The Therapeutic Effect and Possible Mechanism of Guluronic Acid in Copper-Loaded Mice

Xi Yu¹, Yingjuan Liu², Haoyang Sun³, Yan Zheng¹, Keli Ge¹, Yunliang Guo^1, and Weiping Zhu^1,

¹Institute of Integrate Medicine, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao 266023, China

²Institute of Brain Sciences and Diseases, Qingdao University, Qingdao 266071, China

³Department of TCM, Songshan Hospital of Qingdao University Medical College, Qingdao 266021, China

Cite this paper:
Xi Yu, Yingjuan Liu, Haoyang Sun, Yan Zheng, Keli Ge, Yunliang Guo and Weiping Zhu. The Therapeutic Effect and Possible Mechanism of Guluronic Acid in Copper-Loaded Mice. Journal of Food and Nutrition Research. 2024; 12(3):138-143. doi: 10.12691/jfnr-12-3-5

Abstract

Objective: To explore the therapeutic effect and possible mechanism of low molecular weight align--guluronic acid (PG) on the copper-loaded mice, so as to provide a new idea for the prevention and treatment of Wilson's disease. Methods: Fifty healthy male Kunming mice were fed copper-loaded diet to establish the copper-loaded mouse model. The mice in treatment group were given different concentrations of PG by gavage, while the mice in control group were orally given same amount of normal solution simutaneously 1 time per day for 60 days. The neurobehavioral function of mice was evaluated by animal behavior; the liver function indexes of mice such as serum levels of total protein (TP), albumin (ALB) , globulin (GLB) were detected by biochemical assay, and the ratio of ALB/GLB (A/G) was calculated; the expression levels of ceruloplasmin (CER), adenine monophosphate activated protein kinase (AMPK) and phosphorylated-AMPK (p-AMPK) in hepatic cells were detected by Western blotting. Results: Compared with control group, the weight of mice in model (Copper) group decreased significantly (P<0.05); The time of rotating rod shortened significantly (P<0.05) and the climbing time prolonged significantly (P<0.01); The serum level of TB decreased significantly (P<0.05), while the ratio of A/G was significantly increased (P<0.05); The expression of CER enhanced significantly (P<0.05), and the level of p-AMPK/AMPK was significantly increased (P<0.05). After treated with different concentrations of PG, the weight of mice in Copper+PG-H group was significantly higher than that in Copper group (P<0.05); The time of rotating rod prolonged significantly (P<0.01) and the climbing time shortened significantly (P<0.05); The serum level of TB increased significantly (P<0.01), while the ratio of A/G was significantly dropped (P <0.05); The expression of CER reduced significantly (P<0.01) and the level of p-AMPK/AMPK was significantly decreased (P<0.01). Conclusion: PG could adsorb and excrete copper ions, reduce inflammation reaction, improve the hepatic metabolism of copper-loaded mice, so that to act a positive effect on Wilson's disease.

Keywords:
guluronic acid copper load ceruloplasmin phosphorylated-AMPK mice liver

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Ferenci P. Review article: diagnosis and current therapy of Wilson's disease. Aliment Pharmacol Ther, 2004, 19(2): 157-165.
[2]	Zhou XX, He RX, Pu XY, et al. Clinical characteristics of the Wilson disease carrier. Zhonghua Yixue Zazhi, 2019, 99(11): 806-811.
[3]	Yang F, Liao J, Pei R, et al. Autophagy attenuates copper-induced mitochondrial dysfunction by regulating oxidative stress in chicken hepatocytes. Chemosphere, 2018, 204(1): 36-43.
[4]	Narindrasorasak S, Kulkarni P, Deschamps P, et al. Characterization and copper binding properties of human COMMD1 (MURR1). Biochemistry, 2007, 46(11): 3116-3128.
[5]	Xu R, Jiang YF, Zhang YH, et al. The optimal threshold of serum ceruloplasmin in the diagnosis of Wilson's disease: A large hospital-based study. PLoS One, 2018, 13(1): e0190887.
[6]	Gonzalez M, Reyes-Jara A, Suazo M, et al. Expression of copper-related genes in response to copper load. Am J Clin Nutr, 2008, 88(3): 830S-834S.
[7]	Wang J, Ma X, Gao X, et al. Glutathione metabolism is conserved in response to excessive copper exposure between mice liver and Aurelia coerulea polyps. Sci Total Environ, 2023, 881(6): 163382-163389.
[8]	Guo YL, Zhang GF, Liu YJ, et al. The new use of algin in trenttment of hepatolenticular degeneration. ZL 202110645751.9. 2022-09-23.
[9]	Nan B, Zhou Z, Wang GX, et al. The neuroprotective effect and mechanism of algin for Wilson’s disease in mice. Chin J Marin Drug, 2022, 41(4): 36-44.
[10]	Wang Y, Yu X, Liu ZS, et al. The protective effect and mechanism of algin on liver of hepatolenticular degeneration in mice. Chin J Marine Drug, 2022, 41(5): 32-40.
[11]	Zhang J, Zhu M, Wang Q, et al. The combined use of copper sulfate and trichlorfon exerts stronger toxicity on the liver of Zebrafish. Int J Mol Sci, 2023, 24(13): 11203.
[12]	Xu L, Cai YL, Xu ZS, et al. Study of Tiopronin combine Penicillamine to treated in rat model with hepatolenticular degeneration. J Clin Neirol, 2007, 20(6): 450-452.
[13]	Xu Y, Zhu W, Wang T, et al. Low molecule weight fucoidan mitigates atherosclerosis in ApoE (-/-) mouse model through activating multiple signal pathway. Carbohydr Polym, 2019, 206(1): 110-120.
[14]	Schilsky ML. Wilson disease: Clinical manifestations, diagnosis, and treatment. Clin Liver Dis (Hoboken), 2014, 3(5): 104-107.
[15]	Chen L, Min J, Wang F. Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Ther, 2022, 7(1): 378-378.
[16]	Dziezyc-Jaworska K, Litein T, Czlonkoeska A. Clinical manifestations of Wilson disease in organs other than the liver and brain. Ann Transl Med, 2019, 7(Sup 2): S62.
[17]	Penning LC, Berenguer M, Czlonkowska A, et al. A century of progress on Wilson disease and the enduring challenges of genetics, diagnosis, and treatment. Biomedicines, 2023, 11(2):420.
[18]	Zeng BF, Shi R, Wu ML, et al. Research progress into the functional characteristics of alginate oligosaccharides. Food Res Dev, 2022, 43(13): 210-216.
[19]	Li Y, Liu F, Xia B, et al. Removal of copper from aqueous solution by carbon nanotube/calcium alginate composites. J Hazard Mater, 2010, 177(1/3): 876-880.
[20]	Yang RM. Hepatolenticular Degeneration. 1st ed. Beijing: People's Health press, 2015: 126-127.
[21]	Gaware V, Kotade K, Dhamak K, et al. Ceruloplasmin, its role and significance: A review. Int J Biomed Res, 2011, 1(4): 153-162.
[22]	Cauza E, Maier-Dobersberger T, Polli C, et al. Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin. J Hepatol, 1997, 27(2): 358-362.
[23]	Hardie DG, Schaffer BE, Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends in Cell Biology, 2016, 26(3): 190-201.
[24]	Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Revi Mol Cell Biol, 2018, 19(2): 121-135.
[25]	Panda PK, Mukhopadhyay S, Das DN, et al. Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics. Seminars in Cell & Developmental Biology. Academic Press, 2015, 39: 43-55.
[26]	Yang F, Ccan HB, Su RS, et al. Liver mitochondrial dysfunction and electron transport chain defect induced by high dietary copper in broilers. Poult Sci, 2017, 96(9): 3298-3304.
[27]	Liao J, Yang F, Chen H, et al. Effects of copper on oxidative stress and autophagy in hypothalamus of broilers. Ecotoxicology and Environmental Safety, 2019, 185: 109710.