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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Research Article

Betulinic Acid Exerts Anti-inflammatory Activity in Human Periodontal Ligament Cells Stimulated with Lipopolysaccharide and/or High Glucose

Author(s): Ping Hu and Chunxia Zhu*

Volume 23, Issue 1, 2023

Published on: 27 September, 2022

Page: [95 - 104] Pages: 10

DOI: 10.2174/1871530322666220509231119

Price: $65

Abstract

Background: Diabetic patients have weakened periodontal ligaments and an increased risk of periodontitis due to uncontrolled glycemia. Betulinic acid (BA), a hypoglycemic drug, has anti-inflammatory activities.

Objectives: The current study aimed to explore the protective effect of BA on the inflammation in human periodontal ligament cells (PDLCs) stimulated with lipopolysaccharide (LPS) and/or high glucose (HG) status and its mechanisms of action.

Methods: Human PDLCs were exposed to LPS and/or HG, with or without BA intervention. The production of nitrite oxide (NO) and prostaglandin E2 (PGE2) were quantified by Griess reaction and enzyme-linked immunosorbent assay, respectively. Immunoblotting analyses were employed to detect the expression of inducible nitric oxide synthase (iNOS) and the cyclooxygenase-2 (COX- 2), as well as the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa- B (NF-κB) in human PDLCs.

Results: The increased production of iNOS/NO and COX-2/PGE2 and increased phosphorylated levels of IκBα, JNK, and p38 can be detected in human PDLCs with LPS and/or HG situations, while increased phosphorylated ERK can be seen in cells under only LPS condition. Furthermore, the non-toxic concentration of BA (10 μM) prevented NF-κB and MAPKs activation and partly but significantly reversed the induction of COX-2/ PGE2 and iNOS/NO in human PDLCs with LPS and/or HG loaded.

Conclusion: BA was proved for the first time to protect human PDLCs from the LPS-induced and/or HG-induced inflammation, which works through the mechanism involving the action of MAPKs and NF-κB. signaling pathways. Thus, BA could be used to alleviate diabetic complications of periodontitis.

Keywords: Betulinic acid, periodontal ligament cells, lipopolysaccharide, cyclooxygenase-2, nitric oxide synthase, high glucose, mitogen-activated protein kinase, nuclear factor kappa-B.

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[1]
Pihlstrom, B.L.; Michalowicz, B.S.; Johnson, N.W. Periodontal diseases. Lancet, 2005, 366(9499), 1809-1820.
[http://dx.doi.org/10.1016/S0140-6736(05)67728-8] [PMID: 16298220]
[2]
Bostanci, N.; Belibasakis, G.N. Porphyromonas gingivalis: An invasive and evasive opportunistic oral pathogen. FEMS Microbiol. Lett., 2012, 333(1), 1-9.
[http://dx.doi.org/10.1111/j.1574-6968.2012.02579.x] [PMID: 22530835]
[3]
Preshaw, P.M.; Bissett, S.M. Periodontitis and diabetes. Br. Dent. J., 2019, 227(7), 577-584.
[http://dx.doi.org/10.1038/s41415-019-0794-5] [PMID: 31605062]
[4]
Kallens, V.; Tobar, N.; Molina, J.; Bidegain, A.; Smith, P.C.; Porras, O.; Martínez, J. Glucose promotes a pro-oxidant and pro-inflammatory stromal microenvironment which favors motile properties in breast tumor cells. J. Cell. Biochem., 2017, 118(5), 994-1002.
[http://dx.doi.org/10.1002/jcb.25650] [PMID: 27403856]
[5]
Suzuki, T.; Yamashita, S.; Hattori, K.; Matsuda, N.; Hattori, Y. Impact of a long-term high-glucose environment on pro-inflammatory responses in macrophages stimulated with lipopolysaccharide. Naunyn Schmiedebergs Arch. Pharmacol., 2021, 394(10), 2129-2139.
[http://dx.doi.org/10.1007/s00210-021-02137-8] [PMID: 34402957]
[6]
Noguchi, K.; Ishikawa, I. The roles of cyclooxygenase-2 and prostaglandin E2 in periodontal disease. Periodontol. 2000, 2007, 43(1), 85-101.
[http://dx.doi.org/10.1111/j.1600-0757.2006.00170.x] [PMID: 17214837]
[7]
Sun, S.; Zhang, D.; Wu, Y.; Yan, L.; Liu, J.; Pan, C.; Pan, Y. The expression of inducible nitric oxide synthase in the gingiva of rats with periodontitis and diabetes mellitus. Arch. Oral Biol., 2020, 112, 104652.
[http://dx.doi.org/10.1016/j.archoralbio.2020.104652] [PMID: 32114252]
[8]
Chun, K.S.; Surh, Y.J. Signal transduction pathways regulating cyclooxygenase-2 expression: Potential molecular targets for chemoprevention. Biochem. Pharmacol., 2004, 68(6), 1089-1100.
[http://dx.doi.org/10.1016/j.bcp.2004.05.031] [PMID: 15313405]
[9]
Kleinert, H.; Schwarz, P.M.; Förstermann, U. Regulation of the expression of inducible nitric oxide synthase. Biol. Chem., 2003, 384(10-11), 1343-1364.
[http://dx.doi.org/10.1515/BC.2003.152] [PMID: 14669979]
[10]
Morrison, D.K. MAP kinase pathways. Cold Spring Harb. Perspect. Biol., 2012, 4(11), a011254.
[http://dx.doi.org/10.1101/cshperspect.a011254] [PMID: 23125017]
[11]
Kang, S.K.; Park, Y.D.; Kang, S.I.; Kim, D.K.; Kang, K.L.; Lee, S.Y.; Lee, H.J.; Kim, E.C. Role of resistin in the inflammatory response induced by nicotine plus lipopolysaccharide in human periodontal ligament cells in vitro. J. Periodontal Res., 2015, 50(5), 602-613.
[http://dx.doi.org/10.1111/jre.12240] [PMID: 25393899]
[12]
Cho, Y.A.; Jue, S.S.; Bae, W.J.; Heo, S.H.; Shin, S.I.; Kwon, I.K.; Lee, S.C.; Kim, E.C. PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses. J. Dent. Res., 2015, 94(2), 371-380.
[http://dx.doi.org/10.1177/0022034514563335] [PMID: 25512367]
[13]
Choi, E.Y.; Bae, S.H.; Ha, M.H.; Choe, S.H.; Hyeon, J.Y.; Choi, J.I.; Choi, I.S.; Kim, S.J. Genistein suppresses Prevotella intermedia lipopolysaccharide-induced inflammatory response in macrophages and attenuates alveolar bone loss in ligature-induced periodontitis. Arch. Oral Biol., 2016, 62, 70-79.
[http://dx.doi.org/10.1016/j.archoralbio.2015.11.019] [PMID: 26655950]
[14]
Alqahtani, A.; Hamid, K.; Kam, A.; Wong, K.H.; Abdelhak, Z.; Razmovski-Naumovski, V.; Chan, K.; Li, K.M.; Groundwater, P.W.; Li, G.Q. The pentacyclic triterpenoids in herbal medicines and their pharmacological activities in diabetes and diabetic complications. Curr. Med. Chem., 2013, 20(7), 908-931.
[PMID: 23210780]
[15]
Ríos, J.L.; Máñez, S. New pharmacological opportunities for betulinic acid. Planta Med., 2018, 84(1), 8-19.
[http://dx.doi.org/10.1055/s-0043-123472] [PMID: 29202513]
[16]
Amiri, S.; Dastghaib, S.; Ahmadi, M.; Mehrbod, P.; Khadem, F.; Behrouj, H.; Aghanoori, M.R.; Machaj, F.; Ghamsari, M.; Rosik, J.; Hudecki, A.; Afkhami, A.; Hashemi, M.; Los, M.J.; Mokarram, P.; Madrakian, T.; Ghavami, S. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol. Adv., 2020, 38, 107409.
[http://dx.doi.org/10.1016/j.biotechadv.2019.06.008] [PMID: 31220568]
[17]
Zhu, C.; Ji, Y.; Liu, S.; Bian, Z. Follicle-stimulating hormone enhances alveolar bone resorption via upregulation of cyclooxygenase-2. Am. J. Transl. Res., 2016, 8(9), 3861-3871.
[PMID: 27725865]
[18]
Sun, C.; Liu, F.; Cen, S.; Chen, L.; Wang, Y.; Sun, H.; Deng, H.; Hu, R. Tensile strength suppresses the osteogenesis of periodontal ligament cells in inflammatory microenvironments. Mol. Med. Rep., 2017, 16(1), 666-672.
[http://dx.doi.org/10.3892/mmr.2017.6644] [PMID: 28560407]
[19]
Bae, W.J.; Shin, M.R.; Kang, S.K. Zhang-Jun; Kim, J.Y.; Lee, S.C.; Kim, E.C. HIF-2 inhibition supresses inflammatory responses and osteoclastic differentiation in human periodontal ligament cells. J. Cell. Biochem., 2015, 116(7), 1241-1255.
[http://dx.doi.org/10.1002/jcb.25078] [PMID: 25565665]
[20]
Fan, C.; Zhang, X.; Upton, Z. Anti-inflammatory effects of shikonin in human periodontal ligament cells. Pharm. Biol., 2018, 56(1), 415-421.
[http://dx.doi.org/10.1080/13880209.2018.1506482] [PMID: 30392422]
[21]
Lee, S.A.; Park, B.R.; Moon, S.M.; Shin, S.H.; Kim, J.S.; Kim, D.K.; Kim, C.S. Cynaroside protects human periodontal ligament cells from lipopolysaccharide-induced damage and inflammation through suppression of NF-κB activation. Arch. Oral Biol., 2020, 120, 104944.
[http://dx.doi.org/10.1016/j.archoralbio.2020.104944] [PMID: 33099251]
[22]
Lee, S.I.; Yi, J.K.; Bae, W.J.; Lee, S.; Cha, H.J.; Kim, E.C. Thymosin Beta-4 suppresses osteoclastic differentiation and inflammatory responses in human periodontal ligament cells. PLoS One, 2016, 11(1), e0146708.
[http://dx.doi.org/10.1371/journal.pone.0146708] [PMID: 26789270]
[23]
Hua, K.F.; Wang, S.H.; Dong, W.C.; Lin, C.Y.; Ho, C.L.; Wu, T.H. High glucose increases nitric oxide generation in lipopolysaccharide-activated macrophages by enhancing activity of protein kinase C-α/δ and NF-κ. B. Inflamm. Res., 2012, 61(10), 1107-1116.
[http://dx.doi.org/10.1007/s00011-012-0503-1] [PMID: 22706318]
[24]
Yamawaki, H.; Hara, Y. Glyoxal causes inflammatory injury in human vascular endothelial cells. Biochem. Biophys. Res. Commun., 2008, 369(4), 1155-1159.
[http://dx.doi.org/10.1016/j.bbrc.2008.03.020] [PMID: 18343213]
[25]
Grosick, R.; Alvarado-Vazquez, P.A.; Messersmith, A.R.; Romero-Sandoval, E.A. High glucose induces a priming effect in macrophages and exacerbates the production of pro-inflammatory cytokines after a challenge. J. Pain Res., 2018, 11, 1769-1778.
[http://dx.doi.org/10.2147/JPR.S164493] [PMID: 30237731]
[26]
Sheu, M.L.; Ho, F.M.; Yang, R.S.; Chao, K.F.; Lin, W.W.; Lin-Shiau, S.Y.; Liu, S.H. High glucose induces human endothelial cell apoptosis through a phosphoinositide 3-kinase-regulated cyclooxygenase-2 pathway. Arterioscler. Thromb. Vasc. Biol., 2005, 25(3), 539-545.
[http://dx.doi.org/10.1161/01.ATV.0000155462.24263.e4] [PMID: 15653566]
[27]
Wu, C.H.; Wu, C.F.; Huang, H.W.; Jao, Y.C.; Yen, G.C. Naturally occurring flavonoids attenuate high glucose-induced expression of proinflammatory cytokines in human monocytic THP-1 cells. Mol. Nutr. Food Res., 2009, 53(8), 984-995.
[http://dx.doi.org/10.1002/mnfr.200800495] [PMID: 19557821]
[28]
Abikshyeet, P.; Ramesh, V.; Oza, N. Glucose estimation in the salivary secretion of diabetes mellitus patients. Diabetes Metab. Syndr. Obes., 2012, 5, 149-154.
[PMID: 22923999]
[29]
Maruyama, K.; Sato, S. Effect of high-glucose conditions on human periodontal ligament endothelial cells: In vitro analysis. Odontology, 2017, 105(1), 76-83.
[http://dx.doi.org/10.1007/s10266-016-0235-8] [PMID: 27072192]
[30]
Hsieh, C.F.; Liu, C.K.; Lee, C.T.; Yu, L.E.; Wang, J.Y. Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation. Sci. Rep., 2019, 9(1), 840.
[http://dx.doi.org/10.1038/s41598-018-37215-0] [PMID: 30696869]
[31]
Kwon, H.; Lim, W.; Kim, J.; Jeon, S.; Kim, S.; Karna, S.; Cha, H.; Kim, O.; Choi, H. Effect of 635 nm irradiation on high glucose-boosted inflammatory responses in LPS-induced MC3T3-E1 cells. Lasers Med. Sci., 2013, 28(3), 717-724.
[http://dx.doi.org/10.1007/s10103-012-1122-3] [PMID: 22699799]
[32]
Huang, Z.; Dong, X.; Zhuang, X.; Hu, X.; Wang, L.; Liao, X. Exogenous hydrogen sulfide protects against high glucose induced inflammation and cytotoxicity in H9c2 cardiac cells. Mol. Med. Rep., 2016, 14(5), 4911-4917.
[http://dx.doi.org/10.3892/mmr.2016.5846] [PMID: 27748941]
[33]
Quan, X.; Liu, H.; Ye, D.; Ding, X.; Su, X. Forsythoside A alleviates high glucose-induced oxidative stress and inflammation in podocytes by inactivating MAPK signaling via MMP12 inhibition. Diabetes Metab. Syndr. Obes., 2021, 14, 1885-1895.
[http://dx.doi.org/10.2147/DMSO.S305092] [PMID: 33953587]
[34]
Song, S.; Dang, M.; Kumar, M. Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism. Inflammopharmacology, 2019, 27(6), 1243-1254.
[http://dx.doi.org/10.1007/s10787-019-00569-6] [PMID: 30826930]
[35]
Pan, Y.; Wang, Y.; Cai, L.; Cai, Y.; Hu, J.; Yu, C.; Li, J.; Feng, Z.; Yang, S.; Li, X.; Liang, G. Inhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats. Br. J. Pharmacol., 2012, 166(3), 1169-1182.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01854.x] [PMID: 22242942]
[36]
Wang, S.; Yang, Z.; Xiong, F.; Chen, C.; Chao, X.; Huang, J.; Huang, H. Betulinic acid ameliorates experimental diabetic-induced renal inflammation and fibrosis via inhibiting the activation of NF-κB signaling pathway. Mol. Cell. Endocrinol., 2016, 434, 135-143.
[http://dx.doi.org/10.1016/j.mce.2016.06.019] [PMID: 27364889]
[37]
Karna, E.; Palka, J.A. Mechanism of betulinic acid inhibition of collagen biosynthesis in human endometrial adenocarcinoma cells. Neoplasma, 2009, 56(4), 361-366.
[http://dx.doi.org/10.4149/neo_2009_04_361] [PMID: 19469659]
[38]
Kasperczyk, H.; La Ferla-Brühl, K.; Westhoff, M.A.; Behrend, L.; Zwacka, R.M.; Debatin, K.M.; Fulda, S. Betulinic acid as new activator of NF-kappaB: Molecular mechanisms and implications for cancer therapy. Oncogene, 2005, 24(46), 6945-6956.
[http://dx.doi.org/10.1038/sj.onc.1208842] [PMID: 16007147]

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