{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:13:53Z","timestamp":1772756033139,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)","award":["2019R1A2C1084140-13 and 14"],"award-info":[{"award-number":["2019R1A2C1084140-13 and 14"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["F21YY8109033"],"award-info":[{"award-number":["F21YY8109033"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["F22YY8109033"],"award-info":[{"award-number":["F22YY8109033"]}]},{"name":"Korean government (MSIP: Ministry of Science, ICT &amp; Future Planning)","award":["2019R1A2C1084140-13 and 14"],"award-info":[{"award-number":["2019R1A2C1084140-13 and 14"]}]},{"name":"Korean government (MSIP: Ministry of Science, ICT &amp; Future Planning)","award":["F21YY8109033"],"award-info":[{"award-number":["F21YY8109033"]}]},{"name":"Korean government (MSIP: Ministry of Science, ICT &amp; Future Planning)","award":["F22YY8109033"],"award-info":[{"award-number":["F22YY8109033"]}]},{"name":"K21 FOUR Program through the National Research Foundation of Korea (NRF)","award":["2019R1A2C1084140-13 and 14"],"award-info":[{"award-number":["2019R1A2C1084140-13 and 14"]}]},{"name":"K21 FOUR Program through the National Research Foundation of Korea (NRF)","award":["F21YY8109033"],"award-info":[{"award-number":["F21YY8109033"]}]},{"name":"K21 FOUR Program through the National Research Foundation of Korea (NRF)","award":["F22YY8109033"],"award-info":[{"award-number":["F22YY8109033"]}]},{"name":"Ministry of Education, Korea","award":["2019R1A2C1084140-13 and 14"],"award-info":[{"award-number":["2019R1A2C1084140-13 and 14"]}]},{"name":"Ministry of Education, Korea","award":["F21YY8109033"],"award-info":[{"award-number":["F21YY8109033"]}]},{"name":"Ministry of Education, Korea","award":["F22YY8109033"],"award-info":[{"award-number":["F22YY8109033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Complement component 3 (C3) contributes to neurogenesis, neural migration, and synaptic elimination under normal and disease conditions of the brain, even though it has not been studied in the enteric nervous system (ENS). To determine the role of C3 in the regulatory mechanism of ENS during C3 deficiency-induced constipation, the changes in the markers of neuronal and interstitial cells of Cajal (ICCs), the markers for excitatory and inhibitory transmission of ENS, and expression of C3 receptors were analyzed in the mid colon of C3 knockout (KO) mice at 16 weeks of age. Prominent constipation phenotypes, including the decrease in stool parameters, changes in the histological structure, and suppression of mucin secretion, were detected in C3 KO mice compared to wildtype (WT) mice. The expression levels of the neuron specific enolase (NSE), protein gene product 9.5 (PGP9.5), and C-kit markers for myenteric neurons and ICCs were lower in the mid colon of C3 KO mice than WT mice. Excitatory transmission analysis revealed similar suppression of the 5-hydroxytryptamine (5-HT) concentration, expression of 5-HT receptors, acetylcholine (ACh) concentration, ACh esterase (AChE) activity, and expression of muscarinic ACh receptors (mAChRs), despite the mAChRs downstream signaling pathway being activated in the mid colon of C3 KO mice. In inhibitory transmission analysis, C3 KO mice showed an increase in the nitric oxide (NO) concentration and inducible nitric oxide synthase (iNOS) expression, while neuronal NOS (nNOS) expression, cholecystokinin (CCK), and gastrin concentration were decreased in the same mice. Furthermore, the levels of C3a receptor (C3aR) and C3bR expression were enhanced in the mid colon of C3 KO mice compared to the WT mice during C3 deficiency-induced constipation. Overall, these results indicate that a dysregulation of the ENS may play an important role in C3 deficiency-induced constipation in the mid colon of C3 KO mice.<\/jats:p>","DOI":"10.3390\/ijms23126862","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T01:43:27Z","timestamp":1655775807000},"page":"6862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dysregulation of the Enteric Nervous System in the Mid Colon of Complement Component 3 Knockout Mice with Constipation Phenotypes"],"prefix":"10.3390","volume":"23","author":[{"given":"Yun Ju","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee Jin","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"You Jeong","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu Jeong","family":"Roh","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayun","family":"Seol","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hye Sung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nanomechatronics Engineering, College of Nanoscience & Nanotechnology, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5144-1725","authenticated-orcid":false,"given":"Dae Youn","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Science (BK21 FOUR Program) and Life and Industry Convergence Research Institute, College of Natural Resources & LifeScience, Pusan National University, Miryang 50463, Korea"},{"name":"Laboratory Animals Resources Center, Pusan National University, Miryang 50463, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38476","DOI":"10.1074\/jbc.M307017200","article-title":"Formation of high affinity C5 convertase of the classical pathway of complement","volume":"278","author":"Rawal","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.biopha.2017.11.119","article-title":"Enteromorpha and polysaccharides from enteromorpha ameliorate loperamide-induced constipation in mice","volume":"96","author":"Ren","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1111\/1471-0528.16660","article-title":"Dysfunction of complement receptors CR3 (CD11b\/18) and CR4 (CD11c\/18) in pre-eclampsia: A genetic and functional study","volume":"128","author":"Lokki","year":"2021","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3920\/BM2018.0050","article-title":"Effects of long-term administration of Lactobacillus reuteri DSM-17938 on circulating levels of 5-HT and BDNF in adults with functional constipation","volume":"10","author":"Riezzo","year":"2019","journal-title":"Benef. Microbes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"573","DOI":"10.3389\/fpsyt.2019.00573","article-title":"Emerging roles of complement in psychiatric disorders","volume":"10","author":"Druart","year":"2019","journal-title":"Front. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1523\/JNEUROSCI.2117-15.2016","article-title":"Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer\u2019s disease","volume":"36","author":"Lian","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15096","DOI":"10.1038\/ncomms15096","article-title":"Developmental activities of the complement pathway in migrating neurons","volume":"8","author":"Gorelik","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"19737","DOI":"10.1073\/pnas.0609791104","article-title":"Structural transitions of complement component C3 and its activation products","volume":"103","author":"Nishida","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"R1478","DOI":"10.1152\/ajpregu.2000.279.4.R1478","article-title":"Gastrointestinal motility during pregnancy: Role of nitrergic component of NANC nerves","volume":"279","author":"Shah","year":"2000","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"G277","DOI":"10.1152\/ajpgi.1992.263.2.G277","article-title":"NADPH diaphorase and nitric oxide synthase colocalization in enteric neurons of canine proximal colon","volume":"263","author":"Ward","year":"1992","journal-title":"Am. J. Physiol. Gastrointest. Liver. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.neuron.2018.10.031","article-title":"Complement C3aR inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer\u2019s disease","volume":"100","author":"Litvinchuk","year":"2018","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1046\/j.1365-2249.2000.01168.x","article-title":"Cellular localization of complement C3 and C4 transcripts in intestinal specimens from patients with Crohn\u2019s disease","volume":"120","author":"Laufer","year":"2000","journal-title":"Clin. Exp. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s10350-004-6251-8","article-title":"Role of nitric oxide in the colon of patients with slow-transit constipation","volume":"45","author":"Tomita","year":"2002","journal-title":"Dis. Colon Rectum"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJM199005103221903","article-title":"Enhanced local production of complement components in the small intestines of patients with Crohn\u2019s disease","volume":"322","author":"Ahrenstedt","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1136\/gut.33.7.902","article-title":"Surface epithelium related activation of complement differs in Crohn\u2019s disease and ulcerative colitis","volume":"33","author":"Halstensen","year":"1992","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3836","DOI":"10.4049\/jimmunol.172.6.3836","article-title":"Decay-accelerating factor deficiency increases susceptibility to dextran sulfate sodium-induced colitis: Role for complement in inflammatory bowel disease","volume":"172","author":"Lin","year":"2004","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature18283","article-title":"A complement-microglial axis drives synapse loss during virus-induced memory impairment","volume":"534","author":"Vasek","year":"2016","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e21221","DOI":"10.1096\/fj.202000376R","article-title":"Deficiency of complement component 3 may be linked to the development of constipation in FVB\/N-C3em1Hlee\/Korl mice","volume":"35","author":"Park","year":"2021","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"650789","DOI":"10.3389\/fphys.2021.650789","article-title":"Dysbiosis of fecal microbiota from complement 3 knockout mice with constipation phenotypes contributes to development of defecation delay","volume":"12","author":"Choi","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1038\/s41598-022-05708-8","article-title":"Promotion of the inflammatory response in mid colon of complement component 3 knockout mice","volume":"12","author":"Choi","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Furness, J.B. (2006). The Enteric Nervous System, Blackwell Science Ltd.","DOI":"10.1002\/9780470988756"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fendo.2020.00112","article-title":"Gastrin, cholecystokinin, signaling, and biological activities in cellular processes","volume":"11","author":"Zeng","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1159\/000334652","article-title":"Management and pathophysiology of functional gastrointestinal disorders","volume":"85","author":"Fukudo","year":"2012","journal-title":"Digestion"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6076293","DOI":"10.1155\/2021\/6076293","article-title":"Paeoniflorin improved constipation in the loperamide-induced rat model via TGR5\/TRPA1 signaling-mediated 5-hydroxytryptamine secretion","volume":"2021","author":"Zhan","year":"2021","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/1319-3767.105909","article-title":"The importance of interstitial cells of Cajal in the gastrointestinal tract","volume":"19","year":"2013","journal-title":"Saudi. J. Gastroenterol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1111\/j.1440-1746.2005.03809.x","article-title":"Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon","volume":"20","author":"Lee","year":"2005","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1006\/clin.1995.1047","article-title":"Decreased levels of complement receptor 1 (CD35) on B lymphocytes in persons with HIV infection","volume":"75","author":"Munson","year":"1995","journal-title":"Clin. Immunol. Immunopathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1046\/j.1365-2249.1996.17721.x","article-title":"Distribution of activated complement, C3b, and its degraded fragments, iC3b\/C3dg, in the colonic mucosa of ulcerative colitis (UC)","volume":"104","author":"Ueki","year":"1996","journal-title":"Clin. Exp. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/modpathol.3800748","article-title":"Colonic neuropathological aspects in patients with intractable constipation due to obstructed defecation","volume":"20","author":"Bassotti","year":"2007","journal-title":"Mod. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kim, J.E., Choi, Y.J., Lee, S.J., Gong, J.E., Lim, Y., Hong, J.T., and Hwang, D.Y. (2020). Molecular characterization of constipation disease as novel phenotypes in CRISPR-Cas9-generated leptin knockout mice with obesity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249464"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kim, J.E., Go, J., Koh, E.K., Song, S.H., Sung, J.E., Lee, H.A., Lee, Y.H., Hong, J.T., and Hwang, D.Y. (2016). Gallotannin-enriched extract isolated from galla rhois may be a functional candidate with laxative effects for treatment of loperamide-induced constipation of SD rats. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161144"},{"key":"ref_34","first-page":"567","article-title":"Primary gastrointestinal motility disorders in childhood","volume":"64","author":"Yeung","year":"2012","journal-title":"Minerva. Pediatr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1053\/j.gastro.2005.09.031","article-title":"Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome","volume":"130","author":"Atkinson","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.3109\/00365529609036893","article-title":"The expression of complement protein 4 and IgG3 in luminal secretions","volume":"31","author":"Riordan","year":"1996","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.neuron.2012.03.026","article-title":"Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner","volume":"74","author":"Schafer","year":"2012","journal-title":"Neuron"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6484","DOI":"10.1080\/21655979.2021.1973356","article-title":"The mechanism of intestinal flora dysregulation mediated by intestinal bacterial biofilm to induce constipation","volume":"12","author":"Fu","year":"2021","journal-title":"Bioengineered"},{"key":"ref_39","first-page":"5596531","article-title":"Nostoc sphaeroides k\u00fctz polysaccharide improved constipation and promoted intestinal motility in rats","volume":"2021","author":"Liu","year":"2021","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/imr.12500","article-title":"Complement component C3-The \u201cSwiss Army Knife\u201d of innate immunity and host defense","volume":"274","author":"Ricklin","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.3892\/mmr.2015.3737","article-title":"Therapeutic effects of Lactobacillus casei Qian treatment in activated carbon-induced constipated mice","volume":"12","author":"Zhao","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1159\/000051888","article-title":"Patients with constipation-predominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrhea-predominant patients and subjects with normal bowel habits","volume":"63","author":"Miwa","year":"2001","journal-title":"Digestion"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kim, J.E., Go, J., Sung, J.E., Lee, H.A., Yun, W.B., Hong, J.T., and Hwang, D.Y. (2017). Uridine stimulate laxative effect in the loperamide-induced constipation of SD rats through regulation of the mAChRs signaling pathway and mucin secretion. BMC Gastroenterol., 17.","DOI":"10.1186\/s12876-017-0576-y"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kim, J.E., Park, J.W., Kang, M.J., Choi, H.J., Bae, S.J., Choi, Y., Lee, Y.J., Seo, S., Hong, J.T., and Hwang, D.Y. (2019). Laxative effect of spicatoside A by cholinergic regulation of enteric nerve in loperamide-induced constipation: ICR mice model. Molecules, 24.","DOI":"10.3390\/molecules24050896"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.3892\/mmr.2014.2009","article-title":"Component analysis of Pu-erh and its anti-constipation effects","volume":"9","author":"Li","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1111\/j.1476-5381.1995.tb16406.x","article-title":"Study of NO and VIP as non-adrenergic non-cholinergic neurotransmitters in the pig gastric fundus","volume":"116","author":"Lefebvre","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1111\/j.1365-2249.2010.04093.x","article-title":"The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease","volume":"160","author":"Sugihara","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Xia, Y., and Ross, G.D. (2000). Roles of integrins CR3 and CR4 in disease and therapeutic strategies. Therapeutic Interventions in the Complement System, Humana Press.","DOI":"10.1385\/1-59259-017-9:171"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/0092-8674(93)90615-W","article-title":"Targeted disruption of the neuronal nitric oxide synthase gene","volume":"75","author":"Huang","year":"1993","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.4049\/jimmunol.166.4.2635","article-title":"Formation of high-affinity C5 convertases of the alternative pathway of complement","volume":"166","author":"Rawal","year":"2001","journal-title":"J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00384-003-0577-x","article-title":"Decreased interstitial cells of Cajal in the sigmoid colon of patients with slow transit constipation","volume":"19","author":"Tong","year":"2004","journal-title":"Int. J. Colorectal. Dis."},{"key":"ref_52","first-page":"486","article-title":"Effects of zhizhu tongbian decoction on the colon ink propelling rate, GDNF, and NOS mRNA expression in rats with slow transit constipation","volume":"32","author":"Fan","year":"2012","journal-title":"Chin. J. Integr. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhu, F., Xu, S., Zhang, Y., Chen, F., Ji, J., and Xie, G. (2016). Total glucosides of paeony promote intestinal motility in slow transit constipation rats through amelioration of interstitial cells of Cajal. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160398"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"13236","DOI":"10.1073\/pnas.1106746108","article-title":"Unique structure of iC3b resolved at a resolution of 24 A by 3D-electron microscopy","volume":"108","author":"Alcorlo","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kieslich, C.A., and Morikis, D. (2012). The two sides of complement C3d: Evolution of electrostatics in a link between innate and adaptive immunity. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002840"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5758192","DOI":"10.1155\/2016\/5758192","article-title":"Complement receptor type 1 suppresses human B cell functions in SLE patients","volume":"2016","author":"Kremlitzka","year":"2016","journal-title":"J. Immunol. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.1523\/JNEUROSCI.3617-10.2011","article-title":"Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis","volume":"31","author":"Moriyama","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1136\/gut.51.4.496","article-title":"Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation","volume":"51","author":"Lyford","year":"2002","journal-title":"Gut"},{"key":"ref_59","first-page":"649","article-title":"Naringenin induces laxative effects by upregulating the expression levels of c-Kit and SCF, as well as those of aquaporin 3 in mice with loperamide-induced constipation","volume":"41","author":"Yin","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s42826-020-0036-7","article-title":"Compensatory role of C3 convertase on the strain difference for C3 protein expression in FVB\/N, C3H\/HeN and C57BL\/6N mice","volume":"36","author":"Park","year":"2020","journal-title":"Lab. Anim. Res."},{"key":"ref_61","first-page":"458","article-title":"Loperamide-induced constipation activates inflammatory signaling pathways in the mid colon of SD rats via complement C3 and its receptors","volume":"21","author":"Choi","year":"2021","journal-title":"Curr. Mol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6862\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:35:57Z","timestamp":1760139357000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,20]]},"references-count":61,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23126862"],"URL":"https:\/\/doi.org\/10.3390\/ijms23126862","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,20]]}}}