Skip to main content
Log in

Ursolic acid ameliorates Nthy-ori 3-1 cells injury induced by IL-1β through limiting MALAT1/miR-206/PTGS1 ceRNA network and NF-κB signaling pathway

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Ursolic acid (UA) has exhibited anti-inflammatory and anti-oxidative drug effects.

Objectives

In the research, we assessed the effects of UA on Nthy-ori 3-1 cells stimulated by IL-1β and attempted to elucidate the mechanisms underlying the effects.

Methods

Autoimmune thyroiditis (AIT) was simulated using Nthy-ori 3-1 cells by IL-1β (10 μM) treatment. UA (20 μM) was applied to ameliorate the injury of Nthy-ori 3-1 cells. The target of UA was predicted by TCMSP, BATMAN, and GEO database. Targeted relationship between lncRNA MALAT1 and miR-206, as well as miR-206 and PTGS1, was predicted by bioinformatics software and identified by dual luciferase assays. Cytokines in the cell supernatant and the apoptosis of cells were detected by ELISAs and flow cytometry assays, respectively. Expression levels of NF-κB signaling pathway-related proteins were estimated by western blot.

Results

By enquiring TCMSP, BATMAN, and GEO database, PTGS1 was identified as a target of UA. Afterward, a ceRNA network among MALAT1, miR-206, and PTGS1 was constructed. The expression levels of MALAT1 and PTGS1 in AIT tissues were obviously enhanced. Moreover, the ceRNA network formed by MALAT1/miR-206/PTGS1 contributed to the damage of Nthy-ori 3-1 cells induced by IL-1β. However, UA ameliorated the Nthy-ori 3-1 cells injury induced by IL-1β through mediating the MALAT1/miR-206/PTGS1 ceRNA network and NF-κB signaling pathway.

Conclusions

UA treatment significantly relieved the injury of Nthy-ori 3-1 cells via inhibiting the ceRNA mechanism of MALAT1/miR-206/PTGS1 and inflammatory pathways, insinuating that UA may be helpful for the treatment of AIT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Biswas S, Thomas AA, Chen S, Aref-Eshghi E, Feng B, Gonder J, Sadikovic B, Chakrabarti S (2018) MALAT1: an epigenetic regulator of inflammation in diabetic retinopathy. Sci Rep 8:6526

    Article  PubMed  PubMed Central  Google Scholar 

  • Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, Manji N, Allahabadia A, Armitage M, Chatterjee KV et al (2010) Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med 123:183.e181–183.e189

    Article  Google Scholar 

  • Cao DW, Liu MM, Duan R, Tao YF, Zhou JS, Fang WR, Zhu JR, Niu L, Sun JG (2020) The lncRNA Malat1 functions as a ceRNA to contribute to berberine-mediated inhibition of HMGB1 by sponging miR-181c-5p in poststroke inflammation. Acta Pharmacol Sin 41:22–33

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Wang X, Yan X, Cheng X, He X, Zheng W (2018) LncRNA MALAT1 regulates sepsis-induced cardiac inflammation and dysfunction via interaction with miR-125b and p38 MAPK/NFkappaB. Int Immunopharmacol 55:69–76

    Article  CAS  PubMed  Google Scholar 

  • Choi SH, Aid S, Bosetti F (2009) The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci 30:174–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu H, Qu X, Wang F, Chang J, Cheng R, Song X, Chen T, Zhang G (2019) MicroRNA-206 promotes lipopolysaccharide-induced inflammation injury via regulation of IRAK1 in MRC-5 cells. Int Immunopharmacol 73:590–598

    Article  CAS  PubMed  Google Scholar 

  • Dean B, Gibbons A, Gogos A, Udawela M, Thomas E, Scarr E (2018) Studies on prostaglandin-endoperoxide synthase 1: lower levels in schizophrenia and after treatment with antipsychotic drugs in conjunction with aspirin. Int J Neuropsychopharmacol 21:216–225

    Article  CAS  PubMed  Google Scholar 

  • Dey BK, Gagan J, Dutta A (2011) miR-206 and -486 induce myoblast differentiation by downregulating Pax7. Mol Cell Biol 31:203–214

    Article  CAS  PubMed  Google Scholar 

  • Duan X, Zohaib A, Li Y, Zhu B, Ye J, Wan S, Xu Q, Song Y, Chen H, Cao S (2015) miR-206 modulates lipopolysaccharide-mediated inflammatory cytokine production in human astrocytes. Cell Signal 27:61–68

    Article  CAS  PubMed  Google Scholar 

  • Fallahi P, Ferrari SM, Ruffilli I, Elia G, Biricotti M, Vita R, Benvenga S, Antonelli A (2016) The association of other autoimmune diseases in patients with autoimmune thyroiditis: review of the literature and report of a large series of patients. Autoimmun Rev 15:1125–1128

    Article  CAS  PubMed  Google Scholar 

  • Fu X, Zeng L, Liu Z, Ke X, Lei L, Li G (2016) MicroRNA-206 regulates the secretion of inflammatory cytokines and MMP9 expression by targeting TIMP3 in Mycobacterium tuberculosis-infected THP-1 human macrophages. Biochem Biophys Res Commun 477:167–173

    Article  CAS  PubMed  Google Scholar 

  • Habtemariam S (2019) Antioxidant and anti-inflammatory mechanisms of neuroprotection by ursolic acid: addressing brain injury, cerebral ischemia, cognition deficit, anxiety, and depression. Oxidative Med Cell Longev 2019:8512048

    Article  Google Scholar 

  • Hirooka Y, Mitsuma T, Nogimori T, Ishizuki Y (1993) Deregulated production of interleukin-8 (IL-8) in autoimmune thyroid disease studied by newly developed IL-8 radioimmunoassay. Endocr Regul 27:11–15

    CAS  PubMed  Google Scholar 

  • Hussain H, Green IR, Ali I, Khan IA, Ali Z, Al-Sadi AM, Ahmed I (2017) Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016). Expert Opin Ther Pat 27:1061–1072

    Article  CAS  PubMed  Google Scholar 

  • Jaen RI, Prieto P, Casado M, Martin-Sanz P, Bosca L (2018) Post-translational modifications of prostaglandin-endoperoxide synthase 2 in colorectal cancer: an update. World J Gastroenterol 24:5454–5461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin C, Yan B, Lu Q, Lin Y, Ma L (2016) The role of MALAT1/miR-1/slug axis on radioresistance in nasopharyngeal carcinoma. Tumour Biol 37:4025–4033

    Article  CAS  PubMed  Google Scholar 

  • Kargman SL, O'Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S (1995) Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res 55:2556–2559

    CAS  PubMed  Google Scholar 

  • Koehler, V.F., Filmann, N., and Mann, W.A. (2019). Vitamin D status and thyroid autoantibodies in autoimmune thyroiditis. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 51, 792-797.

  • Kong Q, Ma Y, Yu J, Chen X (2017) Predicted molecular targets and pathways for germacrone, curdione, and furanodiene in the treatment of breast cancer using a bioinformatics approach. Sci Rep 7:15543

    Article  PubMed  PubMed Central  Google Scholar 

  • Lei Y, Yang J, Li H, Zhong H, Wan Q (2019) Changes in glucose-lipid metabolism, insulin resistance, and inflammatory factors in patients with autoimmune thyroid disease. J Clin Lab Anal 33:e22929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li D, Hao S, Zhang J (2019) Long non-coding RNA UCA1 exerts growth modulation by miR-15a in human thyroid cancer TPC-1 cells. Artif Cells Nanomed Biotechnol 47:1815–1822

    Article  CAS  PubMed  Google Scholar 

  • Li L, Zhang X, Cui L, Wang L, Liu H, Ji H, Du Y (2013) Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res 1497:32–39

    Article  CAS  PubMed  Google Scholar 

  • Liang WJ, Zeng XY, Jiang SL, Tan HY, Yan MY, Yang HZ (2019) Long non-coding RNA MALAT1 sponges miR-149 to promote inflammatory responses of LPS-induced acute lung injury by targeting MyD88. Cell Biol Int

  • Liu S, Bai Z, Li J (2012) [Comprehensive evaluation of multi-quality characteristic indexes of Chaenomeles speciosa and C. sinensis fruits]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi =. China Journal of Chinese Materia Medica 37:901–907

    PubMed  Google Scholar 

  • Lu, J., Wu, D.M., Zheng, Y.L., Hu, B., Zhang, Z.F., Ye, Q., Liu, C.M., Shan, Q., and Wang, Y.J. (2010a). Ursolic acid attenuates D-galactose-induced inflammatory response in mouse prefrontal cortex through inhibiting AGEs/RAGE/NF-kappaB pathway activation. Cerebral cortex (New York, NY : 1991) 20, 2540-2548.

  • Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF, Ye Q, Liu CM, Shan Q, Wang YJ (2010b) Ursolic acid attenuates D-galactose-induced inflammatory response in mouse prefrontal cortex through inhibiting AGEs/RAGE/NF-κB pathway activation. Cerebral Cortex (New York, NY : 1991) 20:2540–2548

    Google Scholar 

  • Machado DG, Neis VB, Balen GO, Colla A, Cunha MP, Dalmarco JB, Pizzolatti MG, Prediger RD, Rodrigues AL (2012) Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: evidence for the involvement of the dopaminergic system. Pharmacol Biochem Behav 103:204–211

    Article  CAS  PubMed  Google Scholar 

  • Manu KA, Kuttan G (2008) Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F-10 melanoma cells. Int Immunopharmacol 8:974–981

    Article  CAS  PubMed  Google Scholar 

  • Najid A, Simon A, Cook J, Chable-Rabinovitch H, Delage C, Chulia AJ, Rigaud M (1992) Characterization of ursolic acid as a lipoxygenase and cyclooxygenase inhibitor using macrophages, platelets and differentiated HL60 leukemic cells. FEBS Lett 299:213–217

    Article  CAS  PubMed  Google Scholar 

  • Ou C, Geng T, Wang J, Gao X, Chen X, Luo X, Tong X, Cao L, Wang Z, Xiao W (2020) Systematically investigating the pharmacological mechanism of Dazhu Hongjingtian in the prevention and treatment of acute mountain sickness by integrating UPLC/Q-TOF-MS/MS analysis and network pharmacology. J Pharm Biomed Anal 179:113028

    Article  CAS  PubMed  Google Scholar 

  • Park S, Zhu J, Altan-Bonnet G, Cheng SY (2019) Monocyte recruitment and activated inflammation are associated with thyroid carcinogenesis in a mouse model. Am J Cancer Res 9:1439–1453

    CAS  PubMed  PubMed Central  Google Scholar 

  • Patel NA, Moss LD, Lee JY, Tajiri N, Acosta S, Hudson C, Parag S, Cooper DR, Borlongan CV, Bickford PC (2018) Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury. J Neuroinflammation 15:204

    Article  PubMed  PubMed Central  Google Scholar 

  • Peng H, Liu Y, Tian J, Ma J, Tang X, Rui K, Tian X, Mao C, Lu L, Xu H et al (2015) The long noncoding RNA IFNG-AS1 promotes t helper type 1 cells response in patients with Hashimoto’s thyroiditis. Sci Rep 5:17702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez-Munoz A, Vitales-Noyola M, Ramos-Levi A, Serrano-Somavilla A, Gonzalez-Amaro R, Marazuela M (2016) Levels of regulatory T cells CD69(+)NKG2D(+)IL-10(+) are increased in patients with autoimmune thyroid disorders. Endocrine 51:478–489

    Article  CAS  PubMed  Google Scholar 

  • Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, Xu X, Li Y, Wang Y, Yang L (2014) TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminformatics 6:13

    Article  Google Scholar 

  • Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146:353–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shishodia S, Majumdar S, Banerjee S, Aggarwal BB (2003) Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 63:4375–4383

    CAS  PubMed  Google Scholar 

  • Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182

    Article  CAS  PubMed  Google Scholar 

  • Sun W, Zhang L, Li R (2017) Overexpression of miR-206 ameliorates chronic constriction injury-induced neuropathic pain in rats via the MEK/ERK pathway by targeting brain-derived neurotrophic factor. Neurosci Lett 646:68–74

    Article  CAS  PubMed  Google Scholar 

  • Takada K, Nakane T, Masuda K, Ishii H (2010) Ursolic acid and oleanolic acid, members of pentacyclic triterpenoid acids, suppress TNF-alpha-induced E-selectin expression by cultured umbilical vein endothelial cells. Phytomedicine 17:1114–1119

    Article  CAS  PubMed  Google Scholar 

  • Tsai SJ, Yin MC (2008) Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. J Food Sci 73:H174–H178

    Article  CAS  PubMed  Google Scholar 

  • Volzke H, Ludemann J, Robinson DM, Spieker KW, Schwahn C, Kramer A, John U, Meng W (2003) The prevalence of undiagnosed thyroid disorders in a previously iodine-deficient area. Thyroid 13:803–810

    Article  PubMed  Google Scholar 

  • Voorby HA, Kabel PJ, de Haan M, Jeucken PH, van der Gaag RD, de Baets MH, Drexhage HA (1990) Dendritic cells and class II MHC expression on thyrocytes during the autoimmune thyroid disease of the BB rat. Clin Immunol Immunopathol 55:9–22

    Article  CAS  PubMed  Google Scholar 

  • Wang, J., Su, L., Chen, X., Li, P., Cai, Q., Yu, B., Liu, B., Wu, W., and Zhu, Z. (2014). MALAT1 promotes cell proliferation in gastric cancer by recruiting SF2/ASF. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 68, 557-564.

  • Wang Y, Liu Y, Zhang M, Lv L, Zhang X, Zhang P, Zhou Y (2019) Inhibition of PTGS1 promotes osteogenic differentiation of adipose-derived stem cells by suppressing NF-kB signaling. Stem Cell Res Ther 10:57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing H, Guo S, Zhang Y, Zheng Z, Wang H (2016) Upregulation of microRNA-206 enhances lipopolysaccharide-induced inflammation and release of amyloid-β by targeting insulin-like growth factor 1 in microglia. Mol Med Rep 14:1357–1364

    Article  CAS  PubMed  Google Scholar 

  • Xue YZ, Li ZJ, Liu WT, Shan JJ, Wang L, Su Q (2019) Down-regulation of lncRNA MALAT1 alleviates vascular lesion and vascular remodeling of rats with hypertension. Aging 11:5192–5205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao J, Wang XQ, Li YJ, Shan K, Yang H, Wang YN, Yao MD, Liu C, Li XM, Shen Y et al (2016) Long non-coding RNA MALAT1 regulates retinal neurodegeneration through CREB signaling. EMBO Mol Med 8:346–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin R, Li T, Tian JX, Xi P, Liu RH (2018) Ursolic acid, a potential anticancer compound for breast cancer therapy. Crit Rev Food Sci Nutr 58:568–574

    Article  CAS  PubMed  Google Scholar 

  • Yin X, Zhang J, Li C, Zhang Z, Jin T, Song L, Zhang R, Wang W, Tao Y, Wang X (2019) LncRNA HOXA11-AS accumulation-induced microRNA-761 downregulation regulates cell growth by targeting TRIM29 in papillary thyroid cancer. Am J Transl Res 11:6826–6837

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang HX, Kang Y, Li N, Wang HF, Bao YR, Li YW, Li XZ, Jiang Z, Chen G (2020a) Triterpenoids from Liquidambar Fructus induced cell apoptosis via a PI3K-AKT related signal pathway in SMMC7721 cancer cells. Phytochemistry 171:112228

    Article  PubMed  Google Scholar 

  • Zhang N, Liu S, Shi S, Chen Y, Xu F, Wei X, Xu Y (2020b) Solubilization and delivery of Ursolic-acid for modulating tumor microenvironment and regulatory T cell activities in cancer immunotherapy. J Control Release

  • Zhou HJ, Wang LQ, Wang DB, Yu JB, Zhu Y, Xu QS, Zheng XJ, Zhan RY (2018) Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKbeta/NF-kappaB signaling pathway. Am J Physiol Cell Physiol 315:C52–c61

    Article  CAS  PubMed  Google Scholar 

  • Zhuo Y, Zeng Q, Zhang P, Li G, Xie Q, Cheng Y (2017) Functional polymorphism of lncRNA MALAT1 contributes to pulmonary arterial hypertension susceptibility in Chinese people. Clin Chem Lab Med 55:38–46

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jianjia Jiang.

Ethics declarations

Conflict of interests

The authors declared that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mou, L., Liao, L., Zhang, Y. et al. Ursolic acid ameliorates Nthy-ori 3-1 cells injury induced by IL-1β through limiting MALAT1/miR-206/PTGS1 ceRNA network and NF-κB signaling pathway. Psychopharmacology 238, 1141–1156 (2021). https://doi.org/10.1007/s00213-021-05761-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-021-05761-7

Keywords

Navigation