{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:54:22Z","timestamp":1784768062619,"version":"3.55.0"},"reference-count":70,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073922"],"award-info":[{"award-number":["82073922"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81872930"],"award-info":[{"award-number":["81872930"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173884"],"award-info":[{"award-number":["82173884"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood\u2013retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1\/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (Papp, A-to-B) across the ARPE-19 monolayer were greater than Papp, B-to-A. MK571 or bilirubin significantly decreased Papp, A-to-B of fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels.<\/jats:p>","DOI":"10.3390\/ijms23147666","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T21:57:53Z","timestamp":1657576673000},"page":"7666","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood\u2013Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6111-3234","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"first","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9902-793X","authenticated-orcid":false,"given":"Yiting","family":"Yang","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijin","family":"Lin","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijin","family":"Hong","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8217-188X","authenticated-orcid":false,"given":"Han","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yang","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1354-4798","authenticated-orcid":false,"given":"Xiaodong","family":"Liu","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"H201","DOI":"10.1152\/ajpheart.00201.2016","article-title":"Retinal microvascular network alterations: Potential biomarkers of cerebrovascular and neural diseases","volume":"312","author":"Somfai","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4646","DOI":"10.1007\/s00415-020-10304-9","article-title":"Central retina changes in Parkinson\u2019s disease: A systematic review and meta-analysis","volume":"268","author":"Huang","year":"2021","journal-title":"J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/BF00296511","article-title":"Hepatic retinopathy: Morphological features of retinal glial (M\u00fcller) cells accompanying hepatic failure","volume":"90","author":"Reichenbach","year":"1995","journal-title":"Acta Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.3233\/JAD-179932","article-title":"Revolution of Alzheimer precision neurology. Passageway of systems biology and neurophysiology","volume":"64","author":"Hampel","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1016\/S0042-6989(96)00318-5","article-title":"Hepatic retinopathia. Changes in retinal function","volume":"37","author":"Eckstein","year":"1997","journal-title":"Vision Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s00417-003-0639-3","article-title":"Recovery from hepatic retinopathy after liver transplantation","volume":"241","author":"Uhlmann","year":"2003","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1007\/s00535-014-1024-1","article-title":"The association between retinal microvascular changes, metabolic risk factors, and liver histology in pediatric patients with non-alcoholic fatty liver disease (NAFLD)","volume":"50","author":"Liccardo","year":"2015","journal-title":"J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jung, E., and Kim, J. (2018). Aloin inhibits M\u00fcller cells swelling in a rat model of thioacetamide-induced hepatic retinopathy. Molecules, 23.","DOI":"10.3390\/molecules23112806"},{"key":"ref_9","first-page":"681","article-title":"Cirrhosis-induced morphological changes in the retina: Possible role of endogenous opioid","volume":"8","author":"Algazo","year":"2015","journal-title":"Int. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s004010050860","article-title":"Retinal gliopathy accompanying thioacetamide-induced liver insufficiency: Light and electron microscopic observations","volume":"96","author":"Albrecht","year":"1998","journal-title":"Acta Neuropathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1124\/dmd.113.052704","article-title":"Expression of efflux transporters in human ocular tissues","volume":"41","author":"Chen","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1007\/s11095-010-0272-x","article-title":"Lipophilicity and transporter influence on blood-retinal barrier permeability: A comparison with blood-brain barrier permeability","volume":"27","author":"Hosoya","year":"2010","journal-title":"Pharm. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1021\/acs.molpharmaceut.6b00782","article-title":"LC-MS\/MS based quantitation of ABC and SLC transporter proteins in plasma membranes of cultured primary human retinal pigment epithelium cells and immortalized ARPE19 cell line","volume":"14","author":"Pelkonen","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/978-981-13-7647-4_10","article-title":"Roles of drug transporters in blood-retinal barrier","volume":"1141","author":"Liu","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1248\/bpb.28.1","article-title":"Advances in the cell biology of transport via the inner blood-retinal barrier: Establishment of cell lines and transport functions","volume":"28","author":"Hosoya","year":"2005","journal-title":"Biol. Pharm. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1007\/s11095-009-9890-6","article-title":"Efflux protein expression in human retinal pigment epithelium cell lines","volume":"26","author":"Mannermaa","year":"2009","journal-title":"Pharm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1023\/A:1011060705599","article-title":"Expression of multidrug resistance-associated protein (MRP) in human retinal pigment epithelial cells and its interaction with BAPSG, a novel aldose reductase inhibitor","volume":"18","author":"Aukunuru","year":"2001","journal-title":"Pharm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1038\/aps.2016.25","article-title":"Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats","volume":"37","author":"Xu","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41401-019-0242-8","article-title":"Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain","volume":"41","author":"Qin","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1038\/s41401-020-00602-3","article-title":"Bile duct ligation causes opposite impacts on the expression and function of BCRP and P-gp in rat brain partly via affecting membrane expression of ezrin\/radixin\/moesin proteins","volume":"42","author":"Wu","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/j.1478-3231.2012.02862.x","article-title":"P-glycoprotein and multidrug resistance-associated protein 2 are oppositely altered in brain of rats with thioacetamide-induced acute liver failure","volume":"33","author":"Jin","year":"2013","journal-title":"Liver Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/jnc.13666","article-title":"Acute liver failure impairs function and expression of breast cancer-resistant protein (BCRP) at rat blood-brain barrier partly via ammonia-ROS-ERK1\/2 activation","volume":"138","author":"Li","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1167\/iovs.13-13819","article-title":"Impact of P-glycoprotein on blood-retinal barrier permeability: Comparison of blood-aqueous humor and blood-brain barrier using mdr1a knockout rats","volume":"55","author":"Fujii","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/bph.13376","article-title":"Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier","volume":"173","author":"Chapy","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1124\/dmd.108.021121","article-title":"Drug transporter and cytochrome P450 mRNA expression in human ocular barriers: Implications for ocular drug disposition","volume":"36","author":"Zhang","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sreekumar, P.G., Spee, C., Ryan, S.J., Cole, S.P., Kannan, R., and Hinton, D.R. (2012). Mechanism of RPE cell death in alpha-crystallin deficient mice: A novel and critical role for MRP1-mediated GSH efflux. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033420"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S0306-4522(98)00699-X","article-title":"Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina","volume":"92","author":"Gerhart","year":"1999","journal-title":"Neuroscience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.ejphar.2019.01.005","article-title":"Increase in P-glycoprotein levels in the blood-brain barrier of partial portal vein ligation \/chronic hyperammonemia rats is medicated by ammonia\/reactive oxygen species\/ERK1\/2 activation: In vitro and in vivo studies","volume":"846","author":"Zhou","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/s41401-020-0402-x","article-title":"Short-chain fatty acids exert opposite effects on the expression and function of p-glycoprotein and breast cancer resistance protein in rat intestine","volume":"42","author":"Xie","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.3892\/ijo.2016.3423","article-title":"Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562\/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K\/Akt signaling pathway","volume":"48","author":"Chen","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"635636","DOI":"10.3389\/fcell.2021.635636","article-title":"The p38(MAPK)-MK2 signaling axis as a critical link between inflammation and synaptic transmission","volume":"9","author":"Beamer","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1128\/IAI.01330-07","article-title":"Bacillus cereus induces permeability of an in vitro blood-retina barrier","volume":"76","author":"Moyer","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1006\/bbrc.1999.1454","article-title":"Pyridinylimidazole compound SB 203580 inhibits the activity but not the activation of p38 mitogen-activated protein kinase","volume":"263","author":"Kumar","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1038\/sj.onc.1209337","article-title":"MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer","volume":"25","author":"Xu","year":"2006","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/S0022-5347(01)64316-7","article-title":"Excretion of fluorescein in the urine of women with interstitial cystitis","volume":"158","author":"Buffington","year":"1997","journal-title":"J. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hong, S., Li, S., Meng, X., Li, P., Wang, X., Su, M., Liu, X., and Liu, L. (2022). Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin. Acta Pharm. Sin. B, in press.","DOI":"10.1016\/j.apsb.2022.06.010"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF02576788","article-title":"Glutathione in plasma, liver, and kidney in the development of CCl4-induced cirrhosis of the rat","volume":"195","author":"Purucker","year":"1995","journal-title":"Res. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1111\/j.1530-0277.2006.00147.x","article-title":"Abnormal transsulfuration and glutathione metabolism in the micropig model of alcoholic liver disease","volume":"30","author":"Villanueva","year":"2006","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1159\/000197206","article-title":"Gamma-glutamyl transpeptidase: A clinical and experimental study","volume":"5","author":"Ideo","year":"1972","journal-title":"Digestion"},{"key":"ref_40","first-page":"347","article-title":"Gadolinium chloride suppresses hepatic oval cell proliferation in rats with biliary obstruction","volume":"152","author":"Olynyk","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1124\/dmd.106.009415","article-title":"Hepatic and extrahepatic synthesis and disposition of dinitrophenyl-S-glutathione in bile duct-ligated rats","volume":"34","author":"Villanueva","year":"2006","journal-title":"Drug Metab. Dispos."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1111\/j.1365-2362.1987.tb01135.x","article-title":"Decreased production of glutathione in patients with cirrhosis","volume":"17","author":"Burgunder","year":"1987","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Gazzin, S., Berengeno, A.L., Strazielle, N., Fazzari, F., Raseni, A., Ostrow, J.D., Wennberg, R., Ghersi-Egea, J.F., and Tiribelli, C. (2011). Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016165"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.bbrc.2003.10.081","article-title":"Upregulation in the expression of multidrug resistance protein Mrp1 mRNA and protein by increased bilirubin production in rat","volume":"311","author":"Cekic","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1073\/pnas.0308452100","article-title":"Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)","volume":"101","author":"Gennuso","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.neuroscience.2006.10.026","article-title":"Role of multidrug resistance-associated protein 1 expression in the in vitro susceptibility of rat nerve cell to unconjugated bilirubin","volume":"144","author":"Falcao","year":"2007","journal-title":"Neuroscience"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1124\/mol.104.002832","article-title":"Bilirubin: An endogenous product of heme degradation with both cytotoxic and cytoprotective properties","volume":"66","author":"Kapitulnik","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fphar.2012.00131","article-title":"Endothelial cells derived from the blood-brain barrier and islets of langerhans differ in their response to the effects of bilirubin on oxidative stress under hyperglycemic conditions","volume":"3","author":"Kapitulnik","year":"2012","journal-title":"Front. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2174\/156720211795495358","article-title":"Elevated levels of bilirubin and long-term exposure impair human brain microvascular endothelial cell integrity","volume":"8","author":"Palmela","year":"2011","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/15376516.2017.1357775","article-title":"Tet1-mediated DNA demethylation involves in neuron damage induced by bilirubin in vitro","volume":"28","author":"Gou","year":"2018","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Bianco, A., Dvorak, A., Capkova, N., Gironde, C., Tiribelli, C., Furger, C., Vitek, L., and Bellarosa, C. (2020). The extent of intracellular accumulation of bilirubin determines its anti- or pro-oxidant effect. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218101"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.redox.2015.06.008","article-title":"Bilirubin inhibits the up-regulation of inducible nitric oxide synthase by scavenging reactive oxygen species generated by the toll-like receptor 4-dependent activation of NADPH oxidase","volume":"5","author":"Idelman","year":"2015","journal-title":"Redox Biol."},{"key":"ref_53","first-page":"537","article-title":"Association of serum total bilirubin level with diabetic retinopathy in type 2 diabetes mellitus","volume":"28","author":"Ghaffar","year":"2016","journal-title":"J. Ayub Med. Coll. Abbottabad"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"41681","DOI":"10.1038\/srep41681","article-title":"Effect of bilirubin concentration on the risk of diabetic complications: A meta-analysis of epidemiologic studies","volume":"7","author":"Zhu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4603087","DOI":"10.1155\/2018\/4603087","article-title":"The U-shaped association between bilirubin and diabetic retinopathy risk: A five-year cohort based on 5323 male diabetic patients","volume":"2018","author":"Liu","year":"2018","journal-title":"J. Diabetes Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1042\/BJ20040599","article-title":"The human multidrug-resistance-associated protein MRP1 mediates ATP-dependent transport of unconjugated bilirubin","volume":"383","author":"Rigato","year":"2004","journal-title":"Biochem. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1042\/BJ20080918","article-title":"The cytotoxic effect of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells is modulated by the expression level of MRP1 but not MDR1","volume":"417","author":"Corich","year":"2009","journal-title":"Biochem. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mcn.2019.03.003","article-title":"Modulation of Cav2.3 channels by unconjugated bilirubin (UCB)\u2014Candidate mechanism for UCB-induced neuromodulation and neurotoxicity","volume":"96","author":"Albanna","year":"2019","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1021\/mp900019z","article-title":"Formation and efflux of ATP-binding cassette transporter substrate 2,4-dinitrophenyl-S-glutathione from cultured human term placental villous tissue fragments","volume":"6","author":"Vaidya","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1007\/s11095-007-9267-7","article-title":"Multidrug resistance protein 1 (MRP1) in rabbit conjunctival epithelial cells: Its effect on drug efflux and its regulation by adenoviral infection","volume":"24","author":"Yang","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"33356","DOI":"10.1038\/srep33356","article-title":"Persistent inflammatory state after photoreceptor loss in an animal model of retinal degeneration","volume":"6","author":"Noailles","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1167\/iovs.04-1102","article-title":"Thrombin inhibitor reduces leukocyte-endothelial cell interactions and vascular leakage after scatter laser photocoagulation","volume":"46","author":"Musashi","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_63","first-page":"6148515","article-title":"Comparison of three sample preparation procedures for the quantification of L-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma using HPLC-FLD","volume":"2018","author":"Lykkesfeldt","year":"2018","journal-title":"J. Anal. Methods Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jchromb.2008.03.005","article-title":"Highly sensitive method for quantitative determination of bilirubin in biological fluids and tissues","volume":"867","author":"Zelenka","year":"2008","journal-title":"J. Chromatogr. B Analyt. Technol. Biomed. Life Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"15433","DOI":"10.1038\/s41598-018-33032-7","article-title":"Gal epitope expression and immunological properties in iGb3S deficient mice","volume":"8","author":"Shao","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1002\/jat.3645","article-title":"Species differences in bile acids II. Bile acid metabolism","volume":"38","author":"Thakare","year":"2018","journal-title":"J. Appl. Toxicol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1084\/jem.20161387","article-title":"p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation","volume":"214","author":"Chen","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.tiv.2014.05.016","article-title":"Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes","volume":"28","author":"Szabo","year":"2014","journal-title":"Toxicol. In Vitro"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5580","DOI":"10.1038\/s41467-019-13336-6","article-title":"Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut","volume":"10","author":"Praveschotinunt","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/jps.2600790604","article-title":"Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells","volume":"79","author":"Artursson","year":"1990","journal-title":"J. Pharm. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7666\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:48:21Z","timestamp":1760140101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7666"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,11]]},"references-count":70,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147666"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147666","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,11]]}}}