Abstract
In recent years, marine-derived bioactive peptides have gained considerable attention owing to their high biomedical and pharmaceutical potential. In this study, we investigated the hypoglycemic activity of fish roe polypeptide (FRP) in islet β-cells (INS-1) and the molecular mechanism whereby FRP exerts this effect. Insulin secretion, cell viability, cell apoptosis, intracellular reactive oxygen species (ROS), and intracellular antioxidant-related enzymes were detected. The nuclear factor erythroid 2-related factor 2 (Nrf2)/extracellular signal-regulated kinase (ERK) pathway was analyzed to reveal the mechanism underpinning FRP’s hypoglycemic effect. The results showed that FRP treatment promoted insulin secretion and cell viability, reduced apoptosis and intracellular ROS levels, and increased the activity and content of antioxidant-related enzymes. Cell signaling pathway analysis revealed that FRP was able to alleviate H2O2-induced oxidative stress by activating the Nrf2/ERK pathway. This was demonstrated by an evident decrease in cell viability and insulin secretion in the presence of the ERK blocker U0126. Altogether, these results suggest that FRP exerts its hypoglycemic effect by regulating insulin secretion, which is mediated by Nrf2/ERK signaling.
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References
Alshatwi AA, Subash-Babu P (2016) Aloe-emodin protects RIN-5F (pancreatic beta-cell) cell from glucotoxicity via regulation of pro-inflammatory cytokine and downregulation of bax and caspase 3. Biomol Ther 24:49–56. https://doi.org/10.4062/biomolther.2015.056
Biolo G, Massolino B, Di Girolamo FG, Fiotti N, Mearelli F, Mazzucco S, Bertuzzi C, Lazzarini R, Colombatti A, De Cicco M (2018) Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia. PLoS ONE 13:e0190291. https://doi.org/10.1371/journal.pone.0190291
Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99:11908–11913. https://doi.org/10.1073/pnas.172398899
Fardoun RZ (2009) The use of vitamin E in type 2 diabetes mellitus. Clin Exp Hypertens 29:135–148. https://doi.org/10.1080/10641960701361601
Gerber PA, Rutter GA (2017) The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Sign 26:501–518. https://doi.org/10.1089/ars.2016.6755
Giri A, Ohshima T (2012) Bioactive marine peptides: nutraceutical value and novel approaches. Adv Food Nutr Res 65:73–105. https://doi.org/10.1016/b978-0-12-416003-3.00005-6
Gowd V, Bao T, Wang L, Huang Y, Chen S, Zheng X, Cui S, Chen W (2018) Antioxidant and antidiabetic activity of blackberry after gastrointestinal digestion and human gut microbiota fermentation. Food Chem 269:618–627. https://doi.org/10.1016/j.foodchem.2018.07.020
Hasnain SZ, Prins JB, McGuckin MA (2016) Oxidative and endoplasmic reticulum stress in beta-cell dysfunction in diabetes. J Mol Endocrinol 56:R33–R54. https://doi.org/10.1530/JME-15-0232
Juric S, Ferrari G, Velikov KP, Donsi F (2019) High-pressure homogenization treatment to recover bioactive compounds from tomato peels. J Food Eng 262:170–180. https://doi.org/10.1016/j.jfoodeng.2019.06.011
Kang HK, Lee HH, Seo CH, Park Y (2019) Antimicrobial and immunomodulatory properties and applications of marine-derived proteins and peptides. Mar Drugs 17:350. https://doi.org/10.3390/md17060350
Kim MJ, Kim MN, Min SH, Ham D-S, Kim J-W, Yoon K-H, Park KS, Jung HS (2019) Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes. Metabolism 97: 87–91. https://doi.org/10.1016/j.metabol.2018.12.007
Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, Walker EA, Fowler SE, Nathan DM, Kahn SE (2005) Prevention of type 2 diabetes with troglitazone in the diabetes prevention program. Diabetes 54:1150–1156. https://doi.org/10.2337/diabetes.54.4.1150
Kumar A, Jaitak V (2019) Natural products as multidrug resistance modulators in cancer. Eur J Med Chem 176:268–291. https://doi.org/10.1016/j.ejmech.2019.05.027
Kumar P, Rao GN, Pal BB, Pal A (2014) Hyperglycemia-induced oxidative stress induces apoptosis by inhibiting PI3-kinase/Akt and ERK1/2 MAPK mediated signaling pathway causing downregulation of 8-oxoG-DNA glycosylase levels in glial cells. Int J Biochem Cell B 53:302–319. https://doi.org/10.1016/j.biocel.2014.05.038
Lee KM, Kim JH, Choi ES, Kim E, Choi SK, Jeon WB (2019) RGD-containing elastin-like polypeptide improves islet transplantation outcomes in diabetic mice. Acta Biomater 94:351–360. https://doi.org/10.1016/j.actbio.2019.06.011
Li J, Li Q, Li J, Zhou B (2014) Peptides derived from rhopilema esculentum hydrolysate exhibit angiotensin converting enzyme (ACE) inhibitory and antioxidant abilities. Molecules 19:13587–13602. https://doi.org/10.3390/molecules190913587
Liu L, Liang C, Mei P, Zhu H, Hou M, Yu C, Song Z, Bao Y, Huang Y, Yi J, Wang S, Wu Y, Zheng L, Sun Y, Wang G, Huo M, Yang S, Sun L, Li Y (2019) Dracorhodin perchlorate protects pancreatic beta-cells against glucotoxicity- or lipotoxicity-induced dysfunction and apoptosis in vitro and in vivo. FEBS J 286:18. https://doi.org/10.1111/febs.15020
Mandrone M, Bonvicini F, Lianza M, Sanna C, Maxia A, Gentilomi GA, Poli F (2019) Sardinian plants with antimicrobial potential. Biological screening with multivariate data treatment of thirty-six extracts. Ind Crop Prod 137:557–565. https://doi.org/10.1016/j.indcrop.2019.05.069
Masuda Y, Vaziri ND, Li S, Le A, Hajighasemi-Ossareh M, Robles L, Foster CE, Stamos MJ, Al-Abodullah I, Ricordi C, Ichii H (2015) The effect of Nrf2 pathway activation on human pancreatic islet cells. PLos ONE 10:e0131012. https://doi.org/10.1371/journal.pone.0131012
Messer JG, Hopkins RG, Kipp DE (2015) Quercetin metabolites up-regulate the antioxidant response in osteoblasts isolated from fetal rat calvaria. J Cell Biochem 116:1857–1866. https://doi.org/10.1002/jcb.25141
Nolan CJ, Damm P, Prentki M (2011) Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 378:169–181. https://doi.org/10.1016/s0140-6736(11)60614-4
Rajasekar N, Nath C, Hanif K, Shukla R (2017) Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats. Life Sci 173:1–10. https://doi.org/10.1016/j.lfs.2016.09.020
Saggioro EM, Santo DGD, Sales SF, Hauser-Davis RA, Correia FV (2019) Lethal and sublethal effects of acetamiprid on Eisenia andrei: behavior, reproduction, cytotoxicity and oxidative stress. Ecotox Environ Safe 183:109572. https://doi.org/10.1016/j.ecoenv.2019.109572
Sampath C, Rashid MR, Sang S, Ahmedna M (2017) Specific bioactive compounds in ginger and apple alleviate hyperglycemia in mice with high fat diet-induced obesity via Nrf2 mediated pathway. Food Chem 226:79–88. https://doi.org/10.1016/j.foodchem.2017.01.056
Satirapoj B, Watanakijthavonkul K, Supasyndh O (2018) Safety and efficacy of low dose pioglitazone compared with standard dose pioglitazone in type 2 diabetes with chronic kidney disease: a randomized controlled trial. Plos One 13:e0206722. https://doi.org/10.1371/journal.pone.0206722
Schneider CC, Ateschrang A, Konigsrainer I, Glatzle J, Buhler S, Schaefer R, Northoff H, Konigsrainer A, Zieker D (2012) Lactate influences the gene expression profile of human mesenchymal stem cells (hMSC) in a dose dependant manner. Cell Physiol Biochem 30:1547–1556. https://doi.org/10.1159/000343342
Shah P, Mudaliar S (2010) Pioglitazone: side effect and safety profile. Expert Opin Drug Saf 9:347–354. https://doi.org/10.1517/14740331003623218
Shah SR, Iqbal SM, Alweis R, Roark S (2019) A closer look at heart failure in patients with concurrent diabetes mellitus using glucose lowering drugs. Expert Rev Clin Phar 12:45–52. https://doi.org/10.1080/17512433.2019.1552830
Sila A, Bougatef A (2016) Antioxidant peptides from marine by-products: isolation, identification and application in food systems. A review. J Funct Foods 21:10–26. https://doi.org/10.1016/j.jff.2015.11.007
Skelin M, Rupnik M, Cencic A (2010) Pancreatic beta cell lines and their applications in diabetes mellitus research. Altex-Altern Anim Ex 27: 105–113. https://doi.org/10.1117/12.859946
Tan Y, Ichikawa T, Li JQ, Si QS, Yang HT, Chen XB, Goldblatt CS, Meyer CJ, Li XK, Cai L, Cui TX (2011) Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes 60:625–633. https://doi.org/10.2337/db10-1164/-/DC1
Tang X, Yu RQ, Zhou Q, Jiang SY, Le GW (2018) Protective effects of γ-aminobutyric acid against H2O2-induced oxidative stress in RIN-m5F pancreatic cells. Nutr Metab 15:60-. https://doi.org/10.1186/s12986-018-0299-2
Wang SY, Zhao XX, Yang SX, Chen BP, Shi J (2017) Salidroside alleviates high glucose-induced oxidative stress and extracellular matrix accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway. Chem Biol Interact 278:48–53. https://doi.org/10.1016/j.cbi.2017.10.012
Wang X, Gu CS, He W, Ye XL, Chen HL, Zhang XD, Hai CX (2012) Glucose oxidase induces insulin resistance via influencing multiple targets in vitro and in vivo: the central role of oxidative stress. Biochimie 94:1705–1717. https://doi.org/10.1016/j.biochi.2012.03.024
Xiong XW, Sun XP, Wang QZ, Qian XL, Zhang Y, Pan XY, Dong XC (2016) SIRT6 protects against palmitate-induced pancreatic beta-cell dysfunction and apoptosis. J Endocrinol 231:159–165. https://doi.org/10.1530/JOE-16-0317
Yatoo MI, Saxena A, Gopalakris A, Alagawany M, Dhama K (2017) Promising antidiabetic drugs, medicinal plants and herbs: an update. Int J Pharmacol 13:732–745. https://doi.org/10.3923/ijp.2017.732.745
Yun JW, Zhao ZP, Yan X, Vatamaniuk MZ, Lei XG (2019) Glutathione peroxidase-1 inhibits transcription of regenerating islet-derived protein-2 in pancreatic islets. Free Radical Bio Med 134:385–393. https://doi.org/10.1016/j.freeradbiomed.2019.01.024
Zhao LN, Hao LP, Yang XF, Ying CJ, Yu D, Sun XF (2009) The diabetogenic effects of excessive ethanol: reducing β-cell mass, decreasing phosphatidylinositol 3-kinase activity and GLUT-4 expression in rats. Brit J Nutr 101:1467–1473. https://doi.org/10.1017/s0007114508094646
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Number 21605149); National Key R&D Program of China (Grant Number 2017YFF0207800); Natural Science Foundation of Gansu Province (Grant Number 18JR3RA381); Qingdao Science and Technology Project (Grant Number 17-3-3-66-nsh).
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Wenya Chen, Lina Zhang, Jing Chen, and Yongsheng Li. The first draft of the manuscript was written by Wenya Chen, Jianteng Wei and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Chen, W., Wei, J., Zhang, L. et al. Fish Roe Polypeptide Exerts Hypoglycemia Activity via Regulating Insulin Secretion Mediated by Nrf2/ERK Signaling. Int J Pept Res Ther 27, 543–553 (2021). https://doi.org/10.1007/s10989-020-10106-7
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DOI: https://doi.org/10.1007/s10989-020-10106-7