{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:12:20Z","timestamp":1793722340607,"version":"4.6.1"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Slow-transit constipation (STC) is a widespread functional gastrointestinal condition distinguished by decreased colonic motility as an essential clinical characteristic. The excessive autophagy of interstitial cells of Cajal (ICCs) causes phenotypic changes and functional abnormalities, which are important in colonic dysmotility. Naringenin (NAR) has been shown to regulate gastrointestinal motility disorders. The present study aimed to elucidate the regulatory role of naringenin in autophagy in STC and its underlying mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic>, ICCs were stimulated with L-glutamic acid (GA) to induce autophagy and treated with NAR. A CCK8 assay was performed to evaluate the cytotoxic effect of NAR. Annexin V-FITC\/PI staining was used to examine NAR apoptosis. The expression of the autophagy markers Beclin1 and LC3B, as well as proteins related to the AMPK\/mTOR\/ULK1 pathway was investigated through quantitative PCR, Western blot analysis and immunofluorescence staining. The small interfering RNA (siRNA) technique was used to knockdown selective autophagy receptors (NDP52, OPTN, NBR1, and p62) in ICCs. Coimmunoprecipitation (co-IP) was used to evaluate the binding of pS757-ULK1 to the autophagy receptors NDP52 and OPTN in ICCs. Immunofluorescence (IF) staining was performed to observe the colocalization of pS757-ULK1 with exogenous NDP52 and OPTN in ICCs. <jats:italic>In vivo<\/jats:italic>, male C57BL\/6 mice were administered loperamide (10\u00a0mg\/kg) to establish a constipation model and then treated with NAR (75\/150\/300\u00a0mg\/kg) for 2 weeks. Finally, colonic tissues were collected for a histological analysis and immunohistochemical for cell growth factor receptor kit (c-Kit) and anoctamin-1 (ANO1).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results indicated that NAR improved the survival and apoptosis of ICCs after GA by inhibiting autophagy through the partial suppression of the AMPK\/mTOR\/ULK1 signalling pathway. Moreover, NAR inhibited the autophagic degradation of pS757-ULK1 by weakening the interactions between pS757-ULK1 and the selective autophagy receptor genes NDP52 and OPTN. Further research revealed that NAR could increase the moisture content of faeces; increase the rate of small intestinal propulsion in mice; increase the serum concentrations of excitatory neurotransmitters such as GAS, 5-HT, MTL, and SP; and increase the expression levels of ANO1 and c-Kit in the colon, and the molecular mechanism was consistent with the <jats:italic>in vitro<\/jats:italic> results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>NAR attenuates the AMPK\/mTOR\/ULK1 pathway in ICCs, thereby improving STC colonic dysmotility and underscoring its promise as a therapeutic option for STC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1550458","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T09:32:58Z","timestamp":1750152778000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Naringenin attenuates slow-transit constipation by regulating the AMPK\/mTOR\/ULK1 signalling pathway: in vivo and in vitro studies"],"prefix":"10.3389","volume":"16","author":[{"given":"Yahui","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiju","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianlin","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.5603\/FM.a2021.0138","article-title":"Anoctamin 1 and c-Kit immunohistochemical study of interstitial cells of Cajal in the muscularis externa of human gastrointestinal tract","volume":"82","author":"Al-Ahmadi","year":"2023","journal-title":"Folia Morphol. Warsz."},{"key":"B2","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s13105-020-00746-0","article-title":"A current view of molecular dissection in autophagy machinery","volume":"76","author":"Al-Bari","year":"2020","journal-title":"J. Physiol. Biochem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e114607","DOI":"10.1371\/journal.pone.0114607","article-title":"Mimulone-induced autophagy through p53-mediated AMPK\/mTOR pathway increases caspase-mediated apoptotic cell death in A549 human lung cancer cells","volume":"9","author":"An","year":"2014","journal-title":"PloS one"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.3390\/plants9121784","article-title":"Multi-therapeutic potential of naringenin (4',5,7-trihydroxyflavonone): experimental evidence and mechanisms","volume":"9","author":"Arafah","year":"2020","journal-title":"Plants (Basel)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/17474124.2020.1708718","article-title":"An approach to the diagnosis and management of Rome IV functional disorders of chronic constipation","volume":"14","author":"Aziz","year":"2020","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"104923","DOI":"10.1016\/j.yexmp.2024.104923","article-title":"Age-related decline in goblet cell numbers and mucin content of the human colon: implications for lower bowel functions in the elderly","volume":"139","author":"Baidoo","year":"2024","journal-title":"Exp. Mol. Pathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/S2468-1253(21)00111-4","article-title":"Global prevalence of functional constipation according to the Rome criteria: a systematic review and meta-analysis","volume":"6","author":"Barberio","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3237","DOI":"10.1242\/jcs.126128","article-title":"The LIR motif - crucial for selective autophagy","volume":"126","author":"Birgisdottir","year":"2013","journal-title":"J. Cell. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.7150\/ijbs.85443","article-title":"Promotion of ROS-mediated apoptosis, G2\/M arrest, and autophagy by naringenin in non-small cell lung cancer","volume":"20","author":"Chang","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2709","DOI":"10.3748\/wjg.v30.i20.2709","article-title":"Hydrogen-rich water alleviates constipation by attenuating oxidative stress through the sirtuin1\/nuclear factor-erythroid-2-related factor 2\/heme oxygenase-1 signaling pathway","volume":"30","author":"Chen","year":"","journal-title":"World J. Gastroenterol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"817100","DOI":"10.3389\/fendo.2022.817100","article-title":"Neurotransmitter and intestinal interactions: focus on the microbiota-gut-brain Axis in irritable bowel syndrome","volume":"13","author":"Chen","year":"2022","journal-title":"Front. Endocrinol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1142\/S0192415X24500344","article-title":"Quercetin ameliorates myocardial injury in diabetic rats by regulating autophagy and apoptosis through AMPK\/mTOR signaling pathway","volume":"52","author":"Chen","year":"","journal-title":"Am. J. Chin. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1097\/st9.0000000000000052","article-title":"Top 10 research achievements of traditional Chinese medicine in 2023","volume":"2","year":"2024","journal-title":"Sci. Tradit. Chin. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/s002280100300","article-title":"Population pharmacokinetics of free carbamazepine in adult Omani epileptic patients","volume":"57","author":"Deleu","year":"2001","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1113\/JP279102","article-title":"Pacemaker function and neural responsiveness of subserosal interstitial cells of Cajal in the mouse colon","volume":"598","author":"Drumm","year":"2020","journal-title":"J. Physiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"367","DOI":"10.12047\/j.cjap.5616.2018.084","article-title":"Effect of Angelica sinensis radix on colonic morphology and mucus secretion of experimental XuexuBianmi model mice","volume":"34","author":"Du","year":"2018","journal-title":"Chin. J. Appl. Physiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1126\/science.1196371","article-title":"Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy","volume":"331","author":"Egan","year":"2011","journal-title":"Science"},{"key":"B18","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.nutres.2007.12.002","article-title":"Naringenin reduces tumor size and weight lost in N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats","volume":"28","author":"Ekambaram","year":"2008","journal-title":"Nutr. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"4540","DOI":"10.3390\/ijms21124540","article-title":"Understanding the biology of human interstitial cells of cajal in gastrointestinal motility","volume":"21","author":"Foong","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.1017\/S1431927622000836","article-title":"An unexpected alteration colonic mucus appearance in the constipation model via an intestinal microenvironment","volume":"28","author":"Gao","year":"2022","journal-title":"Microsc. Microanal."},{"key":"B21","first-page":"1670","article-title":"Assessing the interstitial cells of Cajal, cells of enteric nervous system and neurotransmitters in slow transit constipation, using immunohistochemistry for CD117, PGP9.5 and serotonin","volume":"56","author":"Geramizadeh","year":"2009","journal-title":"Hepatogastroenterology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"9349","DOI":"10.1111\/jcmm.15586","article-title":"Astragaloside IV alleviates mouse slow transit constipation by modulating gut microbiota profile and promoting butyric acid generation","volume":"24","author":"He","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4713","DOI":"10.1007\/s00018-021-03812-y","article-title":"The enteric nervous system in gastrointestinal disease etiology","volume":"78","author":"Holland","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"5607","DOI":"10.1039\/d0fo00208a","article-title":"Pediococcus pentosaceus B49 from human colostrum ameliorates constipation in mice","volume":"11","author":"Huang","year":"2020","journal-title":"Food Funct."},{"key":"B25","doi-asserted-by":"publisher","first-page":"G552","DOI":"10.1152\/ajpgi.00264.2021","article-title":"Interstitial cells of Cajal and human colon motility in health and disease","volume":"321","author":"Huizinga","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3390\/cells11010030","article-title":"Mitophagy: molecular mechanisms, new concepts on parkin activation and the emerging role of AMPK\/ULK1 Axis","volume":"11","author":"Iorio","year":"2021","journal-title":"Cells"},{"key":"B27","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/sj.ejcn.1602543","article-title":"Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects","volume":"61","author":"Kanaze","year":"2007","journal-title":"Eur. J. Clin. Nutr."},{"key":"B28","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1111\/j.1743-3150.2004.00482.x","article-title":"Regulation of intestinal secretion involved in the interaction between neurotransmitters and prostaglandin E2","volume":"16","author":"Karaki","year":"2004","journal-title":"Neurogastroenterol. Motil."},{"key":"B29","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1111\/j.1365-2982.2011.01729.x","article-title":"Immunoreactivity for Ano1 detects depletion of Kit-positive interstitial cells of Cajal in patients with slow transit constipation","volume":"23","author":"Kashyap","year":"2011","journal-title":"Neurogastroenterol. Motil."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e1000412","DOI":"10.1371\/journal.pbio.1000412","article-title":"Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research","volume":"8","author":"Kilkenny","year":"2010","journal-title":"PLoS Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1080\/13880209.2018.1474932","article-title":"Quercetin promotes gastrointestinal motility and mucin secretion in loperamide-induced constipation of SD rats through regulation of the mAChRs downstream signal","volume":"56","author":"Kim","year":"2018","journal-title":"Pharm. Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"587453","DOI":"10.3389\/fphar.2020.587453","article-title":"A close relationship between networks of interstitial cells of cajal and gastrointestinal transit in vivo","volume":"11","author":"Kishi","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","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":"B35","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cell.2018.09.048","article-title":"Biological functions of autophagy genes: a disease perspective","volume":"176","author":"Levine","year":"2019","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s12866-023-02880-3","article-title":"Protective effect of L-pipecolic acid on constipation in C57BL\/6 mice based on gut microbiome and serum metabolomic","volume":"23","author":"Li","year":"2023","journal-title":"BMC Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"102","DOI":"10.19763\/j.cnki.2096-7403.2022.02.06","article-title":"Effect of runchang tongbian oral liquid on colonic Muc2 of mice with constipation","volume":"23","author":"Li","year":"2022","journal-title":"J. Shanxi Univ. Chin. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"4589","DOI":"10.1113\/JP270511","article-title":"Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon","volume":"593","author":"Lies","year":"2015","journal-title":"J. Physiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1097\/st9.0000000000000038","article-title":"Mechanism of Sishen Pills-Tongxie Yaofang in the treatment of ulcerative colitis based on network pharmacology and experimental verification","volume":"2","author":"Liu","year":"2024","journal-title":"Sci. Tradit. Chin. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1161\/RES.0b013e3182194c29","article-title":"AMPK activates autophagy by phosphorylating ULK1","volume":"108","author":"Mao","year":"2011","journal-title":"Circ. Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/ajg.2013.73","article-title":"Association of low dietary intake of fiber and liquids with constipation: evidence from the National Health and Nutrition Examination Survey","volume":"108","author":"Markland","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1136\/gutjnl-2019-318747","article-title":"microRNA overexpression in slow transit constipation leads to reduced NaV1.5 current and altered smooth muscle contractility","volume":"69","author":"Mazzone","year":"2020","journal-title":"Gut"},{"key":"B43","doi-asserted-by":"publisher","first-page":"3189","DOI":"10.1111\/bph.12955","article-title":"Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP","volume":"172","author":"McGrath","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"10368","DOI":"10.1039\/c9ra10446a","article-title":"Lactobacillus plantarum KFY02 enhances the relieving effect of gardenoside on montmorillonite induced constipation in mice","volume":"10","author":"Mu","year":"2020","journal-title":"RSC Adv."},{"key":"B45","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1007\/s10620-012-2509-5","article-title":"Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota","volume":"58","author":"Musch","year":"2013","journal-title":"Dig. Dis. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1080\/15548627.2017.1285473","article-title":"Autophagy up and down by outsmarting the incredible ULK","volume":"13","author":"Nazio","year":"2017","journal-title":"Autophagy"},{"key":"B47","doi-asserted-by":"publisher","first-page":"337","DOI":"10.3390\/molecules21030337","article-title":"Role of intestinal microbiota in baicalin-induced drug interaction and its pharmacokinetics","volume":"21","author":"Noh","year":"2016","journal-title":"Molecules"},{"key":"B48","first-page":"865","article-title":"Analysis on follow-up efficacy and safety of slow transit constipation treated with individualized deep puncture at Tianshu (ST 25): a multi-central randomized controlled trial","volume":"33","author":"Peng","year":"2012","journal-title":"Zhongguo Zhen Jiu"},{"key":"B49","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s00384-022-04093-y","article-title":"Cecorectal (CRA) versus ileorectal (IRA) anastomosis after colectomy for slow transit constipation (STC): a meta-analysis","volume":"37","author":"Perivoliotis","year":"2022","journal-title":"Int. J. Colorectal. Dis."},{"key":"B50","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1136\/archdischild-2016-310694","article-title":"Psychological maladjustment and quality of life in adolescents with constipation","volume":"102","author":"Ranasinghe","year":"2017","journal-title":"Arch. Dis. Child."},{"key":"B51","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.etp.2009.03.010","article-title":"Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin","volume":"62","author":"Renugadevi","year":"2010","journal-title":"Exp. Toxicol. Pathol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s00104-021-01399-5","article-title":"Chronische obstipation [slow transit constipation]","volume":"93","author":"Sailer","year":"2022","journal-title":"Chirurg"},{"key":"B53","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3390\/ph12010011","article-title":"The therapeutic potential of naringenin: a review of clinical trials","volume":"12","author":"Salehi","year":"2019","journal-title":"Pharm. (Basel)"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1113\/JP284745","article-title":"Interstitial cells of Cajal - pacemakers of the gastrointestinal tract","author":"Sanders","year":"2023","journal-title":"J. Physiol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.tcb.2007.07.009","article-title":"ROS, mitochondria and the regulation of autophagy","volume":"17","author":"Scherz-Shouval","year":"2007","journal-title":"Cell Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1186\/1471-2458-14-374","article-title":"Cost savings of reduced constipation rates attributed to increased dietary fiber intakes: a decision-analytic model","volume":"14","author":"Schmier","year":"2014","journal-title":"BMC Public Health"},{"key":"B57","doi-asserted-by":"publisher","first-page":"102410","DOI":"10.1016\/j.clinre.2024.102410","article-title":"Modified Zhizhu Pill improves the loperamide-induced slow transit constipation via gut microbiota and neurotransmitters in microbiota-gut-brain axis","volume":"48","author":"Shen","year":"2024","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41392-022-01300-8","article-title":"Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets","volume":"8","author":"Shu","year":"2023","journal-title":"Signal. Transduct. Target. Ther."},{"key":"B59","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1111\/j.1365-2559.2006.02493.x","article-title":"Interstitial cells of Cajal in health and disease. Part I: normal ICC structure and function with associated motility disorders","volume":"50","author":"Streutker","year":"2007","journal-title":"Histopathology"},{"key":"B60","doi-asserted-by":"publisher","first-page":"3026","DOI":"10.1007\/s10620-020-06500-2","article-title":"Analysis of gut microbiome and metabolite characteristics in patients with slow transit constipation","volume":"66","author":"Tian","year":"2021","journal-title":"Dig. Dis. Sci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/s00384-004-0679-0","article-title":"Expression of c-kit messenger ribonucleic acid and c-kit protein in sigmoid colon of patients with slow transit constipation","volume":"20","author":"Tong","year":"2005","journal-title":"Int. J. Colorectal. Dis."},{"key":"B62","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1111\/boc.202000008","article-title":"AMP-activated protein kinase (AMPK) regulates autophagy, inflammation and immunity and contributes to osteoclast differentiation and functionabs","volume":"112","author":"Tong","year":"2020","journal-title":"Biol. Cell"},{"key":"B63","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.molcel.2019.01.035","article-title":"FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates","volume":"74","author":"Turco","year":"2019","journal-title":"Mol. Cell"},{"key":"B64","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.molcel.2019.02.010","article-title":"Spatiotemporal control of ULK1 activation by NDP52 and TBK1 during selective autophagy","volume":"74","author":"Vargas","year":"2019","journal-title":"Mol. Cell."},{"key":"B65","doi-asserted-by":"publisher","first-page":"919","DOI":"10.2147\/CIA.S54304","article-title":"Epidemiology and management of chronic constipation in elderly patients","volume":"10","author":"Vazquez Roque","year":"2015","journal-title":"Clin. Interv. Aging."},{"key":"B66","doi-asserted-by":"publisher","first-page":"989","DOI":"10.4103\/1673-5374.233441","article-title":"Puerarin protects rat brain against ischemia\/reperfusion injury by suppressing autophagy via the AMPK-mTOR-ULK1 signaling pathway","volume":"13","author":"Wang","year":"2018","journal-title":"Neural. Regen. Res."},{"key":"B67","doi-asserted-by":"publisher","first-page":"6385","DOI":"10.12998\/wjcc.v10.i19.6385","article-title":"Intestinal mucosal barrier in functional constipation: dose it change?","volume":"10","author":"Wang","year":"","journal-title":"World J. Clin. Cases"},{"key":"B68","doi-asserted-by":"publisher","first-page":"115075","DOI":"10.1016\/j.jep.2022.115075","article-title":"Research progress in the treatment of slow transit constipation by traditional Chinese medicine","volume":"290","author":"Wang","year":"","journal-title":"J. Ethnopharmacol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"152764","DOI":"10.1016\/j.phymed.2018.11.024","article-title":"Chikusetsu saponin IVa attenuates isoprenaline-induced myocardial fibrosis in mice through activation autophagy mediated by AMPK\/mTOR\/ULK1 signaling","volume":"58","author":"Wang","year":"2019","journal-title":"Phytomedicine"},{"key":"B70","doi-asserted-by":"publisher","first-page":"114473","DOI":"10.1016\/j.biopha.2023.114473","article-title":"Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK\/mTOR\/ULK1 pathway","volume":"161","author":"Wang","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B71","doi-asserted-by":"publisher","first-page":"115942","DOI":"10.1016\/j.jep.2022.115942","article-title":"Shenqi granule upregulates CD2AP and \u03b1-actinin4 and activates autophagy through regulation of mTOR\/ULK1 pathway in MPC5 cells","volume":"303","author":"Wei","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s11655-022-3539-2","article-title":"Zhizhu decoction alleviates intestinal barrier damage via regulating SIRT1\/FoxO1 signaling pathway in slow transit constipation model mice","volume":"29","author":"Wen","year":"2023","journal-title":"Chin. J. Integr. Med."},{"key":"B73","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1111\/j.1445-2197.2007.04051.x","article-title":"Slow-transit constipation: evaluation and treatment","volume":"77","author":"Wong","year":"2007","journal-title":"ANZ J. Surg."},{"key":"B74","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1159\/000501959","article-title":"Hesperidin improves colonic motility in loeramide-induced constipation rat model via 5-hydroxytryptamine 4R\/cAMP signaling pathway","volume":"101","author":"Wu","year":"2020","journal-title":"Digestion"},{"key":"B75","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1021\/mp900013d","article-title":"Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides","volume":"6","author":"Xu","year":"2009","journal-title":"Mol. Pharm."},{"key":"B76","doi-asserted-by":"publisher","first-page":"687095","DOI":"10.3389\/fphar.2021.687095","article-title":"Naringenin attenuates non-alcoholic fatty liver disease by enhancing energy expenditure and regulating autophagy via AMPK","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"e3348","DOI":"10.1371\/journal.pone.0003348","article-title":"Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model","volume":"3","author":"Yang","year":"2008","journal-title":"PLoS One"},{"key":"B78","doi-asserted-by":"publisher","first-page":"649","DOI":"10.3892\/ijmm.2017.3301","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":"B79","doi-asserted-by":"publisher","first-page":"4230","DOI":"10.3390\/nu15194230","article-title":"The different ways multi-strain probiotics with different ratios of bifidobacterium and lactobacillus relieve constipation induced by loperamide in mice","volume":"15","author":"Zhang","year":"2023","journal-title":"Nutrients"},{"key":"B80","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/bab.1635","article-title":"Investigation of autophagy and differentiation of myenteric interstitial cells of Cajal in the pathogenesis of gastric motility disorders in rats with functional dyspepsia","volume":"65","author":"Zhang","year":"2018","journal-title":"Biotechnol. Appl. Biochem."},{"key":"B81","doi-asserted-by":"publisher","first-page":"5392","DOI":"10.3748\/wjg.v27.i32.5392","article-title":"Therapeutic effect of Cistanche deserticola on defecation in senile constipation rat model through stem cell factor\/C-kit signaling pathway","volume":"27","author":"Zhang","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"6181","DOI":"10.3390\/ijms22126181","article-title":"EVA1A plays an important role by regulating autophagy in physiological and pathological processes","volume":"22","author":"Zhao","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B83","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1007\/s12664-020-01143-7","article-title":"miR-222 regulates cell growth, apoptosis, and autophagy of interstitial cells of Cajal isolated from slow transit constipation rats by targeting c-kit","volume":"40","author":"Zheng","year":"2021","journal-title":"Indian J. Gastroenterol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1007\/s00210-023-02786-x","article-title":"Effects of natural products on functional constipation: analysis of active ingredient and mechanism","volume":"397","author":"Zhou","year":"2024","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"e0160398","DOI":"10.1371\/journal.pone.0160398","article-title":"Total glucosides of paeony promote intestinal motility in slow transit constipation rats through amelioration of interstitial cells of cajal","volume":"11","author":"Zhu","year":"2016","journal-title":"PLoS One"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1550458\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T09:33:02Z","timestamp":1750152782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1550458\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":85,"alternative-id":["10.3389\/fphar.2025.1550458"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1550458","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,17]]},"article-number":"1550458"}}