The role of carboxymethyl chitosan/Hyaluronic acid embedded gold nanoparticles as hyperlipidemic and leptin resistance agent

Document Type : Original Article


1 Department of nutritional chemistry and metabolism, National Nutrition Institute, 11562, Cairo, Egypt.

2 Pre-Treatment and Finishing of Cellulosic Fabric Department, Institute of Textile Research and Technology, National Research Center, 33- El- Buhouth St, Dokki, Cairo, 12622- Egypt.

3 Chemistry Department, Faculty of Science (Girls Branch), Al-Azhar University, Cairo, Egypt.

4 Botany and Microbiology Department, Faculty of Science, Al-Azhar University, 11884, Cairo, Egypt.


In this work, hyaluronic acid (HA)/carboxymethyl chitosan (CMCTs) blend, embedded with definite amount of gold nanoparticles (AuNPs), were utilized to mitigate lipid profile and leptin resistance in obese rats. AuNPs were produced through Microwave radiation technique, followed by characterization using the state of art analysis; UV and TEM, Average particle size EDX, XRD and IR. Afterward, 70 male albino rats were divided into two main groups: Group one "n=10 rats" fed healthy diet (negative control). The 2nd group fed on the high fructose diet (HFD) for 4 weeks to induce hyperlipidemia and obesity. To this end, the 2nd group is further divided into six sub-groups. The 1st one (G2) received only HFD (positive control), the 2nd subgroups(G3) received HFD+CMCTS+HA, the3rd subgroups (G4) received HFD+ AuNPs, the 4th ,5th and6th subgroups (G5, G6 and G7) received orally; mixture of both HA and CMCTS in different ratios (3:1; 1:1; 1:3 respectively) embedded all with AuNPs (0.01M), in a dose of 2 mg/kg body weight /day for 4 weeks. The impact of polymers blends with AuNPs on Methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumonias (K. pneumonia)and Candida albicans (ATCC 10231) (C. albicans) was investigated. Results had the best the anti-bacterial and fungal effect for polymers blends in all ratios with AuNPs than for polymers and AuNPs separately. All treated groups (G3, G4, G5, G6 and G7) decreased leptin and lipid profile parameters levels (Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL) very low-density lipoprotein (VLDL), atherogenic indices (Atherogenic Index (AI), Atherogenic Coefficient (AC) and Cardiogenic Risk Ratio (CRR)) compared to HFD group. Moreover, the mixture of HA/CMCTS (1:3) adorned AuNPs was more potent than other used ratios in attenuating various biochemical and histological abnormalities resulted due to obesity metabolic disorders. Furthermore, all treated subgroups disclosed normal histopathological heart muscle structures.


Main Subjects

[1].         Fallacara A, Baldini E, Manfredini S, Vertuani S. Hyaluronic acid in the third millennium. Polymers. 2018;10(7):701.
[2].         Highley CB, Prestwich GD, Burdick JA. Recent advances in hyaluronic acid hydrogels for biomedical applications. Current opinion in biotechnology. 2016;40:35-40.
[3].         Tripodo G, Trapani A, Torre ML, Giammona G, Trapani G, Mandracchia D. Hyaluronic acid and its derivatives in drug delivery and imaging: recent advances and challenges. European Journal of Pharmaceutics and Biopharmaceutics. 2015;97:400-16.
[4].         Abou-Okeil A, Fahmy H, Fouda MM, Aly A, Ibrahim H. Hyaluronic acid/oxidized К-carrageenan electrospun nanofibers synthesis and antibacterial properties. BioNanoScience. 2021;11(3):687-95.
[5].         Biswas S, Ahmed T, Islam MM, Islam MS, Rahman MM. Biomedical applications carboxymethyl chitosans. Handbook of Chitin and Chitosan: Volume 3: Chitin-and Chitosan-based Polymer Materials for Various Applications. 2020:433.
[6].         Sionkowska A, Gadomska M, Musiał K, Piątek J. Hyaluronic acid as a component of natural polymer blends for biomedical applications: a review. Molecules. 2020;25(18):4035.
[8].         Hilmi MSF, Azhari S, Hassan MHA. Review on Gold Nanoparticles and Their Applications as Smart Sensing Devices. Malaysian Journal of Science Health & Technology. 2019;4(Special Issue).
[9].         Amina SJ, Guo B. A review on the synthesis and functionalization of gold nanoparticles as a drug delivery vehicle. International Journal of Nanomedicine. 2020;15:9823.
[10].       García-Torra V, Cano A, Espina M, Ettcheto M, Camins A, Barroso E, et al. State of the art on toxicological mechanisms of metal and metal oxide nanoparticles and strategies to reduce toxicological risks. Toxics. 2021;9(8):195.
[11].       Patra JK, Das G, Fraceto LF, Campos EVR, del Pilar Rodriguez-Torres M, Acosta-Torres LS, et al. Nano based drug delivery systems: recent developments and future prospects. Journal of nanobiotechnology. 2018;16(1):1-33.
[12].       Chen H, Ng JP, Tan Y, McGrath K, Bishop DP, Oliver B, et al. Gold nanoparticles improve metabolic profile of mice fed a high-fat diet. Journal of nanobiotechnology. 2018;16(1):1-12.
[13].       Sarkar S, Das D, Dutta P, Kalita J, Wann SB, Manna P. Chitosan: A promising therapeutic agent and effective drug delivery system in managing diabetes mellitus. Carbohydrate polymers. 2020;247:116594.
[14].       Satitsri S, Muanprasat C. Chitin and chitosan derivatives as biomaterial resources for biological and biomedical applications. Molecules. 2020;25(24):5961.
[15].       Yu Y, Luo T, Liu S, Song G, Han J, Wang Y, et al. Chitosan oligosaccharides attenuate atherosclerosis and decrease Non-HDL in ApoE-/-mice. Journal of Atherosclerosis and Thrombosis. 2015:22939.
[16].       Papanastasopoulou C, Papastamataki M, Karampatsis P, Anagnostopoulou E, Papassotiriou I, Sitaras N. Cardiovascular risk and serum hyaluronic acid: a preliminary study in a healthy population of low/intermediate risk. Journal of clinical laboratory analysis. 2017;31(1):e22010.
[17].       Obradovic M, Sudar-Milovanovic E, Soskic S, Essack M, Arya S, Stewart AJ, et al. Leptin and obesity: role and clinical implication. Frontiers in Endocrinology. 2021;12.
[18].       Gray A, Threlkeld R, Feingold K, Anawalt B, Boyce A. Nutritional recommendations for individuals with diabetes.[Updated 2019 Oct 13]. Endotext [Internet]. 2015.
[19].       De Git K, Adan R. Leptin resistance in diet‐induced obesity: the role of hypothalamic inflammation. Obesity reviews. 2015;16(3):207-24.
[20].       Hussein J, El-Naggar ME, Fouda MM, Othman SI, Allam AA, Nadwa EH, et al. Eco-friendly Microwave Synthesis of Gold Nanoparticles for Attenuation of Brain Dysfunction in Diabetic Rats. Journal of Cluster Science. 2021;32(2):423-35.
[21].       Rodriguez-Tudela J, Barchiesi F, Bille J, Chryssanthou E, Cuenca-Estrella M, Denning D, et al. Method for the determination of minimum inhibitory concentration (MIC) by broth dilution of fermentative yeasts. Clinical Microbiology and Infection. 2003;9(8):i-viii.
[22].       Reeves PG. Purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformation of the AIN-76A rodent diet. J Nutr. 1993;123:1939-51.
[23].       Rajasekar P, Ravichandran MK, Anuradha CV. Intraperitoneal L-carnitine regulates lipid metabolism and reduces oxidative stress in fructose-induced hyperlipidemic rats. Diabetologia Croatica. 2005;34(3):87-95.
[24].       Manjula K, Krishna R. Feed efficiency and serobiochemical profile of wistar rats fed with spirulina as functional food. Current Research in Nutrition and Food Science Journal. 2016;4(2):135-40.
[25].       Abdullah A, Bakry S, Abd El-Baky A, Mansour A. Evaluation of the antioxidative, antidiabetic and antilipidemic effect of bitter mel on seeds (citrullus colocynthis) alcoholic extract on female rats. Al-Azhar Bulletin of Science. 2010;21(1-C):13-26.
[26].       Rifai N. Tietz textbook of clinical chemistry and molecular diagnostics: Elsevier Health Sciences; 2017.
[27].       Young DS, Friedman RB. Effects of disease on clinical laboratory tests: Amer Assn for Clinical Chemistry; 2001.
[28].       Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry. 1972;18(6):499-502.
[29].       Selendili O, Günay E, Kaçar E, Çilekar Ş, Öz G, Dumanli A, et al. Atherogenic Indices Can Predict Atherosclerosis in Patients with Sarcoidosis. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 2022;38(4).
[30].       Aniagu SO, Nwinyi FC, Akumka DD, Ajoku GA, Dzarma S, Izebe KS, et al. Toxicity studies in rats fed nature cure bitters. African Journal of Biotechnology. 2005;4(1):72-8.
[31].       Bancroft JD, Gamble M. Theory and practice of histological techniques: Elsevier health sciences; 2008.
[32].       El-Naggar ME, Shaheen TI, Fouda MM, Hebeish AA. Eco-friendly microwave-assisted green and rapid synthesis of well-stabilized gold and core–shell silver–gold nanoparticles. Carbohydrate polymers. 2016;136:1128-36.
[33].       Regiel A, Irusta S, Kyzioł A, Arruebo M, Santamaria J. Preparation and characterization of chitosan–silver nanocomposite films and their antibacterial activity against Staphylococcus aureus. Nanotechnology. 2012;24(1):015101.
[34].       Bedolla-Cázares F, Hernández-Marcelo PE, Gómez-Hurtado MA, Rodríguez-García G, Rosa E, López-Castro Y, et al. Silver nanoparticles from AgNO 3–affinin complex synthesized by an ecofriendly route: Chitosan-based electrospun composite production. Clean Technologies and Environmental Policy. 2017;19(3):897-906.
[35].       Hussein J, El-Naggar ME, Fouda MM, Morsy OM, Ajarem JS, Almalki AM, et al. The efficiency of blackberry loaded AgNPs, AuNPs and Ag@ AuNPs mediated pectin in the treatment of cisplatin-induced cardiotoxicity in experimental rats. International Journal of Biological Macromolecules. 2020;159:1084-93.
[36].       Khan A, Rashid R, Murtaza G, Zahra A. Gold nanoparticles: synthesis and applications in drug delivery. Tropical journal of pharmaceutical research. 2014;13(7):1169-77.
[37].       Fouda MM, Ajarem JS, Maodaa SN, Allam AA, Taher MM, Ahmed M. Carboxymethyl cellulose supported green synthetic features of gold nanoparticles: antioxidant, cell viability, and antibacterial effectiveness. Synthetic Metals. 2020;269:116553.
[38].       Ke X, Sarina S, Zhao J, Zhang X, Chang J, Zhu H. Tuning the reduction power of supported gold nanoparticle photocatalysts for selective reductions by manipulating the wavelength of visible light irradiation. Chemical Communications. 2012;48(29):3509-11.
[39].       Yang S-C, Ryu J, Choi K-O, Kang TS, Lee JK, Song CW, et al. Dynamic light scattering-based method to determine primary particle size of iron oxide nanoparticles in simulated gastrointestinal fluid. Food chemistry. 2014;161:185-91.
[40].       Kaczmarek B, Sionkowska A, Monteiro F, Carvalho A, Łukowicz K, Osyczka A. Characterization of gelatin and chitosan scaffolds cross-linked by addition of dialdehyde starch. Biomedical Materials. 2017;13(1):015016.
[41].       Skopinska-Wisniewska J, Wegrzynowska-Drzymalska K, Bajek A, Maj M, Sionkowska A. Is dialdehyde starch a valuable cross-linking agent for collagen/elastin based materials? Journal of Materials Science: Materials in Medicine. 2016;27(4):1-10.
[42].       Farag RK, Mohamed RR. Synthesis and characterization of carboxymethyl chitosan nanogels for swelling studies and antimicrobial activity. Molecules. 2013;18(1):190-203.
[43].       Taher F, Amin R, Abd El-Aziz A, Abou Senna F, Abou El-Nou M, El-Mehdawy A, editors. Characterization and antibacterial effect of chitosan nanoparticles prepared by ball-milling from shell of shrimp, Penaeus semisulcatus (Crustacea: Penaeidae), Al Azhar Bulletin Sci. Al Azhar Bulletin Sci Conf; 2017.
[44].       Larrañeta E, Henry M, Irwin NJ, Trotter J, Perminova AA, Donnelly RF. Synthesis and characterization of hyaluronic acid hydrogels crosslinked using a solvent-free process for potential biomedical applications. Carbohydrate polymers. 2018;181:1194-205.
[45].       Botteon C, Silva L, Ccana-Ccapatinta G, Silva T, Ambrosio S, Veneziani R, et al. Biosynthesis and characterization of gold nanoparticles using Brazilian red propolis and evaluation of its antimicrobial and anticancer activities. Scientific Reports. 2021;11(1):1-16.
[46].       Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. The Journal of clinical investigation. 2018;128(2):545-55.
[47].       Lozano I, Van der Werf R, Bietiger W, Seyfritz E, Peronet C, Pinget M, et al. High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutrition & metabolism. 2016;13(1):1-13.
[48].       Sandeva RV, Mihaylova SM, Sandeva GN, Trifonova KY, Popova-Katsarova RD. Effect of high-fructose solution on body weight, body fat, blood glucose and triglyceride levels in rats. Journal of Biomedical and Clinical Research. 2015;8(1):5-8.
[49].       Soliman AF, Abdel-Rahman MA, Hamad H, Eltamany EH, Al-Sherbini A-S. The synthesis and characterization of gold nanoparticles with polyunsaturated oils contribute to hypolipidemic and anti-obesity activities in vivo. Egyptian Journal of Chemistry. 2020;63(11):4205-16.
[50].       Ng JP, Chen H, Cortie M, Milthorpe BK, Valenzuela SM. A gold bullet to treat obesity related metabolic disorders. Obesity Research & Clinical Practice. 2014(8):73.
[51].       Patti AM, Katsiki N, Nikolic D, Al-Rasadi K, Rizzo M. Nutraceuticals in lipid-lowering treatment: a narrative review on the role of chitosan. Angiology. 2015;66(5):416-21.
[52].       Chen W-Y, Lin F-H. Oxidized hyaluronic acid hydrogels as a carrier for constant-release clenbuterol against high-fat diet-induced obesity in mice. Frontiers in endocrinology. 2021;12:102.
[53].       Newairy A-SA, Abdou HM. Protective role of flax lignans against lead acetate induced oxidative damage and hyperlipidemia in rats. Food and Chemical Toxicology. 2009;47(4):813-8.
[54].       Chen H, Ng JP, Bishop DP, Milthorpe BK, Valenzuela SM. Gold nanoparticles as cell regulators: beneficial effects of gold nanoparticles on the metabolic profile of mice with pre-existing obesity. Journal of nanobiotechnology. 2018;16(1):1-13.
[55].       Bahijri SM, Alsheikh L, Ajabnoor G, Borai A. Effect of supplementation with chitosan on weight, cardiometabolic, and other risk indices in Wistar rats fed normal and high-fat/high-cholesterol diets ad libitum. Nutrition and Metabolic Insights. 2017;10:1178638817710666.
[56].       Nelson F, Zvirbulis R, Zonca B, Li K, Turner S, Pasierb M, et al. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatology international. 2015;35(1):43-52.
[57].       Liao Z-X, Liu M-C, Kempson IM, Fa Y-C, Huang K-Y. Light-triggered methylcellulose gold nanoparticle hydrogels for leptin release to inhibit fat stores in adipocytes. International Journal of Nanomedicine. 2017;12:7603.
[58].       Handayani D, Febrianingsih E, Kurniawati AD, Kusumastuty I, Nurmalitasari S, Widyanto RM, et al. High-fructose diet initially promotes increased aortic wall thickness, liver steatosis, and cardiac histopathology deterioration, but does not increase body fat index. Journal of Public Health Research. 2021;10(2).
[59].       Fu B, Wang X, Chen Z, Jiang N, Guo Z, Zhang Y, et al. Improved myocardial performance in infarcted rat heart by injection of disulfide-cross-linked chitosan hydrogels loaded with basic fibroblast growth factor. Journal of Materials Chemistry B. 2022.