Lycopene ameliorates diabetes-induced pancreatic, hepatic, and renal damage by modulating the JAK/STAT/SOCS signaling pathway in rats

Document Type : Original Article

Authors

1 Department of Pathology, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur, Türkiye

2 Department of Endocrinology and Metabolism,University, Pamukkale Faculty of Medicine, Denizli, Türkiye

3 Genetic Research Unit, Innovative Technologies Application and Research Center, Süleyman Demirel University, Isparta, Türkiye

Abstract

Objective(s): Emerging evidence suggests that the JAK/STAT/SOCS signaling pathway is crucial for maintaining homeostasis, and its dysregulation contributes to diabetes development. This study aimed to evaluate the roles of SOCS-1 and SOCS-3 in the pancreas, liver, and kidney and to explore the involvement of the JAK/STAT pathway in the molecular mechanisms underlying their effects on inflammation and apoptosis, as well as organ injury in a diabetes mellitus (DM) model. Additionally, we sought to elucidate the role of the JAK/STAT/SOCS pathway in mediating the effects of lycopene (LYC).
Materials and Methods: Forty Sprague-Dawley rats were divided into control, DM, LYC, and LYC+DM groups. Diabetes was induced in the DM groups using streptozotocin. LYC was administered to the LYC and LYC+DM groups for 30 days. After the study, pancreas, liver, and kidney tissues were analyzed using histopathological, immunohistochemical, and PCR methods.
Results: Significant vacuolization and degenerative changes were observed in the DM group’s pancreatic islet cells. Kidney and liver tissues showed hyperemia, hemorrhage, and degenerative changes. Immunohistochemical analysis revealed increased expression of Cas-3, TNF-α, IFN-α, and IL-6, while IL-10 was significantly reduced in the DM group. PCR analysis showed elevated levels of TNF-α and Cas-3, with decreased SOCS-1 and SOCS-3 expression in the DM group.
Conclusion: This study highlights the therapeutic potential of targeting the JAK/STAT/SOCS pathway with lycopene, demonstrating its promise in mitigating diabetes and related complications.

Keywords

Main Subjects

References

1. Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Front Immunol 2020; 11: 1582-1604.
2. Liu Y, Wang W, Zhang J, Gao S, Xu T, Yin Y. JAK/STAT signaling in diabetic kidney disease. Front Cell Dev Biol 2023; 11: 1233259-1233274.
3. Oguntibeju OO. Type 2 diabetes mellitus, oxidative stress and inflammation: Examining the links. Int J Physiol Pathophysiol Pharmacol 2019; 11: 45-63.
4. Yaribeygi H, Sathyapalan T, Atkin SL, Sahebkar A. Molecular mechanisms linking oxidative stress and diabetes mellitus. Oxid Med Cell Longev 2020; 2020: 8609213-8609226.
5. Charlton A, Garzarella J, Jandeleit-Dahm KA, Jha JC. Oxidative stress and inflammation in renal and cardiovascular complications of diabetes. Biology 2020; 10: 18-26.
6. Burgos-Morón E, Abad-Jiménez Z, Martinez de Maranon A, Iannantuoni F, Escribano-López I, López-Domènech S, et al. Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: The battle continues. J Clin Med 2019; 8: 1385-1407.
7. Jin Q, Liu T, Qiao Y, Liu D, Yang L, Mao H, et al. Oxidative stress and inflammation in diabetic nephropathy: Role of polyphenols. Front Immunol 2023; 14: 1185317-1185334.
8. Liu J, Wang F, Luo F. The role of JAK/STAT pathway in fibrotic diseases: Molecular and cellular mechanisms. Biomolecules 2023; 13: 119-134.
9. Zhu M, Wang H, Chen J, Zhu H. Sinomenine improve diabetic nephropathy by inhibiting fibrosis and regulating the JAK2/STAT3/SOCS1 pathway in streptozotocin-induced diabetic rats. Life Sci 2021; 265:118855.
10.    Lopez-Sanz L, Bernal S, Recio C, Lazaro I, Oguiza A, Melgar A, et al. SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition. Lab Invest 2018; 98: 1276-1290.
11.    Lv C, Sun Y, Zhang ZY, Aboelela Z, Qiu X, Meng ZX. β-cell dynamics in type 2 diabetes and in dietary and exercise interventions. Mol Cell Biol 2022; 14: 046-068. 
12.    Rachdaoui N. Insulin: The friend and the foe in the development of type 2 diabetes mellitus. Int J Mol Sci 2020; 21: 1770-1791.
13.    La Manna S, De Benedictis I, Marasco D. Proteomimetics of natural regulators of JAK–STAT pathway: Novel therapeutic perspectives. Front Mol Biosci 2022; 8: 792546-792560.
14.    Haider MJ, Albaqsumi Z, Al-Mulla F, Ahmad R, Al-Rashed F. Socs3 regulates dectin-2-induced inflammation in pbmcs of diabetic patients. Cells 2022; 11: 2670-2685.
15.    Rezende LF, Santos GJ, Carneiro EM, Boschero AC. Ciliary neurotrophic factor protects mice against streptozotocin-induced type 1 diabetes through SOCS3: The role of STAT1/STAT3 ratio in β-cell death. J Biol Chem 2012; 287: 41628-41639.
16.    Lankatillake C, Huynh T, Dias DA. Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants. Plant Methods 2019; 15: 105-140.
17.    Jugran AK, Rawat S, Devkota HP, Bhatt ID, Rawal RS. Diabetes and plant‐derived natural products: From ethnopharmacological approaches to their potential for modern drug discovery and development. Phytother Res 2021; 35: 223-245.
18.    Nanda J, Verma N, Mani MA. Mechanistic review on phytomedicine and natural products in the treatment of diabetes. Curr Diabetes Rev 2023; 19: 44-54.
19.    Tran N, Pham B, Le L. Bioactive compounds in antidiabetic plants: From herbal medicine to modern drug discovery. Biology 2020; 9: 252-283.
20.    Chopra M, Bhaumik A, Reddy AG, Kumar PS, Srikant B. Extraction and isolation of bioactive molecule lycopene from watermelon and evaluation of antidiabetic activity against STZ induced rats. Res J Pharm Technol 2018; 11: 101-106.
21.    Sharma PK, Saxena P, Jaswanth A, Chalamaiah M, Balasubramaniam A. Antidiabetic activity of lycopene niosomes: Experimental observation. J Pharm Drug Dev 2017; 4: 103-111.
22.    Zhu R, Chen B, Bai Y, Miao T, Rui L, Zhang H, et al. Lycopene in protection against obesity and diabetes: A mechanistic review. Pharmacol Res 2020; 159: 104966.
23.    Albrahim T, Alonazi MA. Lycopene corrects metabolic syndrome and liver injury induced by high fat diet in obese rats through antioxidant, anti-inflammatory, antifibrotic pathways. Biomed Pharmacother 2021; 141: 111831-111840.
24.    Kulawik A, Cielecka-Piontek J, Zalewski P. The importance of antioxidant activity for the health-promoting effect of lycopene. Nutrients 2023; 15: 3821-3846.
25.    Ozmen O, Topsakal S, Haligur M, Aydogan A, Dincoglu D. Effects of caffeine and lycopene in experimentally induced diabetes mellitus. Pancreas 2016; 45: 579-583.
26.    Biswas A, Choudhury AD, Agrawal S, Bisen AC, Sanap SN, Verma SK, et al. Recent insights into the etiopathogenesis of diabetic retinopathy and its management. J Ocul Pharmacol Ther 2024; 40: 13-33.
27.    Karahan F, Dede S, Ceylan E. The effect of lycopene treatment on oxidative DNA damage of experimental diabetic rats. Open Clin Biochem J 2018; 8: 1-6.
28.    Haligur M, Topsakal S, Ozmen O. Early degenerative effects of diabetes mellitus on pancreas, liver, and kidney in rats: An immunohistochemical study. J Diabetes Res 2012; 2012: 120645-120655.
29.    Ozmen O, Topsakal S, Unal GO. Experimental model of unpredictable maternal stress and diabetes risk of offspring: An immunohistochemical study. Acta Histochem 2022; 124: 151878.
30.    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 2001; 25: 402-408.
31.    Yang M, Tian M, Zhang X, Xu J, Yang B, Yu J, et al. Role of the JAK2/STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications. Oncotarget 2017; 8: 96958-96969. 
32.    Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 2004; 24: 5434-5446. 
33.    Choi S, Kim H. The Remedial potential of lycopene in pancreatitis through regulation of autophagy. Int J Mol Sci 2020; 21: 5775-5794. 
34.    Róvero Costa M, Leite Garcia J, Cristina Vágula de Almeida Silva C, Junio Togneri Ferron A, Valentini Francisqueti-Ferron F, Kurokawa Hasimoto F, et al. Lycopene modulates pathophysiological processes of non-alcoholic fatty liver disease in obese rats. Antioxidants (Basel) 2019; 8: 276-293. 
35.    Wang Y, Liu Z, Ma J, Xv Q, Gao H, Yin H, et al. Lycopene attenuates the inflammation and apoptosis in aristolochic acid nephropathy by targeting the Nrf2 antioxidant system. Redox Biol 2022; 57: 102494-102512. 
36.    De Candia P, Prattichizzo F, Garavelli S, De Rosa V, Galgani M, Di Rella F, et al. Type 2 diabetes: How much of an autoimmune disease? Front Endocrinol 2019; 10: 451-465.
37.    Paschou SA, Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. On type 1 diabetes mellitus pathogenesis. Endocr Connect 2018; 7: R38-R46.
38.    McDade TW, Georgiev AV, Kuzawa CW. Trade-offs between acquired and innate immune defenses in humans. Evol Med Public Hlth 2016; 2016: 1-16.
39.    Chauhan P, Nair A, Patidar A, Dandapat J, Sarkar A, Saha B. A primer on cytokines. Cytokine 2021; 145: 155458.
40.    Gonzalez Caldito N. Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders. Front Immunol 2023; 14: 1213448-1213459.
41.    Matsushima K, Yang D, Oppenheim JJ. Interleukin-8: An evolving chemokine. Cytokine 2022; 153:155828.
42.    Badr AM, Sharkawy H, Farid AA., El-Deeb S. Curcumin induces regeneration of β cells and suppression of phosphorylated-NF-κB in streptozotocin-induced diabetic mice. J Basic Appl Zool 2020; 81: 1-15.
43.    Cheng Y, Chen Y, Li K, Liu S, Pang C, Gao L, et al. How inflammation dictates diabetic peripheral neuropathy: An enlightening review. CNS Neurosci Ther 2023; 29: 1-15.
44.    Kong M, Xie K, Lv M, Li J, Yao J, Yan K, et al. Anti-inflammatory phytochemicals for the treatment of diabetes and its complications: Lessons learned and future promise. Biomed Pharmacother 2021; 133: 110975-110990.
45.    Menini S, Iacobini C, Vitale M, Pugliese G. The inflammasome in chronic complications of diabetes and related metabolic disorders. Cells 2020; 9:1812-1829.
46.    Owen KL, Brockwell NK, Parker BS. JAK-STAT signaling: A double-edged sword of immune regulation and cancer progression. Cancers 2019; 11: 2002-2028.
47.    Stergioti EM, Manolakou T, Boumpas DT, Banos A. Antiviral innate immune responses in autoimmunity: Receptors, pathways, and therapeutic targeting. Biomedicines 2022; 10: 2820-2848.
48.    Al-Jiffri EH. Association between adipocytokines, systemic inflammation and oxidative stress biomarkers among obese type 2 diabetic patients. Adv Res Gastroenterol Hepatol 2017; 5: 80-85.
49.    Leh HE, Lee LK. Lycopene: A potent antioxidant for the amelioration of type II diabetes mellitus. Molecules 2022; 27: 2335-2355.
50.    Zheng Z, Yin Y, Lu R, Jiang Z. Lycopene ameliorated oxidative stress and inflammation in type 2 diabetic rats. J Food Sci 2019; 84: 1194-1200.
51.    Akarsu E, Sayiner ZA, Balcı SO, Demirel C, Bozdag Z, Korkmaz M, et al. Effects of antidiabetics and exercise therapy on suppressors of cytokine signaling-1, suppressors of cytokine signaling-3, and insulin receptor substrate-1 molecules in diabetes and obesity. Rev Assoc Med Bras 2023; 69: 112-118.
52.    Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, Gough DJ. The JAK/STAT pathway in obesity and diabetes. FEBS J 2016; 283: 3002-3015. 
53.    Eizirik DL, Colli ML Ortis F. The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nat Rev Endocrinol 2009; 5: 219-226.
54.    Barthson J, Germano CM, Moore F, Maida A, Drucker DJ, Marchetti P, Gysemans C, Mathieu C, et al. Cytokines tumor necrosis factor-α and interferon-γ induce pancreatic β-cell apoptosis through STAT1-mediated Bim protein activation. J Biol Chem 2011; 286: 39632-39643.
55.    Eizirik DL, Mandrup-Poulsen T. A choice of death – the signal-transduction of immune-mediated β-cell apoptosis. Diabetologia 2001; 4: 2115-2133.
56.    Gough DJ, Messina NL, Clarke CJ, Johnstone RW, Levy DE. Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity 2012; 36: 166-174.
57.    Stanley WJ, Litwak SA, Quah HS, Tan SM, Kay TW, Tiganis T, et al. Inactivation of protein tyrosine phosphatases enhances interferon signaling in pancreatic islets. Diabetes 2015; 64: 2489-2496.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 4
April 2025
Pages 461-468

Files

Share

How to cite

Statistics