Crocin lessens desipramine-induced phospholipidosis biomarker levels via targeting oxidative stress- related PI3K/Akt/mTOR signaling pathways in the rat liver. Crocin modulating effect in phospholipidosis

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Amal Ahmed El-Sheikh
Heba A. Mahmoud
Eman Ali El-Kordy
Amal M. Abdelsattar
Fatma H. Rizk
Radwa Mahmoud El-Sharaby
Shimaa S. Mashal
Amira A. EL Saadany
Rania H. Shalaby
Amira M. Elshamy
Omnia Safwat El-deeb
Rowida Raafat Ibrahim
Hoda A. Ibrahim


Phospholipidosis, desipramine, crocin, oxidative stress, apoptosis


Background and aim Crocin is a pharmacologically active chemical found in the spice saffron from Crocus sativus L. It possesses antioxidant and anti-radical properties that can minimize the hepatic phospholipidosis triggered using the tricyclic antidepressant desipramine. The aim of this study was to examine the effect of crocin on desipramine-induced hepatic phospholipidosis targeting the oxidative stress-related PI3K/Akt/mTOR signaling pathways.

Methods: Forty adult male rats were divided into 4 groups (n =10): control group, a group receiving intraperitoneal (IP) crocin (50 mg/kg/day), a group receiving IP desipramine (10 mg/kg/day), and a group receiving both IP crocin and desipramine.

Results: After 3 weeks of treatment, the combined treatment group showed diminished desipramine-induced hepatic phospholipidosis, along with significant reductions in total oxidant status (TOS) , the levels of inflammatory markers including interleukin 6 (IL6) and tumor necrosis factor α (TNF-α) and apoptotic markers including caspase3 and Bcl2 (B-cell lymphoma 2) while other markers including total antioxidant capacity (TAC), superoxide dismutase (SOD), phosphoinositide 3-kinases (PI3K), and mammalian target of rapamycin (mTOR) were increased. The gene expression of lysosomal enzymes including ELOVL6, SCD1 and HMGR was notably downregulated, while AP1S1 was upregulated in the combined treatment group compared to the desipramine group. No ultrastructural signs of hepatic phospholipidosis, in the form of multilamellar bodies, were apparent in the combined treatment group.

Conclusions: These data collectively suggest that crocin has a protective effect against desipramine-induced phospholipidosis. (


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1. Kaplowitz N. Drug-induced liver injury. Clin Infect Dis 2004;38:S44–48. doi: 10.1086/381446.
2. Shahane SA, Huang R, Gerhold D, et al. Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format. J Biomol Screen 2014;19:66–76. doi: 10.1177/1087057113502851.
3. Xia Z, Ying G, Hansson A.L, et al. Antidepressant-induced lipidosis with special reference to tricyclic compounds. Prog Neurobiol 2000 Apr;60(6):501–12. doi: 10.1016/s0301-0082(99)00036-2.
4. Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013;93:402–408. doi: 10.1038/clpt.2013.2.
5. Vukotić NT, Đorđević J, Pejić S, et al. Antidepressants- and antipsychotics-induced hepatotoxicity. Arch Toxicol 2021 Mar;95(3):767-789. doi: 10.1007/s00204-020-02963-4.
6. Lucena, MI, Carvajal A, Andrade RJ, et al. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003;2:249–262. doi: 10.1517/14740338.2.3.249.
7. Boehm M, Bonifacino JS. Adaptins. The final recount. Mol Biol Cell 2001;12:2907–2920. doi: 10.1091/mbc.12.10.2907.
8. Sorkin A. Cargo recognition during clathrin-mediated endocytosis: a team effort. Curr Opin Cell Biol 2004;16:392–399. doi: 10.1016/
9. Newell-Litwa K, Seong E, Burmeister M, et al. Neuronal and non-neuronal functions of the AP-3 sorting machinery. J Cell Sci 2007;120:531–541. doi: 10.1242/jcs.03365.
10. Peláez R, Pariente A, Pérez-Sala Á, et al. Sterculic acid: the mechanisms of action beyond stearoyl-coA desaturase inhibition and therapeutic opportunities in human diseases. Cells 2020;9:140. doi: 10.3390/cells9010140.
11. Corominas J, Ramayo-Caldas Y, Puig-Oliveras A, et al. Polymorphism in the ELOVL6 gene is associated with a major QTL effect on fatty acid composition in pigs. PLoS One 2013;8:e53687. doi: 10.1371/journal.pone.0053687.
12. Knebel B, Haas J, Hartwig S, et al. Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PLoS One 2012;7:e31812. doi: 10.1371/journal.pone.0031812.
13. Matsuzaka T, Shimano H, Yahagi N, et al. Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs. J Lipid Res 2002;43:911–920. PMID: 12032166.
14. Thelen AM, Zoncu R. Emerging roles for the lysosome in lipid metabolism. Trends Cell Biol 2017;27:833–850. doi: 10.1016/j.tcb.2017.07.006.
15. Escribano J, Alonso GL, Coca-Prados M, et al. Crocin, safranal and picrocrocin from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer Lett 1996;100,23–30. doi: 10.1016/0304-3835(95)04067-6.
16. Luo L, Fang K, Dan X, et al. Crocin ameliorates hepatic steatosis through activation of AMPK signaling in db/db mice. Lipids Health Dis 2019;18:11. doi: 10.1186/s12944-018-0955-6.
17. Razavi BM, Hosseinzadeh H, Abnous K, et al. Protective effect of crocin on diazinon induced vascular toxicity in subchronic exposure in rat aorta ex-vivo. Drug Chem Toxicol 2014;37:378–383. doi: 10.3109/01480545.2013.866139.
18. Kozisek ME, Deupree JD, Burke WJ, et al. Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies. J Neurosci Methods 2007;163: 83–91. doi: 10.1016/j.jneumeth.2007.02.015.
19. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248–254. doi: 10.1006/abio.1976.9999.
20. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103–1111. doi: 10.1016/j.clinbiochem.2005.08.008.
21. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37:277–285. doi: 10.1016/j.clinbiochem.2003.11.015.
22. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402–408. doi: 10.1006/meth.2001.1262.
23. Kuo J. Electron Microscopy: Methods and Protocols. 2nd ed. Humana Press Inc.: Totowa, NJ, 2007.
24. Halliwell WH. Cationic amphiphilic drug-induced phospholipidosis. Toxicol Pathol 1997;25:53–60. doi: 10.1177/019262339702500111.
25. Breiden B, Sandhoff K. Emerging mechanisms of drug-induced phospholipidosis. Biol Chem 2019;401:31–46. doi: 10.1515/hsz-2019-0270. Erratum in: Biol Chem. 2021 Oct 27, 403(2), 251.
26. Schulze H, Kolter T, Sandhoff K. Principles of lysosomal membrane degradation: Cellular topology and biochemistry of lysosomal lipid degradation. Biochim Biophys Acta 2009;1793: 674–683. doi: 10.1016/j.bbamcr.2008.09.020.
27. Stäubli W, Schweizer W, Suter J. Some properties of myeloid bodies induced in rat liver by an antidepressant drug (maprotiline). Exp Mol Pathol 1978;28:177–195. doi: 10.1016/0014-4800(78)90050-3.
28. Bockhardt H, Lüllmann-Rauch R. Zimelidine-induced lipidosis in rats. Acta Pharmacol Toxicol 1980;47:45–48. doi: 10.1111/j.1600-0773.1980.tb02023.x.
29. Lüllmann-Rauch R, Nässberger L. Citalopram-induced generalized lipidosis in rats. Acta Pharmacol Toxicol 1983;52:161–167. doi: 10.1111/j.1600-0773.1983.tb01080.x.
30. Chen J, Bai L, He Y. A possible case of carbamazepine-induced renal phospholipidosis mimicking Fabry disease. Clin Exp Nephrol 2022;26:303–304. doi: 10.1007/s10157-021-02172-y.
31. Hinkovska-Galcheva, V, Treadwell T, Shillingford JM, et al. Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis. J Lipid Res 2021;62:100089. doi: 10.1016/j.jlr.2021.100089.
32. Sawada H, Takami K, Asahi S. A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci 2005;83:282–292. doi: 10.1093/toxsci/kfh264.
33. Matsuzaka T, Kuba M, Koyasu S, et al. Hepatocyte ELOVL fatty acid elongase 6 determines ceramide acyl-chain length and hepatic insulin sensitivity in mice. Hepatology 2020;71:1609–1625. doi: 10.1002/hep.30953.
34. Matsuzaka T. Role of fatty acid elongase Elovl6 in the regulation of energy metabolism and pathophysiological significance in diabetes. Diabetol Int 2020;12:68–73. doi: 10.1007/s13340-020-00481-3.
35. Rodriguez-Cuenca S, Whyte L, Hagen R, et al. Stearoyl-CoA desaturase 1 is a key determinant of membrane lipid composition in 3t3-l1 adipocytes. PLoS One 2016;11:e0162047. doi: 10.1371/journal.pone.0162047.
36. Datta S, Wang L, Moore DD, et al. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase promoter by nuclear receptors liver receptor homologue-1 and small heterodimer partner: a mechanism for differential regulation of cholesterol synthesis and uptake. J Biol Chem 2006;281:807–812. doi: 10.1074/jbc.M511050200.
37. Wang T, Zhao Y, You Z, et al. Endoplasmic reticulum stress affects cholesterol homeostasis by inhibiting LXRα expression in hepatocytes and macrophages. Nutrients 2020;12:3088. doi: 10.3390/nu12103088.
38. DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother 2007;41:1201–12,11. doi: 10.1345/aph.1K114.
39. Voican CS, Corruble E, Naveau S, et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014;171:404–415. doi: 0.1176/appi.ajp.2013.13050709.
40. Ye H, Nelson LJ, Gómez Del Moral M, et al. Dissecting the molecular pathophysiology of drug-induced liver injury. World J Gastroenterol 2018;24:1373–1385. doi: 10.3748/wjg.v24.i13.1373.
41. Ohkuma S, Poole B. Cytoplasmic vacuolation of mouse peritoneal macrophages and the uptake into lysosomes of weakly basic substances. J Cell Biol 1981;90:656–664. doi: 10.1083/jcb.90.3.656.
42. Morissette G, Moreau E, C-Gaudreault R, et al. Massive cell vacuolization induced by organic amines such as procainamide. J Pharmacol Exp Ther 2004;310:395–406. doi: 10.1124/jpet.104.066084.
43. Trump BF, Goldblatt PJ, Stowell RE. Studies of mouse liver necrosis in vitro. Ultrastructural and cytochemical alterations in hepatic parenchymal cell nuclei. Lab Invest 1965;14:1969–1999. PMID: 5854188.
44. Czaja MJ, Ding WX, Donohue TM, et al. Functions of autophagy in normal and diseased liver. Autophagy 2013;9:1131–1158. doi: 10.4161/auto.25063.
45. Anderson N, Borlak J. Drug-induced phospholipidosis. FEBS Lett 2006;580:5533–5540. doi: 10.1016/j.febslet.2006.08.061.
46. Arimochi H, Morita K. Desipramine induces apoptotic cell death through nonmitochondrial and mitochondrial pathways in different types of human colon carcinoma cells. Pharmacology 2008; 81:164–172. doi: 10.1159/000111144.
47. Ríos-Arrabal S, Artacho-Cordón F, León J. et al. Involvement of free radicals in breast cancer. Springerplus 2013;2:404. doi: 10.1186/2193-1801-2-404.
48. Estaquier J, Vallette F, Vayssiere JL, et al. The mitochondrial pathways of apoptosis. Adv Exp Med Biol 2012;942:157–183. doi: 10.1007/978-94-007-2869-1_7.
49. Yang DK, Kim SJ. Desipramine induces apoptosis in hepatocellular carcinoma cells. Oncol Rep. 2017;38:1029–1034. doi: 10.3892/or.2017.5723.
50. Huang YY, Peng CH, Yang YP, et al. Desipramine activated Bcl-2 expression and inhibited lipopolysaccharide-induced apoptosis in hippocampus-derived adult neural stem cells. J Pharmacol Sci 2007;104:61–72. doi: 10.1254/jphs.fp0061255.
51. Vejux A, Guyot S, Montange T, et al. Phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway are vitamin E inhibitable events associated with 7-ketocholesterol-induced apoptosis. J Nutr Biochem 2009;20:45–61. doi: 10.1016/j.jnutbio.2007.12.001.
52. Feng FB, Qiu HY. Effects of Artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/Akt/mTOR signaling pathway in rat models with rheumatoid arthritis. Biomed Pharmacother 2018;102:1209–1220. doi: 10.1016/j.biopha.2018.03.142.
53. Assimopoulou AN, Sinakos Z, Papageorgiou VP. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res 2005;19:997–1000. doi: 10.1002/ptr.1749.
54. Nam KN, Park YM, Jung HJ, et al. Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. Eur J Pharmacol 2010;648:110–116. doi: 10.1016/j.ejphar.2010.09.003.
55. Amin A, Bajbouj K, Koch A, et al. Defective autophagosome formation in p53-null colorectal cancer reinforces crocin-induced apoptosis. Int J Mol Sci 2015;16:1544–1561. doi: 10.3390/ijms16011544.
56. Lee IA, Lee JH, Baek NI, et al. Antihyperlipidemic effect of crocin isolated from the fructus of Gardenia jasminoides and its metabolite Crocetin. Biol Pharm Bull 2005;28:2106–2110. doi: 10.1248/bpb.28.2106.
57. Behrouz V, Dastkhosh A, Hedayati M, et al. The effect of crocin supplementation on glycemic control, insulin resistance and active AMPK levels in patients with type 2 diabetes: a pilot study. Diabetol Metab Syndr 2020;12:59. doi: 10.1186/s13098-020-00568-6.
58. El-Beshbishy HA, Hassan MH, Aly HA, et al. Crocin "saffron" protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes. Ecotoxicol Environ Saf 2012;83:47–54. doi: 10.1016/j.ecoenv.2012.06.003.
59. Mozaffari S, Ramezany Yasuj S, Motaghinejad M, et al. Crocin acting as a neuroprotective agent against methamphetamine-induced neurodegeneration via CREB-BDNF signaling pathway. Iran J Pharm Res 2019;18:745–758. doi: 10.22037/ijpr.2019.2393.
60. Salahshoor MR, Khashiadeh M, Roshankhah S, et al. Protective effect of crocin on liver toxicity induced by morphine. Res Pharm Sci 2016(11):120–129.
61. Pilichos C, Preza A, Kounavis I, et al. Fine structural alterations induced by cortisol administration in non-adrenalectomized/non-fasted rat hepatocytes. Int Immunopharmacol 2005;5:93–96. doi: 10.1016/j.intimp.2004.09.004.
62. Razavi BM, Hosseinzadeh H, Movassaghi AR, et al. Protective effect of crocin on diazinon induced cardiotoxicity in rats in subchronic exposure. Chem Biol Interact 2013;203:547–555. doi: 10.1016/j.cbi.2013.03.010.
63. Mehri S, Abnous K, Mousavi SH, et al. Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 2012;32:227–235. doi: 10.1007/s10571-011-9752-8.
64. Hosseinzadeh H, Shamsaie F, Mehri S. Antioxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituents, crocin and safranal. Pharmacogn Mag 2009;5:419–424. Corpus ID: 94582248.
65. Xu GL, Yu SQ, Gong ZN, et al. Study of the effect of crocin on rat experimental hyperlipemia and the underlying mechanisms. Zhongguo Zhong Yao Za Zhi 2005;30:369–372. Chinese. PMID: 15806972.
66. Vahdati Hassani F, Mehri S, Abnous K, et al. Protective effect of crocin on BPA-induced liver toxicity in rats through inhibition of oxidative stress and downregulation of MAPK and MAPKAP signaling pathway and miRNA-122 expression. Food Chem Toxicol 2017;107:395–405. doi: 10.1016/j.fct.2017.07.007.
67. Kim EK, Choi EJ. Compromised MAPK signaling in human diseases: an update. Arch Toxicol 2015;89:867–882. doi: 10.1007/s00204-015-1472-2.
68. Esau C, Davis S, Murray SF, et al. MiR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006;3:87–98. doi: 10.1016/j.cmet.2006.01.005.
69. Li K, Li Y, Ma Z, et al. Crocin exerts anti-inflammatory and anti-catabolic effects on rat intervertebral discs by suppressing the activation of JNK. Int J Mol Med. 2015 Nov;36(5):1291-9. DOI: 10.3892/ijmm.2015.2359
70. Qi Y, Chen L, Zhang L, et al. Crocin prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/Akt signalling pathway. Exp Eye Res 2013;107:44–51. doi: 10.1016/j.exer.2012.11.011.
71. Salama RM, Abdel-Latif GA, Abbas SS, et al. Neuroprotective effect of crocin against rotenone-induced Parkinson's disease in rats: Interplay between PI3K/Akt signaling pathway and enhanced expression of miRNA-7 and miRNA-221. Neuropharmacology 2020;164:107900. doi: 10.1016/j.neuropharm.2019.107900.

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