Abstract
Amaç: Diabetes mellitusun en önemli komplikasyonu olan hipergliseminin sebep olduğu oksidatif stres, karaciğer hasarına neden olmaktadır. Hidroksitirosol, zeytinyağında bol miktarda bulunan ve karaciğeri oksidatif hasara karşı da koruyan polifenolik bir bileşiktir. Peroksiredoksin 6 (Prdx6), karaciğerde varlığı bilinen bir anti-oksidatif enzimdir. Bu çalışmanın amacı, hidroksitirozolün diyabete bağlı karaciğer hasarındaki koruyucu rolünde Prdx6 ekspresyonunun etkisini araştırmaktı.
Gereç ve Yöntemler: Erkek Wistar ratlar kontrol grubu (n=10), hidroksitirozol grubu (n=10), streptozotosin grubu (n=10) ve hidroksitirozol+streptozotosin grubu (n=10) olmak üzere dört gruba bölündü. Hayvanların kan glukoz seviyesi streptozotosin enjeksiyonu sonrasında ve deney sonunda da ölçüldü. Karaciğerin genel yapısı ise hematoksilen-eozin boyasıyla incelendi. Prdx6 proteinin ekspresyonu immunohistokimya yöntemi ile belirlendi.
Bulgular: Streptozotosin+hidroksitirozol grubunda kan glukoz seviyesi streptozotosin grubu ile kıyaslandığında daha düşük olarak bulundu (p<0,001) ve hepatositlerdeki histopatolojik bulgularda ise azalma olduğu saptandı. Prdx6 ekspresyonu kontrol ve hidroksitirozol gruplarında benzer olarak bulundu (p=0,590). Ancak streptozotosin ve streptozotosin+hidroksitirozol gruplarında onlardan daha yüksek olduğu saptandı (p<0,001). Streptozotosin+hidroksitirozol grubu Prdx6 ekspresyonu streptozotosin grubuna göre daha düşük olarak bulundu (p<0,001).
Sonuç: Birçok çalışmada antioksidatif etkinliği kanıtlanmış olan hidroksitirozol diyabetik ratlarda kan glukoz seviyesini düşürdüğü, hepatositlerdeki histopatolojik değişikliklere neden olduğu ve antioksidatif Prdx6 ekspresyonunu azalttığı bulunmuştur. Bu azalma bize, hidroksitirozolün doğrudan Prdx6’yı inhibe etmesinden ziyade, Prdx6’dan bağımsız bir şekilde oksidatif stresi azaltmasına bağlı olarak gerçekleşiyor olabileceğini düşündürdü.
References
- Nawrot M, Peschard S, Lestavel S, Staels B. Intestine-liver crosstalk in Type 2 Diabetes and non-alcoholic fatty liver disease. Metabolism. 2021;123:154844.
- Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med. 2020;14(5):583-600.
- Schmatz R, Perreira LB, Stefanello N, Mazzanti C, Spanevello R, Gutierres J, et al. Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin-induced diabetic rats. Biochimie. 2012;94(2):374-83.
- Ge Q, Feng F, Liu L, Chen L, Lv P, Ma S, et al. RNA-Seq analysis of the pathogenesis of STZ-induced male diabetic mouse liver. J Diabetes Complications. 2020;34(2):107444.
- Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction. Pflugers Arch. 2010;460(4):703-18.
- Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress-A concise review. Saudi Pharm J. 2016;24(5):547-53.
- Maddu N. Diseases related to types of free radicals. In: Shalaby E, editor. Antioxidants. IntechOpen Rijeka, Croatia; 2019.
- Guo S, Mao X, Yan Y, Zhang Y, Ming L. Changes of liver transcriptome profiles following oxidative stress in streptozotocin-induced diabetes in mice. PeerJ. 2020;8:e8983.
- Yazdi HB, Hojati V, Shiravi A, Hosseinian S, Vaezi G, Hadjzadeh MA. Liver dysfunction and oxidative stress in streptozotocin-induced diabetic rats: protective role of Artemisia turanica. J Pharmacopuncture. 2019;22(2):109-14.
- Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30(3):734-43.
- Immenschuh S, Baumgart-Vogt E. Peroxiredoxins, oxidative stress, and cell proliferation. Antioxid Redox Signal. 2005;7(5-6):768-77.
- Paula FM, Ferreira SM, Boschero AC, Souza KL. Modulation of the peroxiredoxin system by cytokines in insulin-producing RINm5F cells: down-regulation of PRDX6 increases susceptibility of beta cells to oxidative stress. Mol Cell Endocrinol. 2013;374(1-2):56-64.
- Fisher AB. Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. Antioxid Redox Signal. 2011;15(3):831-44.
- Arriga R, Pacifici F, Capuani B, Coppola A, Orlandi A, Scioli MG, et al. Peroxiredoxin 6 is a key antioxidant enzyme in modulating the link between glycemic and lipogenic metabolism. Oxid Med Cell Longev. 2019;2019:9685607.
- Wang X, Phelan SA, Forsman-Semb K, Taylor EF, Petros C, Brown A, et al. Mice with targeted mutation of peroxiredoxin 6 develop normally but are susceptible to oxidative stress. J Biol Chem. 2003;278(27):25179-90.
- Tu Q, Xiong Y, Fan L, Qiao B, Xia Z, Hu L, et al. Peroxiredoxin 6 attenuates ischemia‑ and hypoxia‑induced liver damage of brain‑dead donors. Mol Med Rep. 2016;13(1):753-61.
- Lee DH, Jung YY, Park MH, Jo MR, Han SB, Yoon DY, et al. Peroxiredoxin 6 confers protection against nonalcoholic fatty liver disease through maintaining mitochondrial function. Antioxid Redox Signal. 2019;31(5):387-402.
- Eismann T, Huber N, Shin T, Kuboki S, Galloway E, Wyder M, et al. Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):G266-74.
- Hu T, He XW, Jiang JG, Xu XL. Hydroxytyrosol and its potential therapeutic effects. J Agric Food Chem. 2014;62(7):1449-55.
- Pan S, Liu L, Pan H, Ma Y, Wang D, Kang K, et al. Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice. Mol Nutr Food Res. 2013;57(7):1218-27.
- Martínez N, Herrera M, Frías L, Provencio M, Pérez-Carrión R, Díaz V, et al. A combination of hydroxytyrosol, omega-3 fatty acids and curcumin improves pain and inflammation among early stage breast cancer patients receiving adjuvant hormonal therapy: results of a pilot study. Clin Transl Oncol. 2019;21(4):489-98.
- Scoditti E, Nestola A, Massaro M, Calabriso N, Storelli C, De Caterina R, et al. Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCα and PKCβ1 inhibition. Atherosclerosis. 2014;232(1):17-24.
- Karković Marković A, Torić J, Barbarić M, Jakobušić Brala C. Hydroxytyrosol, tyrosol and derivatives and their potential effects on human health. Molecules. 2019;24(10):2001.
- Gabbia D, Carpi S, Sarcognato S, Zanotto I, Sayaf K, Colognesi M, et al. The phenolic compounds tyrosol and hydroxytyrosol counteract liver fibrogenesis via the transcriptional modulation of NADPH oxidases and oxidative stress-related miRNAs. Biomed Pharmacother. 2023;157:114014.
- Contreras MDM, Gómez-Cruz I, Feriani A, Alwasel S, Harrath AH, Romero I, et al. Hepatopreventive properties of hydroxytyrosol and mannitol-rich extracts obtained from exhausted olive pomace using green extraction methods. Food Funct. 2022;13(22):11915-28.
- Panera N, Braghini MR, Crudele A, Smeriglio A, Bianchi M, Condorelli AG, et al. Combination treatment with hydroxytyrosol and vitamin E improves NAFLD-related fibrosis. Nutrients. 2022;14(18):3791.
- Pacifici F, Arriga R, Sorice GP, Capuani B, Scioli MG, Pastore D, et al. Peroxiredoxin 6, a novel player in the pathogenesis of diabetes. Diabetes. 2014;63(10):3210-20.
- Conde de la Rosa L, Schoemaker MH, Vrenken TE, Buist-Homan M, Havinga R, Jansen PL, et al. Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. J Hepatol. 2006;44(5):918-29.
- Mendes-Braz M, Martins JO. Diabetes mellitus and liver surgery: the effect of diabetes on oxidative stress and inflammation. Mediators Inflamm. 2018;2018:2456579.
- Shen W, Yang L, Yang Y, Wang P, Tao X, Shen Y, et al. PRDX6 promotes fatty acid oxidation via PLA2-dependent PPARα Activation in rats fed high-fat diet. Antioxid Redox Signal. 2023;38(16-18):1184-200.
Abstract
Aim: Oxidative stress caused by hyperglycemia, which is the most important complication of diabetes mellitus, causes liver damage. Hydroxytyrosol is a polyphenolic compound abundant in olive oil that protects the liver against oxidative damage. Peroxiredoxin 6 (Prdx6) is an anti-oxidative enzyme known to exist in the liver. The aim of this study was to investigate the effect of hydroxytyrosol on Prdx6 expression in diabetes-induced liver injury.
Material and Methods: Male Wistar rats were grouped into four as the control group (n=10), hydroxytyrosol group (n=10), streptozotocin group (n=10), and hydroxytyrosol+streptozotocin group (n=10). Blood glucose levels of the animals were measured after streptozotocin injection and at the end of the experiment. The general structure of the liver was examined with a hematoxylin-eosin stain. Prdx6 protein expression was determined with an immunohistochemical method.
Results: In the streptozotocin+hydroxytyrosol group, blood glucose level was found to be lower when compared with the streptozotocin group (p<0.001), and histopathological findings in hepatocytes were found to decrease. Prdx6 expression was found to be similar in the control and hydroxytyrosol groups (p=0.590). However, it was found to be higher in streptozotocin and streptozotocin+hydroxytyrosol groups (p<0.001). Prdx6 expression of the streptozotocin+hydroxytyrosol group was found lower than the streptozotocin group (p<0.001).
Conclusion: Hydroxytyrosol, the anti-oxidative activity of which has been proven in many studies, was found to relieve blood glucose levels in diabetic rats, cause histopathological changes in hepatocytes, and decrease anti-oxidative Prdx6 expression. This decrease suggested that instead of inhibiting Prdx6, hydroxytyrosol reduced oxidative stress irrespective of Prdx6.
References
- Nawrot M, Peschard S, Lestavel S, Staels B. Intestine-liver crosstalk in Type 2 Diabetes and non-alcoholic fatty liver disease. Metabolism. 2021;123:154844.
- Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med. 2020;14(5):583-600.
- Schmatz R, Perreira LB, Stefanello N, Mazzanti C, Spanevello R, Gutierres J, et al. Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin-induced diabetic rats. Biochimie. 2012;94(2):374-83.
- Ge Q, Feng F, Liu L, Chen L, Lv P, Ma S, et al. RNA-Seq analysis of the pathogenesis of STZ-induced male diabetic mouse liver. J Diabetes Complications. 2020;34(2):107444.
- Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction. Pflugers Arch. 2010;460(4):703-18.
- Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress-A concise review. Saudi Pharm J. 2016;24(5):547-53.
- Maddu N. Diseases related to types of free radicals. In: Shalaby E, editor. Antioxidants. IntechOpen Rijeka, Croatia; 2019.
- Guo S, Mao X, Yan Y, Zhang Y, Ming L. Changes of liver transcriptome profiles following oxidative stress in streptozotocin-induced diabetes in mice. PeerJ. 2020;8:e8983.
- Yazdi HB, Hojati V, Shiravi A, Hosseinian S, Vaezi G, Hadjzadeh MA. Liver dysfunction and oxidative stress in streptozotocin-induced diabetic rats: protective role of Artemisia turanica. J Pharmacopuncture. 2019;22(2):109-14.
- Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30(3):734-43.
- Immenschuh S, Baumgart-Vogt E. Peroxiredoxins, oxidative stress, and cell proliferation. Antioxid Redox Signal. 2005;7(5-6):768-77.
- Paula FM, Ferreira SM, Boschero AC, Souza KL. Modulation of the peroxiredoxin system by cytokines in insulin-producing RINm5F cells: down-regulation of PRDX6 increases susceptibility of beta cells to oxidative stress. Mol Cell Endocrinol. 2013;374(1-2):56-64.
- Fisher AB. Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. Antioxid Redox Signal. 2011;15(3):831-44.
- Arriga R, Pacifici F, Capuani B, Coppola A, Orlandi A, Scioli MG, et al. Peroxiredoxin 6 is a key antioxidant enzyme in modulating the link between glycemic and lipogenic metabolism. Oxid Med Cell Longev. 2019;2019:9685607.
- Wang X, Phelan SA, Forsman-Semb K, Taylor EF, Petros C, Brown A, et al. Mice with targeted mutation of peroxiredoxin 6 develop normally but are susceptible to oxidative stress. J Biol Chem. 2003;278(27):25179-90.
- Tu Q, Xiong Y, Fan L, Qiao B, Xia Z, Hu L, et al. Peroxiredoxin 6 attenuates ischemia‑ and hypoxia‑induced liver damage of brain‑dead donors. Mol Med Rep. 2016;13(1):753-61.
- Lee DH, Jung YY, Park MH, Jo MR, Han SB, Yoon DY, et al. Peroxiredoxin 6 confers protection against nonalcoholic fatty liver disease through maintaining mitochondrial function. Antioxid Redox Signal. 2019;31(5):387-402.
- Eismann T, Huber N, Shin T, Kuboki S, Galloway E, Wyder M, et al. Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):G266-74.
- Hu T, He XW, Jiang JG, Xu XL. Hydroxytyrosol and its potential therapeutic effects. J Agric Food Chem. 2014;62(7):1449-55.
- Pan S, Liu L, Pan H, Ma Y, Wang D, Kang K, et al. Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice. Mol Nutr Food Res. 2013;57(7):1218-27.
- Martínez N, Herrera M, Frías L, Provencio M, Pérez-Carrión R, Díaz V, et al. A combination of hydroxytyrosol, omega-3 fatty acids and curcumin improves pain and inflammation among early stage breast cancer patients receiving adjuvant hormonal therapy: results of a pilot study. Clin Transl Oncol. 2019;21(4):489-98.
- Scoditti E, Nestola A, Massaro M, Calabriso N, Storelli C, De Caterina R, et al. Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCα and PKCβ1 inhibition. Atherosclerosis. 2014;232(1):17-24.
- Karković Marković A, Torić J, Barbarić M, Jakobušić Brala C. Hydroxytyrosol, tyrosol and derivatives and their potential effects on human health. Molecules. 2019;24(10):2001.
- Gabbia D, Carpi S, Sarcognato S, Zanotto I, Sayaf K, Colognesi M, et al. The phenolic compounds tyrosol and hydroxytyrosol counteract liver fibrogenesis via the transcriptional modulation of NADPH oxidases and oxidative stress-related miRNAs. Biomed Pharmacother. 2023;157:114014.
- Contreras MDM, Gómez-Cruz I, Feriani A, Alwasel S, Harrath AH, Romero I, et al. Hepatopreventive properties of hydroxytyrosol and mannitol-rich extracts obtained from exhausted olive pomace using green extraction methods. Food Funct. 2022;13(22):11915-28.
- Panera N, Braghini MR, Crudele A, Smeriglio A, Bianchi M, Condorelli AG, et al. Combination treatment with hydroxytyrosol and vitamin E improves NAFLD-related fibrosis. Nutrients. 2022;14(18):3791.
- Pacifici F, Arriga R, Sorice GP, Capuani B, Scioli MG, Pastore D, et al. Peroxiredoxin 6, a novel player in the pathogenesis of diabetes. Diabetes. 2014;63(10):3210-20.
- Conde de la Rosa L, Schoemaker MH, Vrenken TE, Buist-Homan M, Havinga R, Jansen PL, et al. Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. J Hepatol. 2006;44(5):918-29.
- Mendes-Braz M, Martins JO. Diabetes mellitus and liver surgery: the effect of diabetes on oxidative stress and inflammation. Mediators Inflamm. 2018;2018:2456579.
- Shen W, Yang L, Yang Y, Wang P, Tao X, Shen Y, et al. PRDX6 promotes fatty acid oxidation via PLA2-dependent PPARα Activation in rats fed high-fat diet. Antioxid Redox Signal. 2023;38(16-18):1184-200.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Research Article |
| Authors | |
| Early Pub Date | August 2, 2023 |
| Publication Date | August 30, 2023 |
| Submission Date | March 2, 2023 |
| Published in Issue | Year 2023 Volume: 25 Issue: 2 |
Cite
Duzce Medical Journal is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.