Liver Protection of Hydroxytyrosol Mediated by Spexin and TRPM2

Abstract

Background/Aim: In the study, the role of Spexin (SPX) and TRPM2 in the protective effect of Hydroxytyrosol (HT) in rats given Corn Syrup was evaluated. Material and Method: The rats were divided into 4 groups (6 rats in each) (Control, HT, Corn Syrup, Corn Syrup +HT). Rats were given 30% Corn Syrup with drinking water for 6 weeks. 4 ml/kg/day liquid containing HT was applied by oral gavage alone and together with Corn Syrup for 6 weeks. Molecular parameters SPX and TRPM2 were examined histopathologically in liver tissue. Results: The SPX levels decreased and the TRPM2 levels increased more in the Corn Syrup given Group than the Control Group. SPX levels increased and TRPM2 levels decreased after HT treatment. In the HT Group only, no differences were detected when compared to the control Group. Conclusion: SPX and TRPM2 may mediate the protective effect of HT on the liver in rats given corn syrup.

Keywords

• Corn Syrup
• Hydroxytyrosol
• Spexin
• TRPM2

Spexin ve TRPM2'nin Aracılık Ettiği Hidroksitirozolün Karaciğer Koruması

Abstract

Amaç: Araştırmada Mısır Şurubu verilen sıçanlarda Hidroksitirozol (HT)'ün koruyucu etkisinde Spexin (SPX) ve TRPM2'nin rolü değerlendirildi. Gereç ve Yöntem: Sıçanlar 4 gruba (her grupta 6 sıçan) ayrıldı (Kontrol, HT, Mısır Şurubu, Mısır Şurubu +HT). Sıçanlara 6 hafta süreyle %30'luk Mısır Şurubu içme suyuyla birlikte verildi. HT içeren 4 ml/kg/gün sıvı, tek başına ve Mısır Şurubu ile birlikte 6 hafta süreyle oral gavajla uygulandı. Karaciğer dokusunda SPX ve TRPM2 moleküler parametreleri histopatolojik olarak incelendi. Bulgular: Mısır Şurubu verilen grupta SPX seviyeleri azaldı ve TRPM2 seviyeleri kontrol grubuna göre daha fazla arttı. HT tedavisinden sonra SPX seviyeleri arttı, TRPM2 seviyeleri ise azaldı. Yalnızca HT grubunda kontrol grubuyla karşılaştırıldığında herhangi bir farklılık tespit edilmedi. Sonuç: SPX ve TRPM2, mısır şurubu verilen sıçanlarda HT'nin karaciğer üzerindeki koruyucu etkisine aracılık edebilir.

Keywords

• Mısır Şurubu
• Hidroksitirosol
• Spexin
• TRPM2

References

1. 1. Febbraio MA, Karin M. “Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab 2021;33(12):2316–28.
2. 2. Jung S, Bae H, Song WS, Jang C. Dietary Fructose and Fructose-Induced Pathologies. Annu Rev Nutr 2022;42:45–66.
3. 3. Cicerale S, Lucas LJ, Keast RS. Antimicrobial, antioxidant and antiinflammatory phenolic activities in extra virgin olive oil. Curr Opin Biotechnol 2012;23:129–35.
4. 4. Vilaplana-Pérez C, Auñón D, García-Flores LA, Gil-Izquierdo A. Hydroxytyrosol and potential uses in cardiovascular diseases, cancer, and AIDS. Front Nutr 2014;27:1–18.
5. 5. Catalán U, López de Las Hazas MC, Rubió L et al. Protective effect of hydroxytyrosol and its predominant plasmatic human metabolites against endothelial dysfunction in human aortic endothelial cells. Mol Nutr Food Res 2015;59:2523–36.
6. 6. Cao K, Xu J, Zou X et al. Hydroxytyrosol prevents diet-induced metabolic syndrome and attenuates mitochondrial abnormalities in obese mice. Free Radic Biol Med 2014;67:396–407.
7. 7. Scoditti E, Nestola A, Massaro M et al. Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCα and PKCβ1 inhibition. Atherosclerosis 2014;232:17–24.
8. 8. Türkel İ, Memi G, Yazgan B. Impact of spexin on metabolic diseases and inflammation: An updated minireview. Experimental Biology and Medicine 2022;247:567–73.

9. 9. Zhang Z, Tóth B, Szollosi A, Chen J, Csanády L. Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation. eLife 2018;7:e36409.
10. 10. Hasan R, Zhang X. Ca2+ regulation of TRP ion channels. Int J Mol Sci 2018;19(4):1256.
11. 11. Sumoza-Toledo A, Penner R. TRPM2: A multifunctional ion channel for calcium signaling. J Physiol 2011;589:1515–25.
12. 12. Nagamine K, Kudoh J, Minoshima S et al. Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 1998;5:124–31.
13. 13. Hara Y, Wakamori M, Ishii M et al. LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 2002;9:163–73.
14. 14. Zhang W, Hirschler-Laszkiewicz I, Tong Q et al. TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage. Am J Physiol Cell Physiol 2006;290:C1146–C1159.
15. 15.Gün A, Özer MK, Bilgiç S, Kocaman N, Ozan G. Effect of Caffeic Acid Phenethyl Ester on Vascular Damage Caused by Consumption of High Fructose Corn Syrup in Rat. Oxid Med Cell Longev 2016; 2016:3419479.
16. 16. Kocaman N, Artas G. Can novel adipokines, asprosin and meteorin-like, be biomarkers for malignant mesothelioma? Biotech Histochem 2020;95:171-5.
17. 17. Mirabeau O, Perlas E, Severini C et al. Identification of novel peptide hormones in the human proteome by hidden Markov model screening. Genome Res 2007;17:320–7.
18. 18. Kolodziejski PA, Leciejewska N, Chmurzynska A et al. 30-Day spexin treatment of mice with diet-induced obesity (DIO) and type 2 diabetes (T2DM) increases insulin sensitivity, improves liver functions and metabolic status. Mol Cell Endocrinol 2021;536:111420.
19. 19. Ge JF, Walewski JL, Anglade D, Berk PD. Regulation of hepatocellular fatty acid uptake in mouse models of fatty liver disease with and without functional leptin signaling: roles of NfKB and SREBP-1C and the effects of spexin. Semin Liver Dis 2016;36:360–72.
20. 20. Walewski JL, Ge F, Lobdell H et al. Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity. Obesity 2014;22:1643–52.
21. 21. Behrooz M, Vaghef-Mehrabany E, Ostadrahimi A. Different spexin level in obese vs normal weight children and its relationship with obesity related risk factors. Nutr Metabol Cardiovasc Dis 2020;30:674–82.
22. 22. Gu L, Ding X, Wang Y et al. Spexin alleviates insulin resistance and inhibits hepatic gluconeogenesis via the FoxO1/PGC-1alpha pathway in high-fat-dietinduced rats and insulin resistant cells. Int J Biol Sci 2019;15:2815–29.
23. 23. Zhang L, Li G, She Y, Zhang Z. Low levels of spexin and adiponectin may predict insulin resistance in patients with non-alcoholic fatty liver. Pract Lab Med 2021;24:e00207.
24. 24. V Goulas, V Exarchou, A.N Troganis et al. Phytochemicals in olive-leaf extracts and their antiproliferative activity against cancer and endothelial cells. Mol Nutr Food Res 2009;53(5):600-8.
25. 25. Brown WV, Fujioka K, Wilson PWF, Woodworth KA. Obesity: why be concerned? Am J Med 2009;122:S4-11. 26. Rietjens SJ, Bast A, Haenen GRMM. New insights into controversies on the antioxidant potential of the olive oil antioxidant hydroxytyrosol. J Agric Food Chem 2007;55(18):7609-14.
26. 27. Bouallagui Z, Han J, Isoda H, Sayadi S. Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. Food Chem Toxicol 2011;49(1):179-84.
27. 28. Fki İ, Sayadi S, Mahmoudi A, Daoued İ, Marrekchi R, Ghorbe H. Comparative Study on Beneficial Effects of Hydroxytyrosol- and Oleuropein-Rich Olive Leaf Extracts on High-Fat Diet-Induced Lipid Metabolism Disturbance and Liver Injury in Rats. BioMed Research International 2020; 15:1315202.
28. 29. Valenzuela R, Echeverria F, Ortiz M et al. Hydroxytyrosol prevents reduction in liver activity of Δ-5 and Δ-6 desaturases, oxidative stress, and depletion in long chain polyunsaturated fatty acid content in different tissues of high-fat diet fed mice. Lipids in Health and Disease 2017;16:64.
29. 30. Song K, Wang H, Kamm G.B et al. The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science 2016;353:1393–98.
30. 31. Nilius B, Owsianik G, Voets T, Peters J.A. Transient Receptor Potential Cation Channels in Disease. Physiol Rev 2007;87:165–217.
31. 32. Kheradpezhouh E, Ma L, Morphett A, Barritt GJ, Rychkov GY. TRPM2 channels mediate acetaminophen-induced liver damage. Proc Natl Acad Sci USA 2014;111:3176–81.
32. 33. Malko P,Jiang LH. TRPM2 channel-mediated cell death: an important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biol 2020;37: 101755.