Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Fangchinoline, an Extract of the Stephania tetrandra S. Moore Root, Promoted Oxidative Stress-induced DNA Damage and Apoptosis and Inhibited Akt Signaling in Jurkat T Cells

Author(s): Yanxiong Shao, Chaoran Li, Guojun Miao and Yubo Xu*

Volume 17, 2024

Published on: 28 April, 2023

Article ID: e100223213590 Pages: 11

DOI: 10.2174/1874467216666230210152454

open_access

conference banner
Abstract

Background: Fangchinoline (Fan) is extracted from traditional Chinese medicine (called Fangji), or the root of Stephania tetrandra Moore. Fangji is well-known in Chinese medical literature for treating rheumatic diseases. Sjogren's syndrome (SS) is a rheumatic disease whose progression can be mediated via CD4+ T cell infiltration.

Objective: This study identifies the potential role of Fan in inducing apoptosis in Jurkat T cells.

Methods: First, we explored the biological process (BP) associated with SS development by performing a gene ontology analysis of SS salivary gland-related mRNA microarray data. The effect of Fan on Jurkat cells was investigated by analyzing the viability, proliferation, apoptosis, reactive oxygen species (ROS) production, and DNA damage.

Results: Biological process analysis showed that T cells played a role in salivary gland lesions in patients with SS, indicating the significance of T cell inhibition in SS treatment. Viability assays revealed that the half-maximal inhibitory concentration of Fan was 2.49 μM in Jurkat T cells, while the proliferation assay revealed that Fan had an inhibitory effect on the proliferation of Jurkat T cells. The results of the apoptotic, ROS, agarose gel electrophoresis, and immunofluorescence assays showed that Fan induced oxidative stress-induced apoptosis and DNA damage in a dosedependent manner.

Conclusion: These results indicate that Fan could significantly induce oxidative stress-induced apoptosis and DNA damage and inhibit the proliferation of Jurkat T cells. Moreover, Fan further enhanced the inhibitory effect on DNA damage and apoptosis by inhibiting the pro-survival Akt signal.

Keywords: Fangchinoline, Reactive, Oxygen species, DNA damage, Apoptosis, Akt.

[1]
Shiboski, C.H.; Shiboski, S.C.; Seror, R.; Criswell, L.A.; Labetoulle, M.; Lietman, T.M.; Rasmussen, A.; Scofield, H.; Vitali, C.; Bowman, S.J.; Mariette, X. 2016 American college of rheumatology/european league against rheumatism classification criteria for primary sjögren’s syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol., 2017, 69(1), 35-45.
[http://dx.doi.org/10.1002/art.39859] [PMID: 27785888]
[2]
Nocturne, G.; Mariette, X. Sjögren Syndrome-associated lymphomas: an update on pathogenesis and management. Br. J. Haematol., 2015, 168(3), 317-327.
[http://dx.doi.org/10.1111/bjh.13192] [PMID: 25316606]
[3]
Mingueneau, M.; Boudaoud, S.; Haskett, S.; Reynolds, T.L.; Nocturne, G.; Norton, E.; Zhang, X.; Constant, M.; Park, D.; Wang, W.; Lazure, T.; Le Pajolec, C.; Ergun, A.; Mariette, X. Cytometry by time-of-flight immunophenotyping identifies a blood Sjögren’s signature correlating with disease activity and glandular inflammation. J. Allergy Clin. Immunol., 2016, 137(6), 1809-1821.
[http://dx.doi.org/10.1016/j.jaci.2016.01.024] [PMID: 27045581]
[4]
Maehara, T.; Moriyama, M.; Hayashida, J-N.; Tanaka, A.; Shinozaki, S.; Kubo, Y.; Matsumura, K.; Nakamura, S. Selective localization of T helper subsets in labial salivary glands from primary Sjögren’s syndrome patients. Clin. Exp. Immunol., 2012, 169(2), 89-99.
[http://dx.doi.org/10.1111/j.1365-2249.2012.04606.x] [PMID: 22774983]
[5]
Fu, J.; Pu, Y.; Wang, B.; Li, H.; Yang, X.; Xie, L.; Shi, H.; Wang, Z.; Yin, J.; Zhan, T.; Shao, Y.; Chen, C.; Luo, Q.; Xu, J.; Zong, Z.; Wei, X.; Xiao, W.; Yu, C.; Zheng, L. Pharmacological inhibition of glutaminase 1 normalized the metabolic state and CD4+ T cell response in sjogren’s syndrome. J. Immunol. Res., 2022, 2022, 1-13.
[http://dx.doi.org/10.1155/2022/3210200] [PMID: 35211629]
[6]
Fu, J.; Shi, H.; Wang, B.; Zhan, T.; Shao, Y.; Ye, L.; Wu, S.; Yu, C.; Zheng, L. LncRNA PVT1 links Myc to glycolytic metabolism upon CD4+ T cell activation and Sjögren’s syndrome-like autoimmune response. J. Autoimmun., 2020, 107, 102358.
[http://dx.doi.org/10.1016/j.jaut.2019.102358] [PMID: 31757716]
[7]
Zhang, Y.; Qi, D.; Gao, Y.; Liang, C.; Zhang, Y.; Ma, Z.; Liu, Y.; Peng, H.; Zhang, Y.; Qin, H.; Song, X.; Sun, X.; Li, Y.; Liu, Z. History of uses, phytochemistry, pharmacological activities, quality control and toxicity of the root of Stephania tetrandra S. Moore: A review. J. Ethnopharmacol., 2020, 260, 112995.
[http://dx.doi.org/10.1016/j.jep.2020.112995] [PMID: 32497674]
[8]
Zhang, Y.; Gao, X.; Liu, C.; Wang, M.; Zhang, R.; Sun, J.; Liu, Y. Design, synthesis and in vitro evaluation of fangchinoline derivatives as potential anticancer agents. Bioorg. Chem., 2020, 94, 103431.
[http://dx.doi.org/10.1016/j.bioorg.2019.103431] [PMID: 31759658]
[9]
Liu, T.; Zeng, Q.; Zhao, X.; Wei, W.; Li, Y.; Deng, H.; Song, D. Synthesis and biological evaluation of fangchinoline derivatives as anti-inflammatory agents through inactivation of inflammasome. Molecules, 2019, 24(6), 1154.
[http://dx.doi.org/10.3390/molecules24061154] [PMID: 30909541]
[10]
Shen, Y.C.; Chou, C.J.; Chiou, W.F.; Chen, C.F. Anti-inflammatory effects of the partially purified extract of radix Stephaniae tetrandrae: comparative studies of its active principles tetrandrine and fangchinoline on human polymorphonuclear leukocyte functions. Mol. Pharmacol., 2001, 60(5), 1083-1090.
[http://dx.doi.org/10.1124/mol.60.5.1083] [PMID: 11641437]
[11]
Shao, Y.; Yu, C.; Fu, J.; Zhan, T.; Ye, L. Fangchinoline inhibited proliferation of neoplastic B-lymphoid cells and alleviated Sjögren’s syndrome-like responses in NOD/Ltj mice via the Akt/mTOR pathway. Curr. Mol. Pharmacol., 2022, 15(7), 969-979.
[http://dx.doi.org/10.2174/1874467215666220217103233] [PMID: 35176991]
[12]
Wang, H.; Wang, Y.; Jiang, X.; Wang, Z.; Zhong, B.; Fang, Y. The molecular mechanism of curcumol on inducing cell growth arrest and apoptosis in Jurkat cells, a model of CD4+ T cells. Int. Immunopharmacol., 2014, 21(2), 375-382.
[http://dx.doi.org/10.1016/j.intimp.2014.05.021] [PMID: 24877754]
[13]
Koo, J.H.; Kim, D.H.; Cha, D.; Kang, M.J.; Choi, J.M. LRR domain of NLRX1 protein delivery by dNP2 inhibits T cell functions and alleviates autoimmune encephalomyelitis. Theranostics, 2020, 10(7), 3138-3150.
[http://dx.doi.org/10.7150/thno.43441] [PMID: 32194859]
[14]
Shan, L.; Tong, L.; Hang, L.; Fan, H. Fangchinoline supplementation attenuates inflammatory markers in experimental rheumatoid arthritis-induced rats. Biomed. Pharmacother., 2019, 111, 142-150.
[http://dx.doi.org/10.1016/j.biopha.2018.12.043] [PMID: 30579253]
[15]
Koh, S.B.; Ban, J.Y.; Lee, B.Y.; Seong, Y.H. Protective effects of fangchinoline and tetrandrine on hydrogen peroxide-induced oxidative neuronal cell damage in cultured rat cerebellar granule cells. Planta Med., 2003, 69(6), 506-512.
[http://dx.doi.org/10.1055/s-2003-40647] [PMID: 12865967]
[16]
Jung, Y.Y.; Ha, I.J.; Um, J.Y.; Sethi, G.; Ahn, K.S. Fangchinoline diminishes STAT3 activation by stimulating oxidative stress and targeting SHP-1 protein in multiple myeloma model. J. Adv. Res., 2022, 35, 245-257.
[http://dx.doi.org/10.1016/j.jare.2021.03.008] [PMID: 35024200]
[17]
Stern, M.E.; Gao, J.; Schwalb, T.A.; Ngo, M.; Tieu, D.D.; Chan, C.C.; Reis, B.L.; Whitcup, S.M.; Thompson, D.; Smith, J.A. Conjunctival T-cell subpopulations in Sjögren’s and non-Sjögren’s patients with dry eye. Invest. Ophthalmol. Vis. Sci., 2002, 43(8), 2609-2614.
[PMID: 12147592]
[18]
Adamson, T.C., III; Fox, R.I.; Frisman, D.M.; Howell, F.V. Immunohistologic analysis of lymphoid infiltrates in primary Sjogren’s syndrome using monoclonal antibodies. J. Immunol., 1983, 130(1), 203-208.
[PMID: 6600176]
[19]
Abraham, R.T.; Weiss, A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat. Rev. Immunol., 2004, 4(4), 301-308.
[http://dx.doi.org/10.1038/nri1330] [PMID: 15057788]
[20]
Kim, H.S.; Zhang, Y.H.; Oh, K.W.; Ahn, H.Y. Vasodilating and hypotensive effects of fangchinoline and tetrandrine on the rat aorta and the stroke-prone spontaneously hypertensive rat. J. Ethnopharmacol., 1997, 58(2), 117-123.
[http://dx.doi.org/10.1016/S0378-8741(97)00092-5] [PMID: 9406900]
[21]
Guo, H.; Ouyang, Y.; Wang, J.; Cui, H.; Deng, H.; Zhong, X.; Jian, Z.; Liu, H.; Fang, J.; Zuo, Z.; Wang, X.; Zhao, L.; Geng, Y.; Ouyang, P.; Tang, H. Cu-induced spermatogenesis disease is related to oxidative stress-mediated germ cell apoptosis and DNA damage. J. Hazard. Mater., 2021, 416, 125903.
[http://dx.doi.org/10.1016/j.jhazmat.2021.125903] [PMID: 34492839]
[22]
Danesh Pazhooh, R.; Rahnamay Farnood, P.; Asemi, Z.; Mirsafaei, L.; Yousefi, B.; Mirzaei, H. mTOR pathway and DNA damage response: A therapeutic strategy in cancer therapy. DNA Repair (Amst.), 2021, 104, 103142.
[http://dx.doi.org/10.1016/j.dnarep.2021.103142] [PMID: 34102579]
[23]
Wang, Y.; Sun, D.; Chen, Y.; Xu, J.; Xu, Y.; Yue, X.; Jia, J.; Li, H.; Chen, L. Alkaloids of Delphinium grandiflorum and their implication to H2O2-induced cardiomyocytes injury. Bioorg. Med. Chem., 2021, 37, 116113.
[http://dx.doi.org/10.1016/j.bmc.2021.116113] [PMID: 33744825]
[24]
Kumar, R.; Sharma, A.; Gupta, M.; Padwad, Y.; Sharma, R. Cell-free culture supernatant of probiotic lactobacillus fermentum protects against H2O2-induced premature senescence by suppressing ros-akt-mtor axis in murine preadipocytes. Probiotics Antimicrob. Proteins, 2020, 12(2), 563-576.
[http://dx.doi.org/10.1007/s12602-019-09576-z] [PMID: 31332650]
[25]
Zhang, J.; Zhou, W.; Lin, J.; Wei, P.; Zhang, Y.; Jin, P.; Chen, M.; Man, N.; Wen, L. Autophagic lysosomal reformation depends on mTOR reactivation in H2O2-induced autophagy. Int. J. Biochem. Cell Biol., 2016, 70, 76-81.
[http://dx.doi.org/10.1016/j.biocel.2015.11.009] [PMID: 26589722]
[26]
Peng, J.; He, X.; Zhang, L.; Liu, P. MicroRNA-26a protects vascular smooth muscle cells against H2O2-induced injury through activation of the PTEN/AKT/mTOR pathway. Int. J. Mol. Med., 2018, 42(3), 1367-1378.
[http://dx.doi.org/10.3892/ijmm.2018.3746] [PMID: 29956734]
[27]
Ji, J.; Chen, W.; Lian, W.; Chen, R.; Yang, J.; Zhang, Q.; Weng, Q.; Khan, Z.; Hu, J.; Chen, X.; Zou, P.; Chen, X.; Liang, G. (S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal. Cell Death Dis., 2018, 9(6), 660.
[http://dx.doi.org/10.1038/s41419-018-0667-x] [PMID: 29855474]
[28]
Rodríguez-Rodríguez, N.; Madera-Salcedo, I.K.; Cisneros-Segura, J.A.; García-González, H.B.; Apostolidis, S.A.; Saint-Martin, A.; Esquivel-Velázquez, M.; Nguyen, T.; Romero-Rodríguez, D.P.; Tsokos, G.C.; Alcocer-Varela, J.; Rosetti, F.; Crispín, J.C. Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal. J. Clin. Invest., 2020, 130(11), 5989-6004.
[http://dx.doi.org/10.1172/JCI129479] [PMID: 32750040]
[29]
Rosetti, F.; Madera-Salcedo, I.K.; Rodríguez-Rodríguez, N.; Crispín, J.C. Regulation of activated T cell survival in rheumatic autoimmune diseases. Nat. Rev. Rheumatol., 2022, 18(4), 232-244.
[http://dx.doi.org/10.1038/s41584-021-00741-9] [PMID: 35075294]

© 2024 Bentham Science Publishers | Privacy Policy