Research Advances in Chitosan Oligosaccharides: From Multiple Biological Activities to Clinical Applications

Zhen       Yi; Xiao       Luo; Lei       Zhao
Abstract

Chitosan oligosaccharides (COS), hydrolysed products of chitosan, are low-molecular weight polymers with a positive charge and good biocompatibility. COS have recently been reported to possess various biological activities, including hypoglycaemic, hypolipidaemic, antioxidantantioxidant, immune regulation, anti-inflammatory, antitumour, antibacterial, and tissue engineering activities, exhibiting extensive application prospects. Currently, the biological processes and mechanisms of COS are attractive topics of study, ranging from the genetic, molecular and protein levels. This article reviews the recent discoveries about COS, especially in metabolic regulation, immune function and tissue repair, providing important insights into their multiple biological activities, medical benefits, and therapeutic mechanisms.
Keywords: Chitosan, Chitosan oligosaccharides, biological activities, mechanisms, nanoparticle, tissue engineering.
[1] 
 kim, S.K.; Rajapakse, N. Enzymatic production and biological activities of chitosan oligosaccharides (COS): a review. Carbohydr. Polym.,  2005, 62, 357-368.
[http://dx.doi.org/10.1016/j.carbpol.2005.08.012] 
[2] 
Zhang, J.; Xia, W.; Liu, P.; Cheng, Q.; Tahirou, T.; Gu, W.; Li, B. Chitosan modification and pharmaceutical/biomedical applications. Mar. Drugs,  2010, 8(7), 1962-1987.
[http://dx.doi.org/10.3390/md8071962] [PMID:  20714418] 
[3] 
Liaqat, F.; Eltem, R. Chitooligosaccharides and their biological activities: a comprehensive review. Carbohydr. Polym.,  2018, 184, 243-259.
[http://dx.doi.org/10.1016/j.carbpol.2017.12.067] [PMID:  29352917] 
[4] 
Rahman, M.A.; Ochiai, B. Fabrication and hemocompatibility of carboxy-chitosan stabilized magnetite nanoparticles. Microsyst. Technol.,  2018, 24, 669-681.
[http://dx.doi.org/10.1007/s00542-017-3318-8] 
[5] 
Chokradjaroen, C.; Rujiravanit, R.; Theeramunkong, S.; Saito, N. Degradation of chitosan hydrogel dispersed in dilute carboxylic acids by solution plasma and evaluation of anticancer activity of degraded products. jap. j. app. phy.,,  2018, 57(1), 0102b5.
[http://dx.doi.org/10.7567/jjap.57.0102b5] 
[6] 
Prabaharan, M. Review paper: chitosan derivatives as promising materials for controlled drug delivery. J. Biomater. Appl.,  2008, 23(1), 5-36.
[http://dx.doi.org/10.1177/0885328208091562] [PMID:  18593819] 
[7] 
Ahlafi, H.; Moussout, H.; Boukhlifi, F.; Echetna, M.; Bennani, M.N.; My Slimane, S. Kinetics of N-deacetylation of chitin extracted from shrimp shells collected from coastal area of Morocco. Mediterr. J. Chem.,  2013, 2, 503-513.
[http://dx.doi.org/10.13171/mjc.2.3.2013.22.01.20] 
[8] 
Chae, S.Y.; Jang, M.-K.; Nah, J.-W. Influence of molecular weight on oral absorption of water soluble chitosans. J. Control. Release,  2005, 102(2), 383-394.
[http://dx.doi.org/10.1016/j.jconrel.2004.10.012] [PMID:  15653159] 
[9] 
Mohammedi, Z. Chitosan and chitosan oligosaccharides: applications in medicine, agriculture and biotechnology. Int. J. Bioorganic Chem.,  2017, 2, 102-106.
[10] 
Alam, U.; Asghar, O.; Azmi, S.; Malik, R.A. General aspects of diabetes mellitus. Handb. Clin. Neurol.,  2014, 126, 211-222.
[http://dx.doi.org/10.1016/B978-0-444-53480-4.00015-1] [PMID:  25410224] 
[11] 
Of, D.; Mellitus, D. American diabetes association. Diagnosis and classification of diabetes mellitus. Diabetes Care,  2014, 37(Suppl. 1), S81-S90.
[http://dx.doi.org/10.2337/dc14-S081] [PMID:  24357215] 
[12] 
Grover, M.; Utreja, P. Recent advances in drug delivery systems for anti-diabetic drugs: a review. Curr. Drug Deliv.,  2014, 11(4), 444-457.
[http://dx.doi.org/10.2174/1567201811666140118225021] [PMID:  24438443] 
[13] 
Miura, T.; Usami, M.; Tsuura, Y.; Ishida, H.; Seino, Y. Hypoglycemic and hypolipidemic effect of chitosan in normal and neonatal streptozotocin-induced diabetic mice. Biol. Pharm. Bull.,  1995, 18(11), 1623-1625.
[http://dx.doi.org/10.1248/bpb.18.1623] [PMID:  8593495] 
[14] 
Kondo, Y.; Nakatani, A.; Hayashi, K.; Ito, M. Low molecular weight chitosan prevents the progression of low dose streptozotocin-induced slowly progressive diabetes mellitus in mice. Biol. Pharm. Bull.,  2000, 23(12), 1458-1464.
[http://dx.doi.org/10.1248/bpb.23.1458] [PMID:  11145178] 
[15] 
Lee, H.-W.; Park, Y.-S.; Choi, J.-W.; Yi, S.Y.; Shin, W.-S. Antidiabetic effects of chitosan oligosaccharides in neonatal streptozotocin-induced noninsulin-dependent diabetes mellitus in rats. Biol. Pharm. Bull.,  2003, 26(8), 1100-1103.
[http://dx.doi.org/10.1248/bpb.26.1100] [PMID:  12913258] 
[16] 
Chuanxia, J.U.; Ue, W.Y.; Ang, Z.Y.; Hang, Q.Z.; Ang, X.Y.; Iu, Z.L. Antidiabetic effect and mechanism of chitooligosaccharides. Biol Pharm Bull,  2010, 33, 1511-1516.
[http://dx.doi.org/10.1248/bpb.33.1511] [PMID:  20823566] 
[17] 
Kim, J.N.; Chang, I.Y.; Kim, H.I.; Yoon, S.P. Long-term effects of chitosan oligosaccharide in streptozotocin-induced diabetic rats. Islets,  2009, 1(2), 111-116.
[http://dx.doi.org/10.4161/isl.1.2.9143] [PMID:  21099258] 
[18] 
Liu, B.; Liu, W.S.; Han, B.Q.; Sun, Y.Y. Antidiabetic effects of chitooligosaccharides on pancreatic islet cells in streptozotocin-induced diabetic rats. World J. Gastroenterol.,  2007, 13(5), 725-731.
[http://dx.doi.org/10.3748/wjg.v13.i5.725] [PMID:  17278195] 
[19] 
Kumar, S.G.; Rahman, M.A.; Lee, S.H.; Hwang, H.S.; Kim, H.A.; Yun, J.W. Plasma proteome analysis for anti-obesity and anti-diabetic potentials of chitosan oligosaccharides in ob/ob mice. Proteomics,  2009, 9(8), 2149-2162.
[http://dx.doi.org/10.1002/pmic.200800571] [PMID:  19296549] 
[20] 
Katiyar, D.; Singh, B.; Lall, A.M.; Haldar, C. Efficacy of chitooligosaccharides for the management of diabetes in alloxan induced mice: a correlative study with antihyperlipidemic and antioxidative activity. Eur. J. Pharm. Sci.,  2011, 44(4), 534-543.
[http://dx.doi.org/10.1016/j.ejps.2011.09.015] [PMID:  21964204] 
[21] 
Jo, S.H.; Ha, K.S.; Moon, K.S.; Kim, J.G.; Oh, C.G.; Kim, Y.-C.; Apostolidis, E.; Kwon, Y.-I. Molecular weight dependent glucose lowering effect of low molecular weight Chitosan Oligosaccharide (GO2KA1) on postprandial blood glucose level in SD rats model. Int. J. Mol. Sci.,  2013, 14(7), 14214-14224.
[http://dx.doi.org/10.3390/ijms140714214] [PMID:  23839092] 
[22] 
Kim, J.-G.; Jo, S.-H.; Ha, K.-S.; Kim, S.-C.; Kim, Y.-C.; Apostolidis, E.; Kwon, Y.-I. Effect of long-term supplementation of low molecular weight chitosan oligosaccharide (GO2KA1) on fasting blood glucose and HbA1c in db/db mice model and elucidation of mechanism of action. BMC Complement. Altern. Med.,  2014, 14, 272.
[http://dx.doi.org/10.1186/1472-6882-14-272] [PMID:  25074485] 
[23] 
Kim, H.J.; Ahn, H.Y.; Kwak, J.H.; Shin, D.Y.; Kwon, Y.I.; Oh, C.G.; Lee, J.H. The effects of chitosan oligosaccharide (GO2KA1) supplementation on glucose control in subjects with prediabetes. Food Funct.,  2014, 5(10), 2662-2669.
[http://dx.doi.org/10.1039/C4FO00469H] [PMID:  25222285] 
[24] 
Brahm, A.J.; Hegele, R.A. Combined hyperlipidemia: familial but not (usually) monogenic. Curr. Opin. Lipidol.,  2016, 27(2), 131-140.
[http://dx.doi.org/10.1097/MOL.0000000000000270] [PMID:  26709473] 
[25] 
Anderson, J.W.; Konz, E.C.; Jenkins, D.J.A. Health advantages and disadvantages of weight-reducing diets: a computer analysis and critical review. J. Am. Coll. Nutr.,  2000, 19(5), 578-590.
[http://dx.doi.org/10.1080/07315724.2000.10718955] [PMID:  11022871] 
[26] 
Kang, N.H.; Lee, W.K.; Yi, B.R.; Lee, H.R.; Park, M.A.; Park, S.K.; Park, H.K.; Choi, K.C. Risk of cardiovascular disease is suppressed by dietary supplementation with protamine and chitooligosaccharide in Sprague-Dawley rats. Mol. Med. Rep.,  2013, 7(1), 127-133.
[http://dx.doi.org/10.3892/mmr.2012.1128] [PMID:  23064235] 
[27] 
Yang, X.; Zhang, J.; Chen, L.; Wu, Q.; Yu, C. Chitosan oligosaccharides enhance lipid droplets via down-regulation of PCSK9 gene expression in HepG2 cells. Exp. Cell Res.,  2018, 366(2), 152-160.
[http://dx.doi.org/10.1016/j.yexcr.2018.03.013] [PMID:  29548750] 
[28] 
Chiu, C.Y.; Feng, S.-A.; Liu, S.-H.; Chiang, M.-T. Functional comparison for lipid metabolism and intestinal and fecal microflora enzyme activities between low molecular weight chitosan and chitosan oligosaccharide in high-fat-diet-fed rats. Mar. Drugs,  2017, 15(7), 234.
[http://dx.doi.org/10.3390/md15070234] [PMID:  28737708] 
[29] 
Jiang, Y.; Fu, C.; Liu, G.; Guo, J.; Su, Z. Cholesterol-lowering effects and potential mechanisms of chitooligosaccharide capsules in hyperlipidemic rats. Food Nutr. Res.,  2018, 62, 1-15.
[http://dx.doi.org/10.29219/fnr.v62.1446] [PMID:  29922118] 
[30] 
Somogyi, A.; Rosta, K.; Pusztai, P.; Tulassay, Z.; Nagy, G. Antioxidant measurements. Physiol. Meas.,  2007, 28(4), R41-R55.
[http://dx.doi.org/10.1088/0967-3334/28/4/R01] [PMID:  17395989] 
[31] 
Nguyen, N.T.; Hoang, D.Q.; Nguyen, N.D.; Nguyen, Q.H.; Nguyen, D.H. Preparation, characterization, and antioxidant activity of water-soluble oligochitosan. Green Process. Synth.,  2017, 6, 461-468.
[http://dx.doi.org/10.1515/gps-2016-0126] 
[32] 
Zhang, J.; Zhao, P.; Liu, B.; Meng, X. Use of oligochitosan as an inhibiting agent of apple juice enzymatic browning. J. Food Process. Preserv.,  2017, 41, e13062.
[http://dx.doi.org/10.1111/jfpp.13062] 
[33] 
Mengíbar, M.; Mateos-Aparicio, I.; Miralles, B.; Heras, A. Influence of the physico-chemical characteristics of chito-oligosaccharides (COS) on antioxidant activity. Carbohydr. Polym.,  2013, 97(2), 776-782.
[http://dx.doi.org/10.1016/j.carbpol.2013.05.035] [PMID:  23911515] 
[34] 
Mendis, E.; Kim, M.M.; Rajapakse, N.; Kim, S.K. An in vitro cellular analysis of the radical scavenging efficacy of chitooligosaccharides. Life Sci.,  2007, 80(23), 2118-2127.
[http://dx.doi.org/10.1016/j.lfs.2007.03.016] [PMID:  17475286] 
[35] 
Zhang, Y.; Zhou, X.; Ji, L.; Du, X.; Sang, Q.; Chen, F. Enzymatic single-step preparation and antioxidant activity of hetero-chitooligosaccharides using non-pretreated housefly larvae powder. Carbohydr. Polym.,  2017, 172, 113-119.
[http://dx.doi.org/10.1016/j.carbpol.2017.05.037] [PMID:  28606517] 
[36] 
Liang, T.W.; Chen, W.T.; Lin, Z.H.; Kuo, Y.H.; Nguyen, A.D.; Pan, P.S.; Wang, S.L. An amphiprotic novel chitosanase from bacillus mycoides and its application in the production of chitooligomers with their antioxidant and anti-inflammatory evaluation. Int. J. Mol. Sci.,  2016, 17(8), 1-14.
[http://dx.doi.org/10.3390/ijms17081302] [PMID:  27517920] 
[37] 
Oh, S-H.; Ryu, B.; Ngo, D.-H.; Kim, W.-S.; Kim, D.G.; Kim, S.-K. 4-hydroxybenzaldehyde-chitooligomers suppresses H2O2-induced oxidative damage in microglia BV-2 cells. Carbohydr. Res.,  2017, 440-441, 32-37.
[http://dx.doi.org/10.1016/j.carres.2017.01.007] [PMID:  28192685] 
[38] 
Jia, P.; Yu, L.; Tao, C.; Dai, G.; Zhang, Z.; Liu, S. Chitosan oligosaccharides protect nucleus pulposus cells from hydrogen peroxide-induced apoptosis in a rat experimental model. Biomed. Pharmacother.,  2017, 93, 807-815.
[http://dx.doi.org/10.1016/j.biopha.2017.06.101] [PMID:  28715865] 
[39] 
Luo, Z.; Dong, X.; Ke, Q.; Duan, Q.; Shen, L. Chitooligosaccharides inhibit ethanol-induced oxidative stress via activation of Nrf2 and reduction of MAPK phosphorylation. Oncol. Rep.,  2014, 32(5), 2215-2222.
[http://dx.doi.org/10.3892/or.2014.3463] [PMID:  25189124] 
[40] 
Fang, I.M.; Yang, C.H.; Yang, C.M.; Chen, M.S. Chitosan oligosaccharides attenuates oxidative-stress related retinal degeneration in rats. PLoS One,  2013, 8(10), e77323.
[http://dx.doi.org/10.1371/journal.pone.0077323] [PMID:  24155943] 
[41] 
Frieri, M.; Kumar, K.; Boutin, A. Antibiotic resistance. J. Infect. Public Health,  2017, 10(4), 369-378.
[http://dx.doi.org/10.1016/j.jiph.2016.08.007] [PMID:  27616769] 
[42] 
Qu, Y.; Xu, J.; Zhou, H.; Dong, R.; Kang, M.; Zhao, J. Chitin oligosaccharide (COS) reduces antibiotics dose and prevents antibiotics-caused side effects in adolescent idiopathic scoliosis (AIS) patients with spinal fusion surgery. Mar. Drugs,  2017, 15(3), 70.
[http://dx.doi.org/10.3390/md15030070] [PMID:  28335413] 
[43] 
Kong, S.Z.; Li, D.D.; Luo, H.; Li, W.J.; Huang, Y.M.; Li, J.C.; Hu, Z.; Huang, N.; Guo, M.H.; Chen, Y.; Li, S.D. Anti-photoaging effects of chitosan oligosaccharide in ultraviolet-irradiated hairless mouse skin. Exp. Gerontol.,  2018, 103, 27-34.
[http://dx.doi.org/10.1016/j.exger.2017.12.018] [PMID:  29275159] 
[44] 
Zhang, Y.; Ahmad, K.A.; Khan, F.U.; Yan, S.; Ihsan, A.U.; Ding, Q. Chitosan oligosaccharides prevent doxorubicin-induced oxidative stress and cardiac apoptosis through activating p38 and JNK MAPK mediated Nrf2/ARE pathway. Chem. Biol. Interact.,  2019, 305, 54-65.
[http://dx.doi.org/10.1016/j.cbi.2019.03.027] [PMID:  30928397] 
[45] 
Muzzarelli, R.A.A. Chitins and chitosans as immunoadjuvants and non-allergenic drug carriers. Mar. Drugs,  2010, 8(2), 292-312.
[http://dx.doi.org/10.3390/md8020292] [PMID:  20390107] 
[46] 
Wei, X.; Chen, W.; Mao, F.; Wang, Y. Effect of chitooligosaccharides on mice hematopoietic stem/progenitor cells. Int. J. Biol. Macromol.,  2013, 54, 71-75.
[http://dx.doi.org/10.1016/j.ijbiomac.2012.10.022] [PMID:  23107809] 
[47] 
Roca, M.; Muñiz-Diaz, E.; Mora, J.; Romero-Zayas, I.; Ramón, O.; Roig, I.; Pujol-Moix, N. The scintigraphic index spleen/liver at 30 minutes predicts the success of splenectomy in persistent and chronic primary immune thrombocytopenia. Am. J. Hematol.,  2011, 86(11), 909-913.
[http://dx.doi.org/10.1002/ajh.22147] [PMID:  21948335] 
[48] 
Kong, S.Z.; Li, J.-C.; Li, S.-D.; Liao, M.N.; Li, C.P.; Zheng, P.-J.; Guo, M.-H.; Tan, W.-X.; Zheng, Z.-H.; Hu, Z. Anti-aging effect of chitosan oligosaccharide on d-galactose-induced subacute aging in mice. Mar. Drugs,  2018, 16(6), 181.
[http://dx.doi.org/10.3390/md16060181] [PMID:  29794973] 
[49] 
Zhai, X.; Yang, X.; Zou, P.; Shao, Y.; Yuan, S.; Abd El-Aty, A.M.; Wang, J. Protective effect of chitosan oligosaccharides against cyclophosphamide-induced immunosuppression and irradiation injury in mice. J. Food Sci.,  2018, 83(2), 535-542.
[http://dx.doi.org/10.1111/1750-3841.14048] [PMID:  29350748] 
[50] 
Mei, Y.X.; Chen, H.X.; Zhang, J.; Zhang, X.D.; Liang, Y.X. Protective effect of chitooligosaccharides against cyclophosphamide-induced immunosuppression in mice. Int. J. Biol. Macromol.,  2013, 62, 330-335.
[http://dx.doi.org/10.1016/j.ijbiomac.2013.09.038] [PMID:  24080320] 
[51] 
Zhang, G.; Jia, P.; Cheng, G.; Jiao, S.; Ren, L.; Ji, S.; Hu, T.; Liu, H.; Du, Y. Enhanced immune response to inactivated porcine circovirus type 2 (PCV2) vaccine by conjugation of chitosan oligosaccharides. Carbohydr. Polym.,  2017, 166, 64-72.
[http://dx.doi.org/10.1016/j.carbpol.2017.02.058] [PMID:  28385249] 
[52] 
Wan, J.; Jiang, F.; Xu, Q.; Chen, D.; Yu, B.; Huang, Z.; Mao, X.; Yu, J.; He, J. New insights into the role of chitosan oligosaccharide in enhancing growth performance, antioxidant capacity, immunity and intestinal development of weaned pigs. RSC Advances,  2017, 7, 9669-9679.
[http://dx.doi.org/10.1039/C7RA00142H] 
[53] 
Dewen, Q.; Yijie, D.; Yi, Z.; Shupeng, L.; Fachao, S. Plant immunity inducer development and application. Mol. Plant Microbe Interact.,  2017, 30(5), 355-360.
[http://dx.doi.org/10.1094/MPMI-11-16-0231-CR] [PMID:  28323528] 
[54] 
Mudgal, J.; Mudgal, P.P.; Kinra, M.; Raval, R. Immunomodulatory role of chitosan-based nanoparticles and oligosaccharides in cyclophosphamide-treated mice. Scand. J. Immunol.,  2019, 89(4), e12749.
[http://dx.doi.org/10.1111/sji.12749] [PMID:  30664262] 
[55] 
Hoesel, B.; Schmid, J.A. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer,  2013, 12, 86.
[http://dx.doi.org/10.1186/1476-4598-12-86] [PMID:  23915189] 
[56] 
Okada, F. Inflammation-related carcinogenesis: current findings in epidemiological trends, causes and mechanisms. Yonago Acta Med.,  2014, 57(2), 65-72.
[PMID:  25324587] 
[57] 
Gudmundsdottir, S.; Lieder, R.; Sigurjonsson, O.E.; Petersen, P.H. Chitosan leads to downregulation of YKL-40 and inflammasome activation in human macrophages. J. Biomed. Mater. Res. A,  2015, 103(8), 2778-2785.
[http://dx.doi.org/10.1002/jbm.a.35417] [PMID:  25684555] 
[58] 
Skalli, A.; Castillo, M.; Andree, K.B.; Tort, L.; Furones, D.; Gisbert, E. The LPS derived from the cell walls of the gram-negative bacteria pantoea agglomerans stimulates growth and immune status of rainbow trout (Oncorhynchus mykiss) juveniles. Aquaculture,  2013, 416-417, 272-279.
[http://dx.doi.org/10.1016/j.aquaculture.2013.09.037] 
[59] 
Zhu, J.; Zhang, Y.; Wu, G.; Xiao, Z.; Zhou, H.; Yu, X. Inhibitory effects of oligochitosan on TNF-α, IL-1β and nitric oxide production in lipopolysaccharide-induced RAW264.7 cells. Mol. Med. Rep.,  2015, 11(1), 729-733.
[http://dx.doi.org/10.3892/mmr.2014.2643] [PMID:  25323008] 
[60] 
Hyung, J.H.; Ahn, C.B.; Il Kim, B.; Kim, K.; Je, J.Y. Involvement of Nrf2-mediated heme oxygenase-1 expression in anti-inflammatory action of chitosan oligosaccharides through MAPK activation in murine macrophages. Eur. J. Pharmacol.,  2016, 793, 43-48.
[http://dx.doi.org/10.1016/j.ejphar.2016.11.002] [PMID:  27826077] 
[61] 
Maxwell, T.; Lee, K.; Chun, S.; Nam, K. Mineral-balanced deep sea water enhances the inhibitory effects of chitosan oligosaccharide on atopic dermatitis-like inflammatory response. Biotechnol. Bioprocess Eng.; BBE,  2017, 22, 120-128.
[http://dx.doi.org/10.1007/s12257-017-0091-6] 
[62] 
Li, Y.; Liu, H.; Xu, Q-S.; Du, Y-G.; Xu, J. Chitosan oligosaccharides block LPS-induced O-Glcnacylation of NF-κB and endothelial inflammatory response. Carbohydr. Polym.,  2014, 99, 568-578.
[http://dx.doi.org/10.1016/j.carbpol.2013.08.082] [PMID:  24274545] 
[63] 
Amor, S.; Peferoen, L.A.N.; Vogel, D.Y.S.; Breur, M.; van der Valk, P.; Baker, D.; van Noort, J.M. Inflammation in neurodegenerative diseases--an update. Immunology,  2014, 142(2), 151-166.
[http://dx.doi.org/10.1111/imm.12233] [PMID:  24329535] 
[64] 
Hao, C.; Wang, W.; Wang, S.; Zhang, L.; Guo, Y. An overview of the protective effects of chitosan and acetylated chitosan oligosaccharides against neuronal disorders. Mar. Drugs,  2017, 15(4), 89.
[http://dx.doi.org/10.3390/md15040089] [PMID:  28333077] 
[65] 
Dai, X.; Hou, W.; Sun, Y.; Gao, Z.; Zhu, S.; Jiang, Z. Chitosan oligosaccharides inhibit/disaggregate fibrils and attenuate amyloid β-mediated neurotoxicity. Int. J. Mol. Sci.,  2015, 16(5), 10526-10536.
[http://dx.doi.org/10.3390/ijms160510526] [PMID:  26006224] 
[66] 
Santos-Moriano, P.; Fernandez-Arrojo, L.; Mengibar, M.; Belmonte-Reche, E.; Peñalver, P.; Acosta, F.N.; Ballesteros, A.O.; Morales, J.C.; Kidibule, P.; Fernandez-Lobato, M.; Plou, F.J. Enzymatic production of fully deacetylated chitooligosaccharides and their neu-roprotective and anti-inflammatory properties. Biocatal. Biotransform.,  2018, 36, 57-67.
[http://dx.doi.org/10.1080/10242422.2017.1295231] 
[67] 
Wu, W.; Wei, W.; Lu, M.; Zhu, X.; Liu, N.; Niu, Y.; Sun, T.; Li, Y.; Yu, J. Neuroprotective effect of chitosan oligosaccharide on hypoxic-ischemic brain damage in neonatal rats. Neurochem. Res.,  2017, 42(11), 3186-3198.
[http://dx.doi.org/10.1007/s11064-017-2356-z] [PMID:  28755288] 
[68] 
Jia, S.; Lu, Z.; Gao, Z.; An, J.; Wu, X.; Li, X.; Dai, X.; Zheng, Q.; Sun, Y. Chitosan oligosaccharides alleviate cognitive deficits in an amyloid-β1-42-induced rat model of Alzheimer’s disease. Int. J. Biol. Macromol.,  2016, 83, 416-425.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.11.011] [PMID:  26601759] 
[69] 
Dai, X.; Chang, P.; Li, X.; Gao, Z.; Sun, Y. The inhibitory effect of chitosan oligosaccharides on β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in HEK293 APPswe cells. Neurosci. Lett.,  2018, 665, 80-85.
[http://dx.doi.org/10.1016/j.neulet.2017.11.052] [PMID:  29175631] 
[70] 
Kunanusornchai, W.; Witoonpanich, B.; Tawonsawatruk, T.; Pichyangkura, R.; Chatsudthipong, V.; Muanprasat, C. Chitosan oligosaccharide suppresses synovial inflammation via AMPK activation: an in vitro and in vivo study. pharmacol. res.,  2016, 113(pt a), 458-467.
[http://dx.doi.org/10.1016/j.phrs.2016.09.016] [PMID: 27650754] 
[71] 
Liu, Y.-E.; Tong, C.-C.; Zhang, Y.B.; Cong, P.F.; Shi, X.-Y.; Liu, Y.; Shi, L.; Tong, Z.; Jin, H.-X.; Hou, M.-X. Chitosan oligosaccharide ameliorates acute lung injury induced by blast injury through the DDAH1/ADMA pathway. PLoS One,  2018, 13(2), e0192135.
[http://dx.doi.org/10.1371/journal.pone.0192135] [PMID:  29415054] 
[72] 
Fang, I.M.; Yang, C.M.; Yang, C.H. Chitosan oligosaccharides prevented retinal ischemia and reperfusion injury via reduced oxidative stress and inflammation in rats. Exp. Eye Res.,  2015, 130, 38-50.
[http://dx.doi.org/10.1016/j.exer.2014.12.001] [PMID:  25479043] 
[73] 
Zhang, C.; Liao, Q.; Ming, J.-H.; Hu, G.-L.; Chen, Q.; Liu, S.-Q.; Li, Y-M. The effects of chitosan oligosaccharides on OPG and RANKL expression in a rat osteoarthritis model. Acta Cir. Bras.,  2017, 32(6), 418-428.
[http://dx.doi.org/10.1590/s0102-865020170060000002] [PMID:  28700003] 
[74] 
Li, Z.; Yang, X.; Song, X.; Ma, H.; Zhang, P. chitosan oligosaccharide reduces propofol requirements and propofol-related side effects. Mar. Drugs,  2016, 14(12), 234.
[http://dx.doi.org/10.3390/md14120234] [PMID:  28009824] 
[75] 
Elinav, E.; Nowarski, R.; Thaiss, C.A.; Hu, B.; Jin, C.; Flavell, R.A. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer,  2013, 13(11), 759-771.
[http://dx.doi.org/10.1038/nrc3611] [PMID:  24154716] 
[76] 
Farazi, P.A.; DePinho, R.A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer,  2006, 6(9), 674-687.
[http://dx.doi.org/10.1038/nrc1934] [PMID:  16929323] 
[77] 
Palucka, A.K.; Coussens, L.M. The basis of oncoimmunology. Cell,  2016, 164(6), 1233-1247.
[http://dx.doi.org/10.1016/j.cell.2016.01.049] [PMID:  26967289] 
[78] 
Park, J.K.; Chung, M.J.; Choi, H.N.; Park, Y.I. Effects of the molecular weight and the degree of deacetylation of chitosan oligosaccharides on antitumor activity. Int. J. Mol. Sci.,  2011, 12(1), 266-277.
[http://dx.doi.org/10.3390/ijms12010266] [PMID:  21339986] 
[79] 
Muanprasat, C.; Chatsudthipong, V. Chitosan oligosaccharide: biological activities and potential therapeutic applications. Pharmacol. Ther.,  2017, 170, 80-97.
[http://dx.doi.org/10.1016/j.pharmthera.2016.10.013] [PMID:  27773783] 
[80] 
Jiang, Z.; Li, H.; Qiao, J.; Yang, Y.; Wang, Y.; Liu, W.; Han, B. Potential analysis and preparation of chitosan oligosaccharides as oral nutritional supplements of cancer adjuvant therapy. Int. J. Mol. Sci.,  2019, 20(4), 920.
[http://dx.doi.org/10.3390/ijms20040920] [PMID:  30791594] 
[81] 
Muanprasat, C.; Wongkrasant, P.; Satitsri, S.; Moonwiriyakit, A.; Pongkorpsakol, P.; Mattaveewong, T.; Pichyangkura, R.; Chatsudthipong, V. Activation of AMPK by chitosan oligosaccharide in intestinal epithelial cells: mechanism of action and potential applications in intestinal disorders. Biochem. Pharmacol.,  2015, 96(3), 225-236.
[http://dx.doi.org/10.1016/j.bcp.2015.05.016] [PMID:  26047848] 
[82] 
Mattaveewong, T.; Wongkrasant, P.; Chanchai, S.; Pichyangkura, R.; Chatsudthipong, V.; Muanprasat, C. Chitosan oligosaccharide suppresses tumor progression in a mouse model of colitis-associated colorectal cancer through AMPK activation and suppression of NF-κB and mTOR signaling. Carbohydr. Polym.,  2016, 145, 30-36.
[http://dx.doi.org/10.1016/j.carbpol.2016.02.077] [PMID:  27106148] 
[83] 
Zou, P.; Yuan, S.; Yang, X.; Zhai, X.; Wang, J. Chitosan oligosaccharides with degree of polymerization 2-6 induces apoptosis in human colon carcinoma HCT116 cells. Chem. Biol. Interact.,  2018, 279, 129-135.
[http://dx.doi.org/10.1016/j.cbi.2017.11.010] [PMID:  29155028] 
[84] 
Liu, L.; Xin, Y.; Liu, J.; Zhang, E.; Li, W. Inhibitory effect of chitosan oligosaccharide on human hepatoma cells in vitro. Afr. J. Tradit. Complement. Altern. Med.,  2017, 14(4), 272-277.
[http://dx.doi.org/10.21010/ajtcam.v14i4.30] [PMID:  28638890] 
[85] 
Xu, Q.; Wang, W.; Qu, C.; Gu, J.; Yin, H.; Jia, Z.; Song, L.; Du, Y. Chitosan oligosaccharides inhibit epithelial cell migration through blockade of N-acetylglucosaminyl-transferase V and branched GlcNAc structure. Carbohydr. Polym.,  2017, 170, 241-246.
[http://dx.doi.org/10.1016/j.carbpol.2017.04.075] [PMID:  28521993] 
[86] 
Xu, Q.; Wang, W.; Yang, W.; Du, Y.; Song, L. Chitosan oligosaccharide inhibits EGF-induced cell growth possibly through blockade of epidermal growth factor receptor/mitogen-activated protein kinase pathway. Int. J. Biol. Macromol.,  2017, 98, 502-505.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.02.021] [PMID:  28185929] 
[87] 
Kulikov, S.; Zelenikhin, P.; Murtazina, R.; Khayrullin, R.; Bezrodnikh, E.; Tikhonov, V. Induction of apoptosis of tumor cells by oligochitosans (short chain chitosans). Bionanoscience,  2016, 6, 460-463.
[http://dx.doi.org/10.1007/s12668-016-0243-8] 
[88] 
Zhai, X.; Yuan, S.; Yang, X.; Zou, P.; Shao, Y.; Abd El-Aty, A.M.; Hacımüftüoğlu, A.; Wang, J. Growth-inhibition of S180 residual-tumor by combination of cyclophosphamide and chitosan oligosaccharides in vivo. Life Sci.,  2018, 202, 21-27.
[http://dx.doi.org/10.1016/j.lfs.2018.04.004] [PMID:  29626528] 
[89] 
Zou, P.; Yang, X.; Zhang, Y.; Du, P.; Yuan, S.; Yang, D.; Wang, J. Antitumor effects of orally and intraperitoneally administered chitosan oligosaccharides (COSs) on S180-bearing/residual mouse. J. Food Sci.,  2016, 81(12), H3035-H3042.
[http://dx.doi.org/10.1111/1750-3841.13538] [PMID:  27802366] 
[90] 
Smith, B.R.; Gambhir, S.S. Nanomaterials for in vivo imaging. Chem. Rev.,  2017, 117(3), 901-986.
[http://dx.doi.org/10.1021/acs.chemrev.6b00073] [PMID:  28045253] 
[91] 
Lee, J.Y.; Termsarasab, U.; Lee, M.Y.; Kim, D.H.; Lee, S.Y.; Kim, J.S.; Cho, H.J.; Kim, D.D. Chemosensitizing indomethacin-conjugated chitosan oligosaccharide nanoparticles for tumor-targeted drug delivery. Acta Biomater.,  2017, 57, 262-273.
[http://dx.doi.org/10.1016/j.actbio.2017.05.012] [PMID:  28483700] 
[92] 
Liu, X.; Xia, W.; Jiang, Q.; Yu, P.; Yue, L. Chitosan oligosaccharide-N-chlorokojic acid mannich base polymer as a potential antibacterial material. Carbohydr. Polym.,  2018, 182, 225-234.
[http://dx.doi.org/10.1016/j.carbpol.2017.11.019] [PMID:  29279119] 
[93] 
Zou, P.; Yang, X.; Wang, J.; Li, Y.; Yu, H.; Zhang, Y.; Liu, G. Advances in characterisation and biological activities of chitosan and chitosan oligosaccharides. Food Chem.,  2016, 190, 1174-1181.
[http://dx.doi.org/10.1016/j.foodchem.2015.06.076] [PMID:  26213092] 
[94] 
Je, J.Y.; Kim, S.K. Chitosan derivatives killed bacteria by disrupting the outer and inner membrane. J. Agric. Food Chem.,  2006, 54(18), 6629-6633.
[http://dx.doi.org/10.1021/jf061310p] [PMID:  16939319] 
[95] 
Tang, Y.L.; Shi, Y.H.; Zhao, W.; Hao, G.; Le, G.W. Discovery of a novel antimicrobial peptide using membrane binding-based approach. Food Control,  2009, 20, 149-156.
[http://dx.doi.org/10.1016/j.foodcont.2008.03.006] 
[96] 
Liu, X.; Xia, W.; Jiang, Q.; Xu, Y.; Yu, P. Effect of kojic acid-grafted-chitosan oligosaccharides as a novel antibacterial agent on cell membrane of gram-positive and gram-negative bacteria. J. Biosci. Bioeng.,  2015, 120(3), 335-339.
[http://dx.doi.org/10.1016/j.jbiosc.2015.01.010] [PMID:  25682520] 
[97] 
Yue, L.; Li, J.; Chen, W.; Liu, X.; Jiang, Q.; Xia, W. Geraniol grafted chitosan oligosaccharide as a potential antibacterial agent. Carbohydr. Polym.,  2017, 176, 356-364.
[http://dx.doi.org/10.1016/j.carbpol.2017.07.043] [PMID:  28927618] 
[98] 
Li, Z.; Zhang, M.; Cheng, D.; Yang, R. Preparation of silver nano-particles immobilized onto chitin nano-crystals and their application to cellulose paper for imparting antimicrobial activity. Carbohydr. Polym.,  2016, 151, 834-840.
[http://dx.doi.org/10.1016/j.carbpol.2016.06.012] [PMID:  27474631] 
[99] 
Luo, C.; Liu, W.; Luo, B.; Tian, J.; Wen, W.; Liu, M.; Zhou, C. Antibacterial activity and cytocompatibility of chitooligosaccharide-modified polyurethane membrane via polydopamine adhesive layer. Carbohydr. Polym.,  2017, 156, 235-243.
[http://dx.doi.org/10.1016/j.carbpol.2016.09.036] [PMID:  27842818] 
[100] 
Jiang, W.; Zhou, Z.; Wang, D.; Zhou, X.; Tao, R.; Yang, Y.; Shi, Y.; Zhang, G.; Wang, D.; Zhou, Z. Transglutaminase catalyzed hydrolyzed wheat gliadin grafted with chitosan oligosaccharide and its characterization. Carbohydr. Polym.,  2016, 153, 105-114.
[http://dx.doi.org/10.1016/j.carbpol.2016.07.097] [PMID:  27561477] 
[101] 
Reighard, K.P.; Schoenfisch, M.H. Antibacterial action of nitric oxide-releasing chitosan oligosaccharides against Pseudomonas aeruginosa under aerobic and anaerobic conditions. Antimicrob. Agents Chemother.,  2015, 59(10), 6506-6513.
[http://dx.doi.org/10.1128/AAC.01208-15] [PMID:  26239983] 
[102] 
Reighard, K.P.; Hill, D.B.; Dixon, G.A.; Worley, B.V.; Schoenfisch, M.H. Disruption and eradication of P. aeruginosa biofilms using nitric oxide-releasing chitosan oligosaccharides. Biofouling,  2015, 31(9-10), 775-787.
[http://dx.doi.org/10.1080/08927014.2015.1107548] [PMID:  26610146] 
[103] 
Lu, Y.; Shah, A.; Hunter, R.A.; Soto, R.J.; Schoenfisch, M.H. S-Nitrosothiol-modified nitric oxide-releasing chitosan oligosaccharides as antibacterial agents. Acta Biomater.,  2015, 12, 62-69.
[http://dx.doi.org/10.1016/j.actbio.2014.10.028] [PMID:  25449913] 
[104] 
Sokol, H.; Leducq, V.; Aschard, H.; Pham, H.P.; Jegou, S.; Landman, C.; Cohen, D.; Liguori, G.; Bourrier, A.; Nion-Larmurier, I.; Cosnes, J.; Seksik, P.; Langella, P.; Skurnik, D.; Richard, M.L.; Beaugerie, L. Fungal microbiota dysbiosis in IBD. Gut,  2017, 66(6), 1039-1048.
[http://dx.doi.org/10.1136/gutjnl-2015-310746] [PMID:  26843508] 
[105] 
Coker, O.O.; Dai, Z.; Nie, Y.; Zhao, G.; Cao, L.; Nakatsu, G.; Wu, W.K.; Wong, S.H.; Chen, Z.; Sung, J.J.Y.; Yu, J. Mucosal microbiome dysbiosis in gastric carcinogenesis. Gut,  2018, 67(6), 1024-1032.
[http://dx.doi.org/10.1136/gutjnl-2017-314281] [PMID:  28765474] 
[106] 
Zheng, J.; Yuan, X.; Cheng, G.; Jiao, S.; Feng, C.; Zhao, X.; Yin, H.; Du, Y.; Liu, H. Chitosan oligosaccharides improve the disturbance in glucose metabolism and reverse the dysbiosis of gut microbiota in diabetic mice. Carbohydr. Polym.,  2018, 190, 77-86.
[http://dx.doi.org/10.1016/j.carbpol.2018.02.058] [PMID:  29628262] 
[107] 
Doan, C.T.; Tran, T.N.; Nguyen, V.B.; Nguyen, A.D.; Wang, S.L. Reclamation of marine chitinous materials for chitosanase production via microbial conversion by Paenibacillus macerans. Mar. Drugs,  2018, 16(11), 16.
[http://dx.doi.org/10.3390/md16110429] [PMID:  30400216] 
[108] 
Sheikh, Z.; Najeeb, S.; Khurshid, Z.; Verma, V.; Rashid, H.; Glogauer, M. biodegradable materials for bone repair and tissue engineering applications. Materials (Basel),  2015, 8(9), 5744-5794.
[http://dx.doi.org/10.3390/ma8095273] [PMID:  28793533] 
[109] 
Wang, B.; Tan, L.; Deng, D.; Lu, T.; Zhou, C.; Li, Z.; Tang, Z.; Wu, Z.; Tang, H. Novel stable cytokine delivery system in physiological pH solution: chitosan oligosaccharide/heparin nanoparticles. Int. J. Nanomedicine,  2015, 10, 3417-3427.
[http://dx.doi.org/10.2147/IJN.S82091]] [PMID:  26056441] 
[110] 
Shahverdi, S.; Hajimiri, M.; Esfandiari, M.A.; Larijani, B.; Atyabi, F.; Rajabiani, A.; Dehpour, A.R.; Gharehaghaji, A.A.; Dinarvand, R. Fabrication and structure analysis of poly(lactide-co-glycolic acid)/silk fibroin hybrid scaffold for wound dressing applications. Int. J. Pharm.,  2014, 473(1-2), 345-355.
[http://dx.doi.org/10.1016/j.ijpharm.2014.07.021] [PMID:  25051110] 
[111] 
Okamoto, Y.; Yano, R.; Miyatake, K.; Tomohiro, I.; Shigemasa, Y.; Minami, S. Effects of chitin and chitosan on blood coagulation. Carbohydr. Polym.,  2003, 53, 337-342.
[http://dx.doi.org/10.1016/S0144-8617(03)00076-6] 
[112] 
Alsarra, I.A. Chitosan topical gel formulation in the management of burn wounds. Int. J. Biol. Macromol.,  2009, 45(1), 16-21.
[http://dx.doi.org/10.1016/j.ijbiomac.2009.03.010]] [PMID:  19447254] 
[113] 
Mori, T.; Okumura, M.; Matsuura, M.; Ueno, K.; Tokura, S.; Okamoto, Y.; Minami, S.; Fujinaga, T. Effects of chitin and its derivatives on the proliferation and cytokine production of fibroblasts in vitro. Biomaterials,  1997, 18(13), 947-951.
[http://dx.doi.org/10.1016/S0142-9612(97)00017-3] [PMID:  9199765] 
[114] 
Chandika, P.; Ko, S.C.; Oh, G.W.; Heo, S.Y.; Nguyen, V.T.; Jeon, Y.J.; Lee, B.; Jang, C.H.; Kim, G.; Park, W.S.; Chang, W.; Choi, I.W.; Jung, W.K. Fish collagen/alginate/chitooligosaccharides integrated scaffold for skin tissue regeneration application. Int. J. Biol. Macromol.,  2015, 81, 504-513.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.08.038] [PMID:  26306410] 
[115] 
Li, C.; Fu, R.; Yu, C.; Li, Z.; Guan, H.; Hu, D.; Zhao, D.; Lu, L. Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study. Int. J. Nanomedicine,  2013, 8, 4131-4145.
[http://dx.doi.org/10.2147/IJN.S51679]] [PMID:  24204142] 
[116] 
Li, C.W.; Wang, Q.; Li, J.; Hu, M.; Shi, S.J.; Li, Z.W.; Wu, G.L.; Cui, H.H.; Li, Y.Y.; Zhang, Q.; Yu, X.H.; Lu, L.C. Silver nanoparticles/chitosan oligosaccharide/poly(vinyl alcohol) nanofiber promotes wound healing by activating TGFβ1/Smad signaling pathway. Int. J. Nanomedicine,  2016, 11, 373-386.
[http://dx.doi.org/10.2147/IJN.S91975]] [PMID:  26855575] 
[117] 
Sandri, G.; Aguzzi, C.; Rossi, S.; Bonferoni, M.C.; Bruni, G.; Boselli, C.; Cornaglia, A.I.; Riva, F.; Viseras, C.; Caramella, C.; Ferrari, F. Halloysite and chitosan oligosaccharide nanocomposite for wound healing. Acta Biomater.,  2017, 57, 216-224.
[http://dx.doi.org/10.1016/j.actbio.2017.05.032] [PMID:  28522411] 
[118] 
Chen, Y.; Dan, N.; Dan, W.; Liu, X.; Cong, L. A novel antibacterial acellular porcine dermal matrix cross-linked with oxidized chitosan oligosaccharide and modified by in situ synthesis of silver nanoparticles for wound healing applications. Mater. Sci. Eng. C,  2019, 94, 1020-1036.
[http://dx.doi.org/10.1016/j.msec.2018.10.036] [PMID:  30423683] 
[119] 
Ratanavaraporn, J.; Kanokpanont, S.; Tabata, Y.; Damrongsakkul, S. Growth and osteogenic differentiation of adipose-derived and bone marrow-derived stem cells on chitosan and chitooligosaccharide films. Carbohydr. Polym.,  2009, 78, 873-878.
[http://dx.doi.org/10.1016/j.carbpol.2009.07.006] 
[120] 
Jung, W.K.; Moon, S.H.; Kim, S.K. Effect of chitooligosaccharides on calcium bioavailability and bone strength in ovariectomized rats. Life Sci.,  2006, 78(9), 970-976.
[http://dx.doi.org/10.1016/j.lfs.2005.06.006] [PMID:  16137703] 
[121] 
Bai, B.L.; Xie, Z.J.; Weng, S.J.; Wu, Z.Y.; Li, H.; Tao, Z.S.; Boodhun, V.; Yan, D.Y.; Shen, Z.J.; Tang, J.H.; Yang, L. Chitosan oligosaccharide promotes osteoclast formation by stimulating the activation of MAPK and AKT signaling pathways. J. Biomater. Sci. Polym. Ed.,  2018, 29(10), 1207-1218.
[http://dx.doi.org/10.1080/09205063.2018.1448336] [PMID:  29502489] 
[122] 
Ding, S.-J.; Shie, M.-Y.; Hoshiba, T.; Kawazoe, N.; Chen, G.; Chang, H-C. Osteogenic differentiation and immune response of human bone-marrow-derived mesenchymal stem cells on injectable calcium-silicate-based bone grafts. Tissue Eng. Part A,  2010, 16(7), 2343-2354.
[http://dx.doi.org/10.1089/ten.tea.2009.0749] [PMID:  20205531] 
[123] 
Liu, L.; Li, M.; Yu, M.; Shen, M.; Wang, Q.; Yu, Y.; Xie, J. Natural polysaccharides exhibit anti-tumor activity by targeting gut microbiota. Int. J. Biol. Macromol.,  2019, 121, 743-751.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.10.083] [PMID:  30342142] 
[124] 
Meyer, C.; Stenberg, L.; Gonzalez-Perez, F.; Wrobel, S.; Ronchi, G.; Udina, E.; Suganuma, S.; Geuna, S.; Navarro, X.; Dahlin, L.B.; Grothe, C.; Haastert-Talini, K. Chitosan-film enhanced chitosan nerve guides for long-distance regeneration of peripheral nerves. Biomaterials,  2016, 76, 33-51.
[http://dx.doi.org/10.1016/j.biomaterials.2015.10.040] [PMID:  26517563] 
[125] 
Zhao, Y.; Wang, Y.; Gong, J.; Yang, L.; Niu, C.; Ni, X.; Wang, Y.; Peng, S.; Gu, X.; Sun, C.; Yang, Y. Chitosan degradation products facilitate peripheral nerve regeneration by improving macrophage-constructed microenvironments. Biomaterials,  2017, 134, 64-77.
[http://dx.doi.org/10.1016/j.biomaterials.2017.02.026] [PMID:  28456077] 
[126] 
Wang, Y.; Zhao, Y.; Sun, C.; Hu, W.; Zhao, J.; Li, G.; Zhang, L.; Liu, M.; Liu, Y.; Ding, F.; Yang, Y.; Gu, X. Chitosan degradation products promote nerve regeneration by stimulating schwann cell proliferation via miR-27a/FOXO1 axis. Mol. Neurobiol.,  2016, 53(1), 28-39.
[http://dx.doi.org/10.1007/s12035-014-8968-2] [PMID:  25399953] 
[127] 
Phil, L.; Naveed, M.; Mohammad, I.S.; Bo, L.; Bin, D. Chitooligosaccharide: an evaluation of physicochemical and biological properties with the proposition for determination of thermal degradation products. Biomed. Pharmacother.,  2018, 102, 438-451.
[http://dx.doi.org/10.1016/j.biopha.2018.03.108] [PMID:  29579704] 
[128] 
Park, P.J.; Je, J.Y.; Jung, W.K.; Ahn, C.B.; Kim, S.K. Anticoagulant activity of heterochitosans and their oligosaccharide sulfates. Eur. Food Res. Technol.,  2004, 219, 529-533.
[http://dx.doi.org/10.1007/s00217-004-0977-3] 
[129] 
Liu, X.; Jiang, Q.; Xia, W. One-step procedure for enhancing the antibacterial and antioxidant properties of a polysaccharide polymer: kojic acid grafted onto chitosan. Int. J. Biol. Macromol.,  2018, 113, 1125-1133.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.03.007] [PMID:  29505872] 
[130] 
Das, S.; Ghosh, S.; De, A.K.; Bera, T. Oral delivery of ursolic acid-loaded nanostructured lipid carrier coated with chitosan oligosaccharides: development, characterization, in vitro and in vivo assessment for the therapy of leishmaniasis. Int. J. Biol. Macromol.,  2017, 102, 996-1008.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.04.098] [PMID:  28465178] 
[131] 
Yang, J.; Wu, Y.; Shen, Y.; Zhou, C.; Li, Y.-F.; He, R.-R.; Liu, M. Enhanced therapeutic efficacy of doxorubicin for breast cancer using chitosan oligosaccharide-modified halloysite nanotubes. ACS Appl. Mater. Interfaces,  2016, 8(40), 26578-26590.
[http://dx.doi.org/10.1021/acsami.6b09074] [PMID:  27628202] 
[132] 
Dramou, P.; Fizir, M.; Taleb, A.; Itatahine, A.; Dahiru, N.S.; Mehdi, Y.A.; Wei, L.; Zhang, J.; He, H. Folic acid-conjugated chitosan oligosaccharide-magnetic halloysite nanotubes as a delivery system for camptothecin. Carbohydr. Polym.,  2018, 197, 117-127.
[http://dx.doi.org/10.1016/j.carbpol.2018.05.071] [PMID:  30007596] 
[133] 
Tahvilian, R.; Tajani, B.; Sadrjavadi, K.; Fattahi, A. Preparation and characterization of pH-sensitive camptothecin-cis-aconityl grafted chitosan oligosaccharide nanomicelles. Int. J. Biol. Macromol.,  2016, 92, 795-802.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.07.100] [PMID:  27481344] 
[134] 
Sang, M.; Zhang, Z.; Liu, F.; Hu, L.; Li, L.; Chen, L.; Feng, F.; Liu, W.; Qu, W. Multifunctional hyaluronic acid-decorated redox-responsive magnetic complex micelle for targeted drug delivery with enhanced antitumor efficiency and anti-cell-migration activity. J. Biomed. Nanotechnol.,  2018, 14(3), 477-495.
[http://dx.doi.org/10.1166/jbn.2018.2541] [PMID:  29663921] 
[135] 
Oliveira, A.V.; Rosa da Costa, A.M.; Silva, G.A. Non-viral strategies for ocular gene delivery. Mater. Sci. Eng. C,  2017, 77, 1275-1289.
[http://dx.doi.org/10.1016/j.msec.2017.04.068] [PMID:  28532005] 
[136] 
Kumari, M.; Liu, C.H.; Wu, W.C. Efficient gene delivery by oligochitosan conjugated serum albumin: Facile synthesis, polyplex stability, and transfection. Carbohydr. Polym.,  2018, 183, 37-49.
[http://dx.doi.org/10.1016/j.carbpol.2017.11.013] [PMID:  29352891] 
[137] 
El-Sayed, N.S.; Sharma, M.; Aliabadi, H.M.; El-Meligy, M.G.; El-Zaity, A.K.; Nageib, Z.A.; Tiwari, R.K. Synthesis, characterization, and in vitro cytotoxicity of fatty acyl-CGKRK-chitosan oligosaccharides conjugates for siRNA delivery. Int. J. Biol. Macromol.,  2018, 112, 694-702.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.01.213] [PMID:  29408713] 
[138] 
Delgado, D.; del Pozo-Rodríguez, A.; Angeles Solinís, M.; Bartkowiak, A.; Rodríguez-Gascón, A. New gene delivery system based on oligochitosan and solid lipid nanoparticles: ‘in vitro’ and ‘in vivo’ evaluation. Eur. J. Pharm. Sci.,  2013, 50(3-4), 484-491.
[http://dx.doi.org/10.1016/j.ejps.2013.08.013] [PMID:  23981333] 
Cite As
Current Medicinal Chemistry

Research Advances in Chitosan Oligosaccharides: From Multiple Biological Activities to Clinical Applications

Abstract
