Protective effects of crocin and gallic acid on the liver damage induced by methylglyoxal in male mice: role of inflammatory factors Crocin, Gallic acid and hepatoprotective
Gastroenterology and Hepatology from Bed to Bench,
Vol. 16 No. 1 (2023),
2 January 2023
Aim: This study aims to evaluate whether biochemical alterations caused by methylglyoxal (MG), improves by the administration of gallic acid (GA), crocin (Cr), and metformin (MT) in the liver.
Background: MG is produced naturally through various physiological processes, but high levels of MG cause inflammation in hepatocytes. Normal liver function is essential for maintaining glucose homeostasis. Gallic acid and crocin can reduce inflammation.
Methods: This experiment was done in 5 weeks. 50 male NMRI mice were randomly divided into 5 groups (n=10): 1) Control, 2) MG (600 mg/Kg/d, p.o.), 3) MG+GA (30 mg/kg/day, p.o.), 4) MG+Cr (60 mg/kg/day, p.o.), 5) MG+MT (150 mg/kg/day, p.o.). After one week of habituation, MG was administered for four weeks. Gallic acid, crocin, and metformin were administered in the last two weeks. Biochemical and histologic evaluations were assessed after plasma collection and tissue sample preparation.
Results: Gallic acid and crocin-received groups significantly reduced fasting blood glucose, total cholesterol, triglyceride levels, and elevated insulin sensitivity. Administration of MG exerted a marked increase in the levels of hepatic enzymes. Treatment with gallic acid, crocin, and metformin significantly decreased them. The altered levels of inflammatory factors in the diabetic group were significantly improved in the diabetic-treated groups. High levels of steatosis and red blood cells (RBCs) accumulation in the MG group markedly recovered in other treated mice.
Conclusion: Harmful effects of accumulated MG in the liver of diabetic mice were effectively attenuated by using gallic acid and crocin.
- Methylglyoxal, Gallic acid, Crocin, TNF-α, Liver
How to Cite
Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Baltimore) 2019;47:22–27.
Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4–14.
Lee BH, Hsu WH, Chang YY, Kuo HF, Hsu YW, Pan TM. Ankaflavin: a natural novel PPARγ agonist upregulates Nrf2 to attenuate methylglyoxal-induced diabetes in vivo. Free Radic Biol Med 2012;53:2008-2016.
Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci 2020;21:6275.
Saki K, Mansouri V, Abdi S, Fathi M, Razzaghi Z, Haghazali M. Assessment of common and differentially expressed proteins between diabetes mellitus and fatty liver disease: a network analysis. Gastroenterol Hepatol From Bed to Bench 2021;14:94.
Zhang J, Zhang L, Zhang S, Yu Q, Xiong F, Huang K, et al. HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. Mol Cell Endocrinol 2017;454:103–11.
Tang D, Kang R, Livesey KM, Cheh C-W, Farkas A, Loughran P, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol 2010;190:881–892.
Yang L, Zhou L, Wang X, Wang W, Wang J. Inhibition of HMGB1 involved in the protective of salidroside on liver injury in diabetes mice. Int Immunopharmacol 2020;89:106987.
Chen M, Huang W, Wang C, Nie H, Li G, Sun T, et al. High-mobility group box 1 exacerbates CCl4-induced acute liver injury in mice. Clin Immunol 2014;153:56–63.
Römermann D, Ansari N, Schultz‐Moreira AR, Michael A, Marhenke S, Hardtke‐Wolenski M, et al. Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury. Liver Int 2020;40:1225-1238.
Qian H, Chao X, Williams J, Fulte S, Li T, Yang L, et al. Autophagy in liver diseases: A review. Mol Aspects Med 2021;100973.
Horiuchi T, Sakata N, Narumi Y, Kimura T, Hayashi T, Nagano K, et al. Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. J Biol Chem 2017;292:8436–8446.
Silvares RR, Pereira ENG da S, Flores EEI, Estato V, Reis PA, Silva IJ da, et al. Combined therapy with metformin and insulin attenuates systemic and hepatic alterations in a model of high‐fat diet‐/streptozotocin‐induced diabetes. Int J Exp Pathol 2016;97:266–277.
Yin H, Huang L, Ouyang T, Chen L. Baicalein improves liver inflammation in diabetic db/db mice by regulating HMGB1/TLR4/NF-κB signaling pathway. Int Immunopharmacol 2018;55:55–62.
Kim JK, Shin KK, Kim H, Hong YH, Choi W, Kwak Y-S, et al. Korean red ginseng exerts anti-inflammatory and autophagy-promoting activities in aged mice. J Ginseng Res 2021;45:717–725.
Zhou J, Massey S, Story D, Li L. Metformin: an old drug with new applications. Int J Mol Sci 2018;19:2863.
Yanardag R, Ozsoy-Sacan O, Bolkent S, Orak H, Karabulut-Bulan O. Protective effects of metformin treatment on the liver injury of streptozotocin-diabetic rats. Hum Exp Toxicol 2005;24:129–135.
Mojadami S, Ahangarpour A, Mard SA, Khorsandi L. Diabetic nephropathy induced by methylglyoxal: gallic acid regulates kidney microRNAs and glyoxalase1–Nrf2 in male mice. Arch Physiol Biochem 2021;1–8.
Kahkeshani N, Farzaei F, Fotouhi M, Alavi SS, Bahramsoltani R, Naseri R, et al. Pharmacological effects of gallic acid in health and diseases: A mechanistic review. Iran J Basic Med Sci 2019;22:225.
Latief U, Husain H, Mukherjee D, Ahmad R. Hepatoprotective efficacy of gallic acid during Nitrosodiethylamine-induced liver inflammation in Wistar rats. J Basic Appl Zool 2016;76:31–41.
de Oliveira LS, Thomé GR, Lopes TF, Reichert KP, de Oliveira JS, da Silva Pereira A, et al. Effects of gallic acid on delta–aminolevulinic dehydratase activity and in the biochemical, histological and oxidative stress parameters in the liver and kidney of diabetic rats. Biomed Pharmacother 2016;84:1291–1299.
Bashar SM, Elhadidy MG, Mostafa AF, Hamed B, Helmy S, Abd-Elmoniem HA. Hepatoprotective effect of gallic acid against type 2-induced diabetic liver injury in male rats through modulation of fetuin-A and GLP-1 with involvement of ERK1/2/NF-κB and Wnt1/β-catenin signaling pathways. Gen Physiol Biophys 2021;40:221–234.
Pashirzad M, Shafiee M, Avan A, Ryzhikov M, Fiuji H, Bahreyni A, et al. Therapeutic potency of crocin in the treatment of inflammatory diseases: Current status and perspective. J Cell Physiol 2019;234:14601–14611.
Yaribeygi H, Mohammadi MT, Sahebkar A. Crocin potentiates antioxidant defense system and improves oxidative damage in liver tissue in diabetic rats. Biomed Pharmacother 2018;98:333–337.
Chhimwal J, Sharma S, Kulurkar P, Patial V. Crocin attenuates CCl4-induced liver fibrosis via PPAR-γ mediated modulation of inflammation and fibrogenesis in rats. Hum Exp Toxicol 2020;39:1639-1649.
Kalantar M, Kalantari H, Goudarzi M, Khorsandi L, Bakhit S, Kalantar H. Crocin ameliorates methotrexate-induced liver injury via inhibition of oxidative stress and inflammation in rats. Pharmacol Reports 2019;71:746–752.
Radmehr V, Ahangarpour A, Mard SA, Khorsandi L. Crocin ameliorates MicroRNAs-associated ER stress in type 2 diabetes induced by methylglyoxal. Iran J Basic Med Sci 2022;25:179–186.
Topsakal S, Ozmen O, Cicek E, Comlekci S. The ameliorative effect of gallic acid on pancreas lesions induced by 2.45 GHz electromagnetic radiation (Wi-Fi) in young rats. J Radiat Res Appl Sci 2017;10:233–240.
Vakili A, Einali MR, Bandegi AR. Protective effect of crocin against cerebral ischemia in a dose-dependent manner in a rat model of ischemic stroke. J Stroke Cerebrovasc Dis 2014;23:106–113.
Qi SS, Zheng HX, Jiang H, Yuan LP, Dong LC. Protective effects of chromium picolinate against diabetic-induced renal dysfunction and renal fibrosis in streptozotocin-induced diabetic rats. Biomolecules 2020;10:398.
Sharma R, Tiwari S. Renal gluconeogenesis in insulin resistance: A culprit for hyperglycemia in diabetes. World J Diabetes 2021;12:556.
Schalkwijk CG, Stehouwer CDA. Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications, and other age-related diseases. Physiol Rev 2020;100:407–461.
Hanssen NMJ, Stehouwer CDA, Schalkwijk CG. Methylglyoxal stress, the glyoxalase system, and diabetic chronic kidney disease. Curr Opin Nephrol Hypertens 2019;28:26–33.
Biddinger SB, Hernandez-Ono A, Rask-Madsen C, Haas JT, Alemán JO, Suzuki R, et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab 2008;7:125–134.
Shirali S, Zahra Bathaie S, Nakhjavani M. Effect of crocin on the insulin resistance and lipid profile of streptozotocin‐induced diabetic rats. Phyther Res 2013;27:1042–1047.
Hewedy WA. Effects of treatment with sitagliptin on hepatotoxicity induced by acetaminophen in mice. Brazilian J Pharm Sci 2021;56.
Sun L, Wen S, Li Q, Lai X, Chen R, Zhang Z, et al. L-theanine relieves acute alcoholic liver injury by regulating the TNF-α/NF-κB signaling pathway in C57BL/6J mice. J Funct Foods 2021;86:104699.
Fouad D, Badr A, Attia HA. Hepatoprotective activity of raspberry ketone is mediated via inhibition of the NF-κB/TNF-α/caspase axis and mitochondrial apoptosis in chemically induced acute liver injury. Toxicol Res (Camb) 2019;8:663–676.
Ramos V, Kowaltowski A, Kakimoto P. Autophagy in hepatic steatosis: A structured review. Front cell Dev Biol 2021;9:801.
Hosny S, Sahyon H, Youssef M, Negm A. Prunus Armeniaca L. Seed extract and its amygdalin containing fraction induced mitochondrial-mediated apoptosis and autophagy in liver carcinogenesis. Anti-Cancer Agents Med Chem (Formerly Curr Med Chem Agents) 2021;21:621–629.
- Abstract Viewed: 40 times
- PDF Downloaded: 12 times