{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T03:49:45Z","timestamp":1761709785696,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004156","name":"Mahidol University","doi-asserted-by":"publisher","award":["A48\/2562"],"award-info":[{"award-number":["A48\/2562"]}],"id":[{"id":"10.13039\/501100004156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["DBG6180029"],"award-info":[{"award-number":["DBG6180029"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chitosan oligosaccharide (COS), a natural polymer derived from chitosan, exerts several biological activities including anti-inflammation, anti-tumor, anti-metabolic syndrome, and drug delivery enhancer. Since COS is vastly distributed to kidney and eliminated in urine, it may have a potential advantage as the therapeutics of kidney diseases. Polycystic kidney disease (PKD) is a common genetic disorder characterized by multiple fluid-filled cysts, replacing normal renal parenchyma and leading to impaired renal function and end-stage renal disease (ESRD). The effective treatment for PKD still needs to be further elucidated. Interestingly, AMP-activated protein kinase (AMPK) has been proposed as a drug target for PKD. This study aimed to investigate the effect of COS on renal cyst enlargement and its underlying mechanisms. We found that COS at the concentrations of 50 and 100 \u00b5g\/mL decreased renal cyst growth without cytotoxicity, as measured by MTT assay. Immunoblotting analysis showed that COS at 100 \u00b5g\/mL activated AMPK, and this effect was abolished by STO-609, a calcium\/calmodulin-dependent protein kinase kinase beta (CaMKK\u03b2) inhibitor. Moreover, COS elevated the level of intracellular calcium. These results suggest that COS inhibits cyst progression by activation of AMPK via CaMKK\u03b2. Therefore, COS may hold the potential for pharmaceutical application in PKD.<\/jats:p>","DOI":"10.3390\/molecules25235589","type":"journal-article","created":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T03:51:16Z","timestamp":1606535476000},"page":"5589","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel Potential Application of Chitosan Oligosaccharide for Attenuation of Renal Cyst Growth in the Treatment of Polycystic Kidney Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4641-5829","authenticated-orcid":false,"given":"Nutthapoom","family":"Pathomthongtaweechai","sequence":"first","affiliation":[{"name":"Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakan 10540, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunhapas","family":"Soodvilai","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rath","family":"Pichyangkura","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chatchai","family":"Muanprasat","sequence":"additional","affiliation":[{"name":"Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakan 10540, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"ref_1","first-page":"1356","article-title":"Prevalence of autosomal dominant polycystic kidney disease in the European Union","volume":"32","author":"Willey","year":"2017","journal-title":"Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. Eur. Ren. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41572-018-0047-y","article-title":"Polycystic kidney disease","volume":"4","author":"Bergmann","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1681\/ASN.2018050493","article-title":"Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing","volume":"29","author":"Lanktree","year":"2018","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1681\/ASN.2017050483","article-title":"Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases","volume":"29","author":"Torres","year":"2018","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1007\/s00018-012-1188-x","article-title":"Polycystins and cellular Ca2+ signaling","volume":"70","author":"Mekahli","year":"2013","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41581-019-0143-6","article-title":"Structure and function of polycystins: Insights into polycystic kidney disease","volume":"15","author":"Douguet","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1159\/000486932","article-title":"New Insights into Cystic Kidney Diseases","volume":"195","author":"Mochizuki","year":"2018","journal-title":"Contrib. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s10157-012-0741-0","article-title":"Autosomal dominant polycystic kidney disease: Recent advances in pathogenesis and potential therapies","volume":"17","author":"Mochizuki","year":"2013","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.5500\/wjt.v2.i4.51","article-title":"Current state of renal transplant immunosuppression: Present and future","volume":"2","author":"Kalluri","year":"2012","journal-title":"World J. Transplant."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.bbadis.2010.11.005","article-title":"Cyclic AMP-mediated cyst expansion","volume":"1812","author":"Wallace","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1681\/ASN.2013040398","article-title":"Strategies targeting cAMP signaling in the treatment of polycystic kidney disease","volume":"25","author":"Torres","year":"2014","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1083\/jcb.201006173","article-title":"The cell biology of polycystic kidney disease","volume":"191","author":"Chapin","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.molmed.2011.06.003","article-title":"mTOR signaling in polycystic kidney disease","volume":"17","author":"Natoli","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1681\/ASN.2014121192","article-title":"The Future of Polycystic Kidney Disease Research\u2014As Seen By the 12 Kaplan Awardees","volume":"26","author":"Antignac","year":"2015","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/s41573-019-0019-2","article-title":"AMP-activated protein kinase: The current landscape for drug development","volume":"18","author":"Steinberg","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Glosse, P., and F\u00f6ller, M. (2018). AMP-Activated Protein Kinase (AMPK)-Dependent Regulation of Renal Transport. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113481"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1097\/MNH.0000000000000349","article-title":"Role of AMP-activated protein kinase in kidney tubular transport, metabolism, and disease","volume":"26","author":"Rajani","year":"2017","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/nm.3092","article-title":"Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy","volume":"19","author":"Rowe","year":"2013","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1073\/pnas.1011498108","article-title":"Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis","volume":"108","author":"Takiar","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.pharmthera.2016.10.013","article-title":"Chitosan oligosaccharide: Biological activities and potential therapeutic applications","volume":"170","author":"Muanprasat","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.foodchem.2013.10.083","article-title":"Recent developments in chitosanase research and its biotechnological applications: A review","volume":"150","author":"Thadathil","year":"2014","journal-title":"Food Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.ijbiomac.2019.01.192","article-title":"Chitosan oligosaccharide (COS): An overview","volume":"129","author":"Naveed","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.biopha.2018.03.108","article-title":"Chitooligosaccharide: An evaluation of physicochemical and biological properties with the proposition for determination of thermal degradation products","volume":"102","author":"Phil","year":"2018","journal-title":"Biomed. Pharmacother. Biomed. Pharmacother."},{"key":"ref_26","first-page":"467","article-title":"Targeted therapy using nanotechnology: Focus on cancer","volume":"9","author":"Sanna","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.drudis.2013.06.014","article-title":"Polymer gene delivery: Overcoming the obstacles","volume":"18","author":"Aied","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1021\/bm100158p","article-title":"Pharmacokinetics and biodegradation mechanisms of a versatile carboxymethyl derivative of chitosan in rats: In vivo and in vitro evaluation","volume":"11","author":"Dong","year":"2010","journal-title":"Biomacromolecules"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1007\/s10856-012-4747-7","article-title":"Effects of molecular weights on the absorption, distribution and urinary excretion of intraperitoneally administrated carboxymethyl chitosan in rats","volume":"23","author":"Dong","year":"2012","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1016\/j.fct.2011.04.036","article-title":"Protective effects of chitosan oligosaccharide on paraquat-induced nephrotoxicity in rats","volume":"49","author":"Yoon","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/j.2042-7158.1997.tb06099.x","article-title":"Effect of chitosan on renal function in patients with chronic renal failure","volume":"49","author":"Jing","year":"1997","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.bcp.2015.05.016","article-title":"Activation of AMPK by chitosan oligosaccharide in intestinal epithelial cells: Mechanism of action and potential applications in intestinal disorders","volume":"96","author":"Muanprasat","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ejphar.2013.12.013","article-title":"Pranlukast inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase","volume":"724","author":"Pathomthongtaweechai","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yuajit, C., Homvisasevongsa, S., Chatsudthipong, L., Soodvilai, S., Muanprasat, C., and Chatsudthipong, V. (2013). Steviol reduces MDCK Cyst formation and growth by inhibiting CFTR channel activity and promoting proteasome-mediated CFTR degradation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058871"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.biopha.2017.07.165","article-title":"Steviol stabilizes polycystin 1 expression and promotes lysosomal degradation of CFTR and \u03b2-catenin proteins in renal epithelial cells","volume":"94","author":"Yuajit","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ejphar.2010.12.008","article-title":"Curcumin inhibits renal cyst formation and enlargement in vitro by regulating intracellular signaling pathways","volume":"654","author":"Gao","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1681\/ASN.2007070828","article-title":"Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease","volume":"19","author":"Yang","year":"2008","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/978-1-4939-7598-3_12","article-title":"Compound C\/Dorsomorphin: Its Use and Misuse as an AMPK Inhibitor","volume":"1732","author":"Dasgupta","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.phrs.2016.09.016","article-title":"Chitosan oligosaccharide suppresses synovial inflammation via AMPK activation: An in vitro and in vivo study","volume":"113","author":"Kunanusornchai","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.phrs.2012.03.013","article-title":"Chitosan oligosaccharide as potential therapy of inflammatory bowel disease: Therapeutic efficacy and possible mechanisms of action","volume":"66","author":"Yousef","year":"2012","journal-title":"Pharmacol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1681\/ASN.2008090927","article-title":"Calcimimetic inhibits late-stage cyst growth in ADPKD","volume":"20","author":"Gattone","year":"2009","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1093\/ndt\/gfn527","article-title":"Effect of calcium-sensing receptor activation in models of autosomal recessive or dominant polycystic kidney disease","volume":"24","author":"Wang","year":"2009","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"F485","DOI":"10.1152\/ajprenal.00608.2009","article-title":"Physiology and pathophysiology of the calcium-sensing receptor in the kidney","volume":"298","author":"Riccardi","year":"2010","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/nrneph.2016.59","article-title":"Localization and function of the renal calcium-sensing receptor","volume":"12","author":"Riccardi","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1152\/physiol.00042.2014","article-title":"Calcium Sensing in the Renal Tubule","volume":"30","author":"Toka","year":"2015","journal-title":"Physiology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1073\/pnas.0610157104","article-title":"Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase","volume":"104","author":"Zheng","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","first-page":"5132","article-title":"Activation of the Ca2+-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane","volume":"126","author":"Jouret","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Rowart, P., Wu, J., Caplan, M.J., and Jouret, F. (2018). Implications of AMPK in the Formation of Epithelial Tight Junctions. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072040"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.carbpol.2015.04.036","article-title":"Polymeric nanoparticles based on chitooligosaccharide as drug carriers for co-delivery of all-trans-retinoic acid and paclitaxel","volume":"129","author":"Zhang","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.apsb.2013.12.005","article-title":"Kidney-targeted drug delivery systems","volume":"4","author":"Zhou","year":"2014","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Qui\u00f1ones, J.P., Peniche, H., and Peniche, C. (2018). Chitosan Based Self-Assembled Nanoparticles in Drug Delivery. Polymers, 10.","DOI":"10.20944\/preprints201802.0012.v1"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/j.carbpol.2011.10.060","article-title":"Chitosan oligomers as drug carriers for renal delivery of zidovudine","volume":"87","author":"Liang","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/j.1742-4658.2004.04495.x","article-title":"Degradation of chitosans with chitinase B from Serratia marcescens. Production of chito-oligosaccharides and insight into enzyme processivity","volume":"272","author":"Horn","year":"2005","journal-title":"FEBS J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s12010-008-8328-7","article-title":"Purification and characterization of thermostable chitinase from Bacillus Licheniformis SK-1","volume":"157","author":"Kudan","year":"2009","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Liang, S., Sun, Y., and Dai, X. (2018). A Review of the Preparation, Analysis and Biological Functions of Chitooligosaccharide. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082197"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10856-008-3575-2","article-title":"The fundamental parameters of chitosan in polymer scaffolds affecting osteoblasts (MC3T3-E1)","volume":"20","author":"Suphasiriroj","year":"2009","journal-title":"J. Mater. Sci. Mater. Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/23\/5589\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:38:41Z","timestamp":1760179121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/23\/5589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,27]]},"references-count":56,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["molecules25235589"],"URL":"https:\/\/doi.org\/10.3390\/molecules25235589","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2020,11,27]]}}}