
Bascil MS, Oztekin H (2012) A study on hepatitis disease diagnosis using probabilistic neural network. J Med Syst 36:1603–1606. https://doi.org/10.1007/s10916-010-9621-x
Ceccarelli S, Panera N, Mina M, Gnani D, De Stefanis C, Crudele A, Rychlicki C, Petrini S, Bruscalupi G, Agostinelli L, Stronati L, Cucchiara S, Musso G, Furlanello C, Svegliati-Baroni G, Nobili V, Alisi A (2015) LPS-induced TNF-alpha factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease. Oncotarget 6:41434–41452. https://doi.org/10.18632/oncotarget.5163
Chen Y, Zeng L, Yang J, Wang Y, Yao F, Wu Y, Wang D, Hu Y, Liu J (2017) Anti-DHAV-1 reproduction and immuno-regulatory effects of a flavonoid prescription on duck virus hepatitis. Pharm Biol 55:1545–1552. https://doi.org/10.1080/13880209.2017.1309554
Cheng P, Wang T, Li W, Muhammad I, Wang H, Sun X, Yang Y, Li J, Xiao T, Zhang X (2017) Baicalin alleviates lipopolysaccharide-induced liver inflammation in chicken by suppressing TLR4-mediated NF-kappaB pathway. Front Pharmacol 8:547. https://doi.org/10.3389/fphar.2017.00547
Czaja AJ (2015) Diagnosis and management of autoimmune hepatitis. Clinics in liver disease 19:57–79. https://doi.org/10.1016/j.cld.2014.09.004
Czaja AJ (2016) Diagnosis and management of autoimmune hepatitis: current status and future directions. Gut and liver 10:177–203. https://doi.org/10.5009/gnl15352
Dinda B, Dinda S, DasSharma S, Banik R, Chakraborty A, Dinda M (2017) Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. Eur J Med Chem 131:68–80. https://doi.org/10.1016/j.ejmech.2017.03.004
Filliol A, Piquet-Pellorce C, Raguenes-Nicol C, Dion S, Farooq M, Lucas-Clerc C, Vandenabeele P, Bertrand MJM, Le Seyec J, Samson M (2017) RIPK1 protects hepatocytes from Kupffer cells-mediated TNF-induced apoptosis in mouse models of PAMP-induced hepatitis. J Hepatol 66:1205–1213. https://doi.org/10.1016/j.jhep.2017.01.005
Gunes H, Mete R, Aydin M, Topcu B, Oran M, Dogan M, Yildirim O, Erdem I, Eren Topkaya A, Gurel A (2015) Relationship among MIF, MCP-1, viral loads, and HBs Ag levels in chronic hepatitis B patients. Turk J Med Sci 45:634–637
Han MS, Barrett T, Brehm MA, Davis RJ (2016) Inflammation mediated by JNK in myeloid cells promotes the development of hepatitis and hepatocellular carcinoma. Cell Rep 15:19–26. https://doi.org/10.1016/j.celrep.2016.03.008
He P, Wu Y, Shun J, Liang Y, Cheng M, Wang Y (2017) Baicalin ameliorates liver injury induced by chronic plus binge ethanol feeding by modulating oxidative stress and inflammation via CYP2E1 and NRF2 in mice. 2017:4820414. doi:https://doi.org/10.1155/2017/4820414
Ish-Shalom S, Lichter A (2010) Analysis of fungal gene expression by real time quantitative PCR. Methods Mol Biol 638:103–114. https://doi.org/10.1007/978-1-60761-611-5_7
Liang HX, Sun LB, Liu NJ (2019) Neferine inhibits proliferation, migration and invasion of U251 glioma cells by down-regulation of miR-10b. Biomed Pharmacother 109:1032–1040. https://doi.org/10.1016/j.biopha.2018.10.122
Liang Z, Ren C (2018) Emodin attenuates apoptosis and inflammation induced by LPS through up-regulating lncRNA TUG1 in murine chondrogenic ATDC5 cells. Biomed Pharmacother 103:897–902. https://doi.org/10.1016/j.biopha.2018.04.085
Long Y, Wang X, Youmans DT, Cech TR (2017) How do lncRNAs regulate transcription? 3:eaao2110. doi:https://doi.org/10.1126/sciadv.aao2110
Lopez-Izquierdo R, Udaondo MA, Zarzosa P, Garcia-Ramon E, Garcinuno S, Bratos MA, Orduna A, Rodriguez-Torres A, Almaraz A (2007) Seroprevalence of viral hepatitis in a representative general population of an urban public health area in Castilla y Leon (Spain). Enferm Infecc Microbiol Clin 25:317–323
Lu L, Rao L, Jia H, Chen J, Lu X, Yang G, Li Q, Lee KKH, Yang L (2017) Baicalin positively regulates osteoclast function by activating MAPK/Mitf signalling. J Cell Mol Med 21:1361–1372. https://doi.org/10.1111/jcmm.13066
Mathy NW, Chen XM (2017) Long non-coding RNAs (lncRNAs) and their transcriptional control of inflammatory responses. J Biol Chem 292:12375–12382. https://doi.org/10.1074/jbc.R116.760884
Mourtzikou A, Alepaki M, Stamouli M, Pouliakis A, Skliris A, Karakitsos P (2014) Evaluation of serum levels of IL-6, TNF-α, IL-10, IL-2 and IL-4 in patients with chronic hepatitis. Inmunología 33:41–50
Nainan OV, Xia G, Vaughan G, Margolis HS (2006) Diagnosis of hepatitis a virus infection: a molecular approach. Clin Microbiol Rev 19:63–79. https://doi.org/10.1128/cmr.19.1.63-79.2006
Narsale AA, Enos RT, Puppa MJ, Chatterjee S, Murphy EA, Fayad R, Pena MO, Durstine JL, Carson JA (2015) Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression. PLoS One 10:e0119888. https://doi.org/10.1371/journal.pone.0119888
Rathee P, Chaudhary H, Rathee S, Rathee D, Kumar V, Kohli K (2009) Mechanism of action of flavonoids as anti-inflammatory agents: a review. Inflamma Allergy Drug Targets 8:229–235
Rorato R, Borges BC, Uchoa ET, Antunes-Rodrigues J, Elias CF, Elias LLK (2017) LPS-induced low-grade inflammation increases hypothalamic JNK expression and causes central insulin resistance irrespective of body weight changes. Int J Mol Sci 18. https://doi.org/10.3390/ijms18071431
Sahebjam F, Vierling JM (2015) Autoimmune hepatitis. Front Med 9:187–219. https://doi.org/10.1007/s11684-015-0386-y
Salaritabar A, Darvishi B, Hadjiakhoondi F, Manayi A, Sureda A, Nabavi SF, Fitzpatrick LR, Nabavi SM, Bishayee A (2017) Therapeutic potential of flavonoids in inflammatory bowel disease: a comprehensive review. World J Gastroenterol 23:5097–5114. https://doi.org/10.3748/wjg.v23.i28.5097
Schlabe S, Rockstroh JK (2018) Advances in the treatment of HIV/HCV coinfection in adults. Expert Opin Pharmacother 19:49–64. https://doi.org/10.1080/14656566.2017.1419185
Sinn DH, Cho EJ, Kim JH, Kim DY, Kim YJ, Choi MS (2017) Current status and strategies for viral hepatitis control in Korea. 23:189–195. https://doi.org/10.3350/cmh.2017.0033
Sowndhararajan K, Deepa P, Kim M, Park SJ, Kim S (2018) Neuroprotective and cognitive enhancement potentials of baicalin: a review 8. doi:https://doi.org/10.3390/brainsci8060104
Su S, Liu J, He K, Zhang M, Feng C, Peng F, Li B, Xia X (2016) Overexpression of the long noncoding RNA TUG1 protects against cold-induced injury of mouse livers by inhibiting apoptosis and inflammation. FEBS J 283:1261–1274. https://doi.org/10.1111/febs.13660
Sun SJ, Wu XP, Song HL, Li GQ (2015) Baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation, oxidative stress and P38MAPK pathway in rat. Int J Clin Exp Med 8:22063–22072
Wang X, Quinn PJ (2010) Lipopolysaccharide: biosynthetic pathway and structure modification. Prog Lipid Res 49:97–107. https://doi.org/10.1016/j.plipres.2009.06.002
Wyns H, Plessers E, De Backer P, Meyer E, Croubels S (2015) In vivo porcine lipopolysaccharide inflammation models to study immunomodulation of drugs. Vet Immunol Immunopathol 166:58–69. https://doi.org/10.1016/j.vetimm.2015.06.001
Yu X, Lan P, Hou X, Han Q, Lu N, Li T, Jiao C, Zhang J, Zhang C, Tian Z (2017) HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1beta production via suppressing the NF-kappaB pathway and ROS production. J Hepatol 66:693–702. https://doi.org/10.1016/j.jhep.2016.12.018
Zhang EB, Yin DD, Sun M, Kong R, Liu XH, You LH, Han L, Xia R, Wang KM, Yang JS, De W, Shu YQ, Wang ZX (2014) P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression. Cell Death Dis 5:e1243. https://doi.org/10.1038/cddis.2014.201
Zhang H, Li H, Ge A, Guo E, Liu S, Zhang L (2018) Long non-coding RNA TUG1 inhibits apoptosis and inflammatory response in LPS-treated H9c2 cells by down-regulation of miR-29b. Biomed Pharmacother 101:663–669. https://doi.org/10.1016/j.biopha.2018.02.129
Zhang J, Zhang H, Deng X, Zhang N, Liu B, Xin S, Li G, Xu K (2018) Baicalin attenuates non-alcoholic steatohepatitis by suppressing key regulators of lipid metabolism, inflammation and fibrosis in mice. Life Sci 192:46–54. https://doi.org/10.1016/j.lfs.2017.11.027
Zhong X, Liu H (2018) Baicalin attenuates diet induced nonalcoholic steatohepatitis by inhibiting inflammation and oxidative stress via suppressing JNK signaling pathways. Biomed Pharmacother 98:111–117. https://doi.org/10.1016/j.biopha.2017.12.026
Author information
Authors and Affiliations
Contributions
Yanqiu Huang, Aiying Zhao: conceived and designed the experiments.
Yanqiu Huang, Mengyan Sun, Xuefang Yang, Aiyu Ma, Yujie Ma: data collection.
Yanqiu Huang, Aiying Zhao: manuscript writing.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Highlights
1. Baicalin relieves L-02 cell apoptosis and inflammatory reaction stimulated by LPS.
2. Baicalin promotes TUG1 expression in L-02 cells.
3. Baicalin mitigates LPS-stimulated activation of p38MAPK and JNK pathways.
4. TUG1 knockdown activates p38MAPK and JNK pathways.
5. Baicalin also relieves LPS-caused THLE2 cell apoptosis and inflammatory reaction.
This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1007/s13105-023-00951-7
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Huang, Y., Sun, M., Yang, X. et al. RETRACTED ARTICLE: Baicalin relieves inflammation stimulated by lipopolysaccharide via upregulating TUG1 in liver cells. J Physiol Biochem 75, 463–473 (2019). https://doi.org/10.1007/s13105-019-00698-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13105-019-00698-0