Login Register Cart 0
Generic placeholder image

Current Chinese Science

Editor-in-Chief

ISSN (Print): 2210-2981
ISSN (Online): 2210-2914

Back
Journal Home About Journal Editorial Board Current Issue Volumes/Issues
Subscribe
Research Article

Artesunate Reverses Clozapine-induced Lipid Metabolism Disorder in BRL-3A Cells by Effecting AMPK Pathway

Author(s): Yali Cui, Lingyun Ling, Qingjun Huang and Haiyun Xu*

Volume 3, Issue 3, 2023

Published on: 11 January, 2023

Page: [194 - 203] Pages: 10

DOI: 10.2174/2210298103666221214165254

Price: $65

Abstract

Background: Clozapine (CLZ) is the only registered drug for treatment-resistant schizophrenia and also associated with metabolic abnormalities, including obesity, hyperglycemia, and dyslipidemia.

Objective: This study aimed to examine the effects of CLZ on lipid metabolism in BRL-3A cells, measure possible effects of artesunate (ART) on the CLZ-induced alterations in lipid metabolism, and explore the molecular mechanism underlying the CLZ- and ART-induced changes in the cells.

Methods: BRL-3A cells were cultured in DMEM at different conditions in the CLZ experiment (20, 30, or 40 μM CLZ), CLZ-ART experiment (40 μM CLZ followed by ART at 5, 10, or 20 μM), or CLZ-ART experiment consisting DMSO, CLZ, CLZ+ART, and ART groups. In addition to cell viability assessment, triglyceride, total and free cholesterol in BRL-3A cells were measured by biochemistry analyses, and levels of lipid metabolism-related genes and relevant proteins were evaluated by means of quantitative PCR and Western blot.

Results: CLZ in the used range increased levels of free and total cholesterol in BRL-3A while upregulated mRNA levels of HMGCR, PPARα, and PPARγ. Moreover, the treatment increased SREBP-1c mRNA and protein levels in the cells, although it showed no impact on the phosphorylation of AMPK. ART treatment following CLZ exposure reversed the CLZ-induced high levels of free and total cholesterol in BRL-3A. ART effectively ameliorated or normalized the CLZ-induced changes in the HMGCR, PPARα, PPARγ, and SREBP-1c. Furthermore, ART increased AMPK phosphorylation in BRL-3A.

Conclusion: These results suggest that ART exerts a cholesterol-lowering effect in BRL-3A by affecting the AMPK/SREBP-1c/PPARγ pathway.

« Previous Next »
Graphical Abstract

[1]
Naheed, M.; Green, B. Focus on clozapine. Curr. Med. Res. Opin., 2001, 17(3), 223-229.
[http://dx.doi.org/10.1185/03007990152673864] [PMID: 11900316]
[2]
Stille, G.; Lauener, H.; Eichenberger, E. The pharmacology of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine (clozapine). Farmaco, Prat., 1971, 26(10), 603-625.
[PMID: 5157543]
[3]
Cheine, M.V.; Wahlbeck, K.; Rimón, M. Pharmacological treatment of schizophrenia resistant to first-line treatment: a critical systematic review and meta-analysis. Int. J. Psychiatry Clin. Pract., 1999, 3(3), 159-169.
[http://dx.doi.org/10.3109/13651509909022729] [PMID: 24927201]
[4]
Lieberman, J.A.; Phillips, M.; Gu, H.; Stroup, S.; Zhang, P.; Kong, L.; Ji, Z.; Koch, G.; Hamer, R.M. Atypical and conventional antipsy-chotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology, 2003, 28(5), 995-1003.
[http://dx.doi.org/10.1038/sj.npp.1300157] [PMID: 12700715]
[5]
Meltzer, H.Y. Update on typical and atypical antipsychotic drugs. Annu. Rev. Med., 2013, 64(1), 393-406.
[http://dx.doi.org/10.1146/annurev-med-050911-161504] [PMID: 23020880]
[6]
Howes, O.D.; McCutcheon, R.; Agid, O.; de Bartolomeis, A.; van Beveren, N.J.M.; Birnbaum, M.L.; Bloomfield, M.A.P.; Bressan, R.A.; Buchanan, R.W.; Carpenter, W.T.; Castle, D.J.; Citrome, L.; Daskalakis, Z.J.; Davidson, M.; Drake, R.J.; Dursun, S.; Ebdrup, B.H.; Elkis, H.; Falkai, P.; Fleischacker, W.W.; Gadelha, A.; Gaughran, F.; Glenthøj, B.Y.; Graff-Guerrero, A.; Hallak, J.E.C.; Honer, W.G.; Kennedy, J.; Kinon, B.J.; Lawrie, S.M.; Lee, J.; Leweke, F.M.; MacCabe, J.H.; McNabb, C.B.; Meltzer, H.; Möller, H.J.; Nakajima, S.; Pantelis, C.; Reis Marques, T.; Remington, G.; Rossell, S.L.; Russell, B.R.; Siu, C.O.; Suzuki, T.; Sommer, I.E.; Taylor, D.; Thomas, N.; Üçok, A.; Umbricht, D.; Walters, J.T.R.; Kane, J.; Correll, C.U. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am. J. Psychiatry, 2017, 174(3), 216-229.
[http://dx.doi.org/10.1176/appi.ajp.2016.16050503] [PMID: 27919182]
[7]
Okhuijsen-Pfeifer, C.; Huijsman, E.A.H.; Hasan, A.; Sommer, I.E.C.; Leucht, S.; Kahn, R.S.; Luykx, J.J. Clozapine as a first- or second-line treatment in schizophrenia: a systematic review and meta-analysis. Acta Psychiatr. Scand., 2018, 138(4), 281-288.
[http://dx.doi.org/10.1111/acps.12954] [PMID: 30218445]
[8]
Flanagan, R. Side effects of clozapine and some other psychoactive drugs. Curr. Drug Saf., 2008, 3(2), 115-122.
[http://dx.doi.org/10.2174/157488608784529251] [PMID: 18690989]
[9]
Hodge, K.; Jespersen, S. Side-effects and treatment with clozapine: A comparison between the views of consumers and their clinicians. Int. J. Ment. Health Nurs., 2008, 17(1), 2-8.
[http://dx.doi.org/10.1111/j.1447-0349.2007.00506.x] [PMID: 18211398]
[10]
De Hert, M.; Detraux, J.; van Winkel, R.; Yu, W.; Correll, C.U. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat. Rev. Endocrinol., 2012, 8(2), 114-126.
[http://dx.doi.org/10.1038/nrendo.2011.156] [PMID: 22009159]
[11]
Vancampfort, D.; Stubbs, B.; Mitchell, A.J.; De Hert, M.; Wampers, M.; Ward, P.B.; Rosenbaum, S.; Correll, C.U. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry, 2015, 14(3), 339-347.
[http://dx.doi.org/10.1002/wps.20252] [PMID: 26407790]
[12]
Xu, H.; Zhuang, X. Atypical antipsychotics-induced metabolic syndrome and nonalcoholic fatty liver disease: a critical review. Neuropsychiatr. Dis. Treat., 2019, 15, 2087-2099.
[http://dx.doi.org/10.2147/NDT.S208061] [PMID: 31413575]
[13]
Mitchell, A.J.; Vancampfort, D.; Sweers, K.; van Winkel, R.; Yu, W.; De Hert, M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr. Bull., 2013, 39(2), 306-318.
[http://dx.doi.org/10.1093/schbul/sbr148] [PMID: 22207632]
[14]
Galassi, A.; Reynolds, K.; He, J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am. J. Med., 2006, 119(10), 812-819.
[http://dx.doi.org/10.1016/j.amjmed.2006.02.031] [PMID: 17000207]
[15]
Gami, A.S.; Witt, B.J.; Howard, D.E.; Erwin, P.J.; Gami, L.A.; Somers, V.K.; Montori, V.M. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J. Am. Coll. Cardiol., 2007, 49(4), 403-414.
[http://dx.doi.org/10.1016/j.jacc.2006.09.032] [PMID: 17258085]
[16]
Mottillo, S.; Filion, K.B.; Genest, J.; Joseph, L.; Pilote, L.; Poirier, P. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J. Am. Coll. Cardiol., 2010, 56(14), 1113-1132.
[17]
Maayan, L.; Vakhrusheva, J.; Correll, C.U. Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Neuropsychopharmacology, 2010, 35(7), 1520-1530.
[http://dx.doi.org/10.1038/npp.2010.21] [PMID: 20336059]
[18]
Baptista, T.; ElFakih, Y.; Uzcátegui, E.; Sandia, I.; Tálamo, E.; Araujo de Baptista, E.; Beaulieu, S. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs, 2008, 22(6), 477-495.
[http://dx.doi.org/10.2165/00023210-200822060-00003] [PMID: 18484791]
[19]
Zheng, W.; Xiang, Y.T.; Xiang, Y.Q.; Li, X.B.; Ungvari, G.S.; Chiu, H.F.K.; Correll, C.U. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr. Scand., 2016, 134(5), 385-398.
[http://dx.doi.org/10.1111/acps.12631] [PMID: 27585549]
[20]
Wang, Y.L.; Wang, Z.J.; Shen, H.L.; Yin, M.; Tang, K.X. Effects of artesunate and ursolic acid on hyperlipidemia and its complications in rabbit. Eur. J. Pharm. Sci., 2013, 50(3-4), 366-371.
[http://dx.doi.org/10.1016/j.ejps.2013.08.003] [PMID: 23954455]
[21]
Yuliang, W.; Zejian, W.; Hanlin, S.; Ming, Y.; Kexuan, T. The hypolipidemic effect of artesunate and ursolic acid in rats. Pak. J. Pharm. Sci., 2015, 28(3), 871-874.
[PMID: 26004719]
[22]
Jang, B.C. Artesunate inhibits adipogeneis in 3T3-L1 preadipocytes by reducing the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3. Biochem. Biophys. Res. Commun., 2016, 474(1), 220-225.
[http://dx.doi.org/10.1016/j.bbrc.2016.04.109] [PMID: 27109481]
[23]
Li, Y.; Su, R.; Xu, S.; Huang, Q.; Xu, H. Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides. Neuropsychiatr. Dis. Treat., 2017, 13, 2477-2487.
[http://dx.doi.org/10.2147/NDT.S145069] [PMID: 29026311]
[24]
Mondola, P.; Santillo, M.; Santangelo, F.; Caporale, C.; Belfiore, A.; Bifulco, M. Purification and characterization of a calf thymus protein active on lipid metabolism. Int. J. Biochem., 1989, 21(9), 1009-1014.
[http://dx.doi.org/10.1016/0020-711X(89)90233-4]
[25]
Mondola, P.; Santillo, M.; De Mercato, R.; Santangelo, F. The effect of l-Carnitine on cholesterol metabolism in rat (Rattus bubalus) hepatocyte cells. Int. J. Biochem., 1992, 24(7), 1047-1050.
[http://dx.doi.org/10.1016/0020-711X(92)90372-8] [PMID: 1397497]
[26]
Giudetti, A.M.; Damiano, F.; Gnoni, G.V.; Siculella, L. Low level of hydrogen peroxide induces lipid synthesis in BRL-3A cells through a CAP-independent SREBP-1a activation. Int. J. Biochem. Cell Biol., 2013, 45(7), 1419-1426.
[http://dx.doi.org/10.1016/j.biocel.2013.04.004] [PMID: 23583293]
[27]
Zhao, X.J.; Yu, H.W.; Yang, Y.Z.; Wu, W.Y.; Chen, T.Y.; Jia, K.K.; Kang, L.L.; Jiao, R.Q.; Kong, L.D. Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway. Redox Biol., 2018, 18, 124-137.
[http://dx.doi.org/10.1016/j.redox.2018.07.002] [PMID: 30014902]
[28]
Li, L.; He, M.; Xiao, H.; Liu, X.; Wang, K.; Zhang, Y. Acetic acid influences BRL-3A cell lipid metabolism via the AMPK signalling pathway. Cell. Physiol. Biochem., 2018, 45(5), 2021-2030.
[http://dx.doi.org/10.1159/000487980] [PMID: 29529605]
[29]
Chen, F.; Zhou, Y.; Yang, K.; Shen, M.; Wang, Y. NPY stimulates cholesterol synthesis acutely by activating the SREBP2-HMGCR pathway through the Y1 and Y5 receptors in murine hepatocytes. Life Sci., 2020, 262, 118478.
[http://dx.doi.org/10.1016/j.lfs.2020.118478] [PMID: 32976883]
[30]
Lauressergues, E.; Staels, B.; Valeille, K.; Majd, Z.; Hum, D.W.; Duriez, P.; Cussac, D. Antipsychotic drug action on SREBPs-related lipogenesis and cholesterogenesis in primary rat hepatocytes. Naunyn Schmiedebergs Arch. Pharmacol., 2010, 381(5), 427-439.
[http://dx.doi.org/10.1007/s00210-010-0499-4] [PMID: 20333360]
[31]
Park, K.G.; Min, A.K.; Koh, E.H.; Kim, H.S.; Kim, M.O.; Park, H.S. Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK- independent pathways. Hepatology, 2008, 48(5), 1477-1486.
[32]
Ruderman, N.; Prentki, M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat. Rev. Drug Discov., 2004, 3(4), 340-351.
[http://dx.doi.org/10.1038/nrd1344] [PMID: 15060529]
[33]
Viollet, B.; Foretz, M.; Guigas, B.; Horman, S.; Dentin, R.; Bertrand, L.; Hue, L.; Andreelli, F. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J. Physiol., 2006, 574(1), 41-53.
[http://dx.doi.org/10.1113/jphysiol.2006.108506] [PMID: 16644802]
[34]
Ferré, P.; Azzout-Marniche, D.; Foufelle, F. AMP-activated protein kinase and hepatic genes involved in glucose metabolism. Biochem. Soc. Trans., 2003, 31(1), 220-223.
[http://dx.doi.org/10.1042/bst0310220] [PMID: 12546689]
[35]
Rutter, G.A.; da SILVA XAVIER, G.; Leclerc, I. Roles of 5′-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem. J., 2003, 375(1), 1-16.
[http://dx.doi.org/10.1042/bj20030048] [PMID: 12839490]
[36]
Donnelly, K.L.; Smith, C.I.; Schwarzenberg, S.J.; Jessurun, J.; Boldt, M.D.; Parks, E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest., 2005, 115(5), 1343-1351.
[http://dx.doi.org/10.1172/JCI23621] [PMID: 15864352]
[37]
Alphonse, P.A.S.; Jones, P.J.H. Revisiting human cholesterol synthesis and absorption: the reciprocity paradigm and its key regulators. Lipids, 2016, 51(5), 519-536.
[http://dx.doi.org/10.1007/s11745-015-4096-7] [PMID: 26620375]
[38]
Adebayo, J.O.; Igunnu, A.; Arise, R.O.; Malomo, S.O. Effects of co- administration of artesunate and amodiaquine on some cardiovascular disease indices in rats. Food Chem. Toxicol., 2011, 49(1), 45-48.
[39]
Obianime, A.W.; Aprioku, S.J. Comparative study of artesunate, ACTs and their combinants on the spermatic parameters of the male guinea pig. Niger. J. Physiol. Sci., 2009, 24(1), 1-6.
[http://dx.doi.org/10.4314/njps.v24i1.46372] [PMID: 19826457]
[40]
Pu, S.; Liu, Y.; Liang, S.; Liu, P.; Qian, H.; Wu, Q.; Wang, Y. The metabolic changes of artesunate and ursolic acid on syrian golden hamsters fed with the high-fat diet. Molecules, 2020, 25(6), 1392.
[http://dx.doi.org/10.3390/molecules25061392] [PMID: 32197531]
[41]
Vik-Mo, A.O.; Fernø, J.; Skrede, S.; Steen, V.M. Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS- and liver cells. BMC Pharmacol., 2009, 9(1), 10.
[http://dx.doi.org/10.1186/1471-2210-9-10] [PMID: 19715613]
[42]
Meaney, S. Epigenetic regulation of cholesterol homeostasis. Front. Genet., 2014, 5, 311.
[http://dx.doi.org/10.3389/fgene.2014.00311] [PMID: 25309573]
[43]
Wei, S.; Liu, L.; Chen, Z.; Yin, W.; Liu, Y.; Ouyang, Q.; Zeng, F.; Nie, Y.; Chen, T. Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence. J. Cell. Mol. Med., 2020, 24(1), 276-284.
[http://dx.doi.org/10.1111/jcmm.14717] [PMID: 31746143]
[44]
Miettinen, T.A.; Gylling, H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large dose of statin treatment. Eur. J. Clin. Invest., 2003, 33(11), 976-982.
[http://dx.doi.org/10.1046/j.1365-2362.2003.01229.x] [PMID: 14636301]
[45]
Adams, C.M.; Goldstein, J.L.; Brown, M.S. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Proc. Natl. Acad. Sci. USA, 2003, 100(19), 10647-10652.
[http://dx.doi.org/10.1073/pnas.1534833100] [PMID: 12963821]
[46]
Berthold, H.; Laaksonen, R.; Lehtimäki, T.; Gylling, H.; Krone, W.; Gouni-Berthold, I. SREBP-1c gene polymorphism is associated with increased inhibition of cholesterol-absorption in response to ezetimibe treatment. Exp. Clin. Endocrinol. Diabetes, 2008, 116(5), 262-267.
[http://dx.doi.org/10.1055/s-2007-993144] [PMID: 18072016]
[47]
Lefebvre, P.; Chinetti, G.; Fruchart, J.C.; Staels, B. Sorting out the roles of PPAR in energy metabolism and vascular homeostasis. J. Clin. Invest., 2006, 116(3), 571-580.
[http://dx.doi.org/10.1172/JCI27989] [PMID: 16511589]
[48]
Yamashita, S.; Masuda, D.; Matsuzawa, Y. pemafibrate, a new selective pparα modulator: Drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr. Atheroscler. Rep., 2020, 22(1), 5.
[http://dx.doi.org/10.1007/s11883-020-0823-5] [PMID: 31974794]
[49]
Lapinskas, P.J.; Brown, S.; Leesnitzer, L.M.; Blanchard, S.; Swanson, C.; Cattley, R.C. Role of PPARalpha in mediating the effects of phthalates and metabolites in the liver. Toxicology, 2005, 207(1), 149-163.
[50]
Jia, Y.; Bhuiyan, M.J.H.; Jun, H.; Lee, J.H.; Hoang, M.H.; Lee, H.J.; Kim, N.; Lee, D.; Hwang, K.Y.; Hwang, B.Y.; Choi, D.W.; Lee, S.J. Ursolic acid is a PPAR-α agonist that regulates hepatic lipid metabolism. Bioorg. Med. Chem. Lett., 2011, 21(19), 5876-5880.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.095] [PMID: 21855333]
[51]
Berger, J.; Moller, D.E. The mechanisms of action of PPARs. Annu. Rev. Med., 2002, 53(1), 409-435.
[http://dx.doi.org/10.1146/annurev.med.53.082901.104018] [PMID: 11818483]
[52]
Boitier, E.; Gautier, J.C.; Roberts, R. Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease. Comp. Hepatol., 2003, 2(1), 3.
[http://dx.doi.org/10.1186/1476-5926-2-3] [PMID: 12622871]
[53]
Yahaghi, L.; Yaghmaei, P.; Hayati-Roodbari, N.; Irani, S.; Ebrahim-Habibi, A. Betanin effect on PPAR-α and SREBP-1c expression in NMRI mice model of steatohepatitis with fibrosis. Physiol. Int., 2020, 107(1), 67-81.
[http://dx.doi.org/10.1556/2060.2020.00001] [PMID: 32491288]
[54]
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108(8), 1167-1174.
[http://dx.doi.org/10.1172/JCI13505] [PMID: 11602624]
[55]
You, M.; Matsumoto, M.; Pacold, C.M.; Cho, W.K.; Crabb, D.W. The role of AMP-activated protein kinase in the action of ethanol in the liver. Gastroenterology, 2004, 127(6), 1798-1808.
[http://dx.doi.org/10.1053/j.gastro.2004.09.049] [PMID: 15578517]
[56]
Foretz, M.; Ancellin, N.; Andreelli, F.; Saintillan, Y.; Grondin, P.; Kahn, A.; Thorens, B.; Vaulont, S.; Viollet, B. Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes, 2005, 54(5), 1331-1339.
[http://dx.doi.org/10.2337/diabetes.54.5.1331] [PMID: 15855317]
[57]
Yang, J.; Craddock, L.; Hong, S.; Liu, Z.M. AMP-activated protein kinase suppresses LXR-dependent sterol regulatory element-binding protein-1c transcription in rat hepatoma McA-RH7777 cells. J. Cell. Biochem., 2009, 106(3), 414-426.
[http://dx.doi.org/10.1002/jcb.22024] [PMID: 19125418]
[58]
Li, Y.; Xu, S.; Mihaylova, M.M.; Zheng, B.; Hou, X.; Jiang, B.; Park, O.; Luo, Z.; Lefai, E.; Shyy, J.Y.J.; Gao, B.; Wierzbicki, M.; Verbeuren, T.J.; Shaw, R.J.; Cohen, R.A.; Zang, M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab., 2011, 13(4), 376-388.
[http://dx.doi.org/10.1016/j.cmet.2011.03.009] [PMID: 21459323]
[59]
Jung, M.; Lee, J.H.; Lee, C.; Park, J.H.; Park, Y.R.; Moon, K.C. Prognostic implication of pAMPK immunohistochemical staining by subcellular location and its association with SMAD protein expression in clear cell renal cell carcinoma. Cancers (Basel), 2019, 11(10), 1602.
[http://dx.doi.org/10.3390/cancers11101602] [PMID: 31640193]
[60]
Yin, S.; Yang, H.; Zhao, X.; Wei, S.; Tao, Y.; Liu, M.; Bo, R.; Li, J. Antimalarial agent artesunate induces G0/G1 cell cycle arrest and apoptosis via increasing intracellular ROS levels in normal liver cells. Hum. Exp. Toxicol., 2020, 39(12), 1681-1689.
[http://dx.doi.org/10.1177/0960327120937331] [PMID: 32633561]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy