{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:52:58Z","timestamp":1791928378594,"version":"4.3.4"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T00:00:00Z","timestamp":1715990400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T00:00:00Z","timestamp":1715990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012533","name":"Minia University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012533","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Naunyn-Schmiedeberg's Arch Pharmacol"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The defect in the hepatobiliary transport system results in an impairment of bile flow, leading to accumulation of toxic compounds with subsequent liver disorders. Vincamine, a plant indole alkaloid that is utilized as a dietary supplement, has been known for its promising pharmacological activities. For the first time, the present study was planned to estimate, at the molecular level, the potentiality of vincamine against alfa-naphthyl isothiocyanate (ANIT)-induced hepatic cholestasis. Liver function tests were analyzed. Hepatic activity of SOD and levels of GSH and MDA were assessed. Hepatic contents of bax, bcl2, NF-kB, PPAR\u03b3, catalase, heme-oxygenase-1, NTCP, and BSEP were evaluated using ELISA. mRNA levels of <jats:italic>NF-kB, IL-1\u03b2, IL-6, TNF\u03b1, PDGF, klf6, PPAR\u03b3<\/jats:italic>, and <jats:italic>P53<\/jats:italic> were examined using qRT-PCR. PI3K, Akt and cleaved caspase-3 proteins were assessed using western blotting. Histopathological analyses were performed using hematoxylin &amp; eosin staining. ANIT-induced hepatic cholestasis elevated liver function tests, including AST, ALT, GGT, ALP, and total bilirubin. ANIT reduced the protein expression of NTCP and BSEP hepatic transporters. It induced the expression of the inflammatory genes, <jats:italic>TNF\u03b1, IL-6, IL-1\u03b2<\/jats:italic>, and <jats:italic>PDGF<\/jats:italic>, and the expression of NF-kB at the genetic and protein level and suppressed the anti-inflammatory genes, klf6 and <jats:italic>PPAR\u03b3<\/jats:italic>. Also, antioxidant markers were reduced during ANIT induction such as GSH, SOD, catalase, heme-oxygenase-1 and PI3K\/Akt pathway, while MDA levels were elevated. Furthermore, the expression of <jats:italic>P53<\/jats:italic> gene, bax and cleaved caspase 3 proteins were activated, while bcl2 was inhibited. Also, the histopathological analysis showed degeneration of hepatocytes and inflammatory cellular infiltrates. However, vincamine treatment modulated all these markers. It improved liver function tests. It inhibited the expression of <jats:italic>NF-kB, TNF\u03b1, IL-6, IL-1\u03b2<\/jats:italic> and <jats:italic>PDGF<\/jats:italic> and activated the expression of <jats:italic>klf6<\/jats:italic> and <jats:italic>PPAR\u03b3<\/jats:italic>. Furthermore, vincamine reduced MDA levels and induced GSH, SOD, catalase, heme-oxygenase-1 and PI3K\/Akt pathway. Additionally, it inhibited expression of <jats:italic>P53<\/jats:italic> gene, bax and cleaved caspase 3 proteins. More interestingly, vincamine showed better outcomes on the hepatic histopathological analysis and improved the alterations induced by ANIT. Vincamine alleviated hepatic dysfunction during ANIT-induced intrahepatic cholestasis through its anti-inflammatory and antioxidant efficacies by the modulation of NF-kB\/PDGF\/klf6\/PPAR\u03b3 and PI3K\/Akt pathways.<\/jats:p>","DOI":"10.1007\/s00210-024-03119-2","type":"journal-article","created":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T10:01:52Z","timestamp":1716026512000},"page":"7981-7994","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Vincamine alleviates intrahepatic cholestasis in rats through modulation of NF-kB\/PDGF\/klf6\/PPAR\u03b3 and PI3K\/Akt pathways"],"prefix":"10.1007","volume":"397","author":[{"given":"Rania","family":"Alaaeldin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusra A.","family":"Eisa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud A.","family":"El-Rehany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0734-5007","authenticated-orcid":false,"given":"Moustafa","family":"Fathy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,18]]},"reference":[{"key":"3119_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.121562","volume":"320","author":"M Abdelnaser","year":"2023","unstructured":"Abdelnaser M, Alaaeldin R, Attya ME, Fathy M (2023) Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB\/MAPK signaling pathways. Life Sci 320:121562","journal-title":"Life Sci"},{"key":"3119_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2020.105458","volume":"207","author":"M Akhtar","year":"2020","unstructured":"Akhtar M, Guo S, Guo Y-f, Zahoor A, Shaukat A, Chen Y, Umar T, Deng PG, Guo M (2020) Upregulated-gene expression of pro-inflammatory cytokines (TNF-\u03b1, IL-1\u03b2 and IL-6) via TLRs following NF-\u03baB and MAPKs in bovine mastitis. Acta Trop 207:105458","journal-title":"Acta Trop"},{"key":"3119_CR3","doi-asserted-by":"publisher","first-page":"7629","DOI":"10.3390\/molecules26247629","volume":"26","author":"R Alaaeldin","year":"2021","unstructured":"Alaaeldin R, Abdel-Rahman IA, Hassan HA, Youssef N, Allam AE, Abdelwahab SF, Zhao Q-L, Fathy M (2021a) Carpachromene ameliorates insulin resistance in HepG2 cells via modulating IR\/IRS1\/PI3k\/Akt\/GSK3\/FoxO1 pathway. Molecules 26:7629","journal-title":"Molecules"},{"key":"3119_CR4","doi-asserted-by":"publisher","first-page":"2383","DOI":"10.21873\/anticanres.15013","volume":"41","author":"R Alaaeldin","year":"2021","unstructured":"Alaaeldin R, Abuo-Rahma GE-DA, Zhao Q-L, Fathy M (2021b) Modulation of apoptosis and epithelial-Mesenchymal transition E-cadherin\/TGF-\u03b2\/Snail\/TWIST pathways by a new ciprofloxacin chalcone in breast cancer cells. Anticancer Res 41:2383\u20132395","journal-title":"Anticancer Res"},{"key":"3119_CR5","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1111\/fcp.12708","volume":"36","author":"R Alaaeldin","year":"2022","unstructured":"Alaaeldin R, Mustafa M, Abuo-Rahma GEDA, Fathy M (2022) In vitro inhibition and molecular docking of a new ciprofloxacin-chalcone against SARS-CoV-2 main protease. Fundam Clin Pharmacol 36:160\u2013170","journal-title":"Fundam Clin Pharmacol"},{"key":"3119_CR6","doi-asserted-by":"publisher","first-page":"4665","DOI":"10.3390\/molecules28124665","volume":"28","author":"R Alaaeldin","year":"2023","unstructured":"Alaaeldin R, Mohyeldin RH, Bekhit AA, Gomaa W, Zhao Q-L, Fathy M (2023) Vincamine Ameliorates Epithelial-Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis in Rats; Targeting TGF-\u03b2\/MAPK\/Snai1 Pathway. Molecules 28:4665","journal-title":"Molecules"},{"key":"3119_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.104626","volume":"107","author":"S Al-Rashed","year":"2021","unstructured":"Al-Rashed S, Baker A, Ahmad SS, Syed A, Bahkali AH, Elgorban AM, Khan MS (2021) Vincamine, a safe natural alkaloid, represents a novel anticancer agent. Bioorg Chem 107:104626","journal-title":"Bioorg Chem"},{"key":"3119_CR8","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1093\/hmg\/ddh261","volume":"13","author":"L Alvarez","year":"2004","unstructured":"Alvarez L, Jara P, S\u00e1nchez-Sabat\u00e9 E, Hierro L, Larrauri J, D\u00edaz MC, Camarena C, De la Vega A, Frauca E, L\u00f3pez-Collazo E, Lapunzina P (2004) Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum Mol Genet 13:2451\u20132460","journal-title":"Hum Mol Genet"},{"key":"3119_CR9","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1080\/01926230600918892","volume":"34","author":"K Amin","year":"2006","unstructured":"Amin K, Ip C, Sato B, Le T, Green CE, Tyson CA, Behrsing HP (2006) Characterization of ANIT-induced toxicity using precision-cut rat and dog liver slices cultured in a dynamic organ roller system. Toxicol Pathol 34:776\u2013784","journal-title":"Toxicol Pathol"},{"key":"3119_CR10","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1152\/physiolgenomics.00025.2005","volume":"21","author":"RD Barber","year":"2005","unstructured":"Barber RD, Harmer DW, Coleman RA, Clark BJ (2005) GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues. Physiol Genomics 21:389\u2013395","journal-title":"Physiol Genomics"},{"key":"3119_CR11","doi-asserted-by":"publisher","first-page":"6767735","DOI":"10.1155\/2023\/6767735","volume":"2023","author":"AA Bekhit","year":"2023","unstructured":"Bekhit AA, Beshay ON, Fawzy MA, Abdel-Hafez SMN, Batiha GE-S, Ataya FS, Fathy M (2023) Curative Effect of AD-MSCs against Cisplatin-Induced Hepatotoxicity in Rats is Potentiated by Azilsartan: Targeting Oxidative Stress, MAPK, and Apoptosis Signaling Pathways. Stem Cells Int 2023:6767735","journal-title":"Stem Cells Int"},{"key":"3119_CR12","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.jhep.2006.12.001","volume":"46","author":"JL Boyer","year":"2007","unstructured":"Boyer JL (2007) New perspectives for the treatment of cholestasis: lessons from basic science applied clinically. J Hepatol 46:365\u2013371","journal-title":"J Hepatol"},{"key":"3119_CR13","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.jhep.2021.02.011","volume":"75","author":"JL Boyer","year":"2021","unstructured":"Boyer JL, Soroka CJ (2021) Bile formation and secretion: An update. J Hepatol 75:190\u2013201","journal-title":"J Hepatol"},{"key":"3119_CR14","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248\u2013254","journal-title":"Anal Biochem"},{"key":"3119_CR15","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.jep.2015.12.033","volume":"179","author":"H Chen","year":"2016","unstructured":"Chen H, Huang X, Min J, Li W, Zhang R, Zhao W, Liu C, Yi L, Mi S, Wang N, Wang Q, Zhu C (2016) Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis, due to Fxr-mediated regulation of Bsep and Mrp2. J Ethnopharmacol 179:197\u2013207","journal-title":"J Ethnopharmacol"},{"key":"3119_CR16","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1055\/s-0030-1253228","volume":"30","author":"BL Copple","year":"2010","unstructured":"Copple BL, Jaeschke H, Klaassen CD (2010) Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis 30:195\u2013204","journal-title":"Semin Liver Dis"},{"key":"3119_CR17","doi-asserted-by":"publisher","first-page":"18","DOI":"10.2741\/3981","volume":"17","author":"FA Crocenzi","year":"2012","unstructured":"Crocenzi FA, Zucchetti AE, Boaglio AC, Barosso IR, Sanchez Pozzi EJ, Mottino AD, Roma MG (2012) Localization status of hepatocellular transporters in cholestasis. Front Biosci 17:18","journal-title":"Front Biosci"},{"key":"3119_CR18","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1093\/toxsci\/kfp094","volume":"110","author":"YJ Cui","year":"2009","unstructured":"Cui YJ, Aleksunes LM, Tanaka Y, Goedken MJ, Klaassen CD (2009) Compensatory induction of liver efflux transporters in response to ANIT-induced liver injury is impaired in FXR-null mice. Toxicol Sci 110:47\u201360","journal-title":"Toxicol Sci"},{"key":"3119_CR19","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.ejphar.2008.06.044","volume":"590","author":"Y Ding","year":"2008","unstructured":"Ding Y, Zhao L, Mei H, Zhang S-L, Huang Z-H, Duan Y-Y, Ye P (2008) Exploration of Emodin to treat alpha-naphthylisothiocyanate-induced cholestatic hepatitis via anti-inflammatory pathway. Eur J Pharmacol 590:377\u2013386","journal-title":"Eur J Pharmacol"},{"key":"3119_CR20","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.119224","volume":"272","author":"RM El-Sayed","year":"2021","unstructured":"El-Sayed RM, Abo El Gheit RE, Badawi GA (2021) Vincamine protects against cisplatin induced nephrotoxicity via activation of Nrf2\/HO-1 and hindering TLR4\/ IFN-\u03b3\/CD44 cells inflammatory cascade. Life Sci 272:119224","journal-title":"Life Sci"},{"key":"3119_CR21","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s12199-013-0336-8","volume":"18","author":"M Fathy","year":"2013","unstructured":"Fathy M, Nikaido T (2013) In vivo modulation of iNOS pathway in hepatocellular carcinoma by Nigella sativa. Environ Health Prev Med 18:377\u2013385","journal-title":"Environ Health Prev Med"},{"key":"3119_CR22","doi-asserted-by":"publisher","first-page":"10669","DOI":"10.3390\/ijms221910669","volume":"22","author":"MA Fawzy","year":"2021","unstructured":"Fawzy MA, Maher SA, Bakkar SM, El-Rehany MA, Fathy M (2021) Pantoprazole Attenuates MAPK (ERK1\/2, JNK, p38)-NF-kappaB and Apoptosis Signaling Pathways after Renal Ischemia\/Reperfusion Injury in Rats. Int J Mol Sci 22:10669","journal-title":"Int J Mol Sci"},{"key":"3119_CR23","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.3390\/molecules27041383","volume":"27","author":"MA Fawzy","year":"2022","unstructured":"Fawzy MA, Maher SA, El-Rehany MA, Welson NN, Albezrah NKA, Batiha GE-S, Fathy M (2022) Vincamine Modulates the Effect of Pantoprazole in Renal Ischemia\/Reperfusion Injury by Attenuating MAPK and Apoptosis Signaling Pathways. Molecules 27:1383","journal-title":"Molecules"},{"key":"3119_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.121343","volume":"314","author":"MA Fawzy","year":"2023","unstructured":"Fawzy MA, Nasr G, Ali FE, Fathy M (2023) Quercetin potentiates the hepatoprotective effect of sildenafil and\/or pentoxifylline against intrahepatic cholestasis: Role of Nrf2\/ARE, TLR4\/NF-\u03baB, and NLRP3\/IL-1\u03b2 signaling pathways. Life Sci 314:121343","journal-title":"Life Sci"},{"key":"3119_CR25","doi-asserted-by":"crossref","unstructured":"Geier A, Wagner M, Dietrich CG, Trauner M (2007) Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration.\u00a0Biochim Biophys Acta\u00a01773:283\u2013308","DOI":"10.1016\/j.bbamcr.2006.04.014"},{"key":"3119_CR26","doi-asserted-by":"publisher","first-page":"2793","DOI":"10.1210\/me.2002-0020","volume":"16","author":"GD Girnun","year":"2002","unstructured":"Girnun GD, Domann FE, Moore SA, Robbins ME (2002) Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter. Mol Endocrinol 16:2793\u20132801","journal-title":"Mol Endocrinol"},{"key":"3119_CR27","volume-title":"Antibodies: a laboratory manual","author":"EA Greenfield","year":"2013","unstructured":"Greenfield EA (2013) Antibodies: a laboratory manual. Cold Spring Harbor Laboratory Press"},{"key":"3119_CR28","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1111\/j.1440-1746.2010.06592.x","volume":"26","author":"H Jaeschke","year":"2011","unstructured":"Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 26:173\u2013179","journal-title":"J Gastroenterol Hepatol"},{"key":"3119_CR29","doi-asserted-by":"publisher","first-page":"10902","DOI":"10.1096\/fj.201900867RR","volume":"33","author":"G-D Kim","year":"2019","unstructured":"Kim G-D, Ng HP, Patel N, Mahabeleshwar GH (2019) Kruppel-like factor 6 and miR-223 signaling axis regulates macrophage-mediated inflammation. FASEB J 33:10902","journal-title":"FASEB J"},{"issue":"2","key":"3119_CR30","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1055\/s-0030-1253227","volume":"30","author":"A Kosters","year":"2010","unstructured":"Kosters A, Karpen SJ (2010) The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis 30(2):186\u2013194","journal-title":"Semin Liver Dis"},{"issue":"2","key":"3119_CR31","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1055\/s-0030-1253222","volume":"30","author":"P Lam","year":"2010","unstructured":"Lam P, Soroka CJ, Boyer JL (2010) The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease. Semin Liver Dis 30(2):125\u2013133","journal-title":"Semin Liver Dis"},{"key":"3119_CR32","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1111\/j.1742-4658.2010.07581.x","volume":"277","author":"M Li","year":"2010","unstructured":"Li M, Li Z, Sun X, Yang L, Fang P, Liu Y, Li W, Xu J, Lu J, Xie M (2010) Heme oxygenase-1\/p21WAF1 mediates peroxisome proliferator-activated receptor-\u03b3 signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J 277:1543\u20131550","journal-title":"FEBS J"},{"key":"3119_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.toxlet.2016.09.002","volume":"261","author":"X Li","year":"2016","unstructured":"Li X, Jin Q, Yao Q, Xu B, Li Z, Tu C (2016) Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2\/4-NF-kappaB signaling pathways. Toxicol Lett 261:1\u201312","journal-title":"Toxicol Lett"},{"key":"3119_CR34","doi-asserted-by":"crossref","unstructured":"Liao Z, Zhang J, Liu B, Yan T, Xu F, Xiao F, Wu B, Bi K, Jia Y (2019) Polysaccharide from okra (Abelmoschus esculentus (L.) Moench) improves antioxidant capacity via PI3K\/AKT pathways and Nrf2 translocation in a type 2 diabetes model. Molecules 24(10):1906","DOI":"10.3390\/molecules24101906"},{"key":"3119_CR35","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1016\/j.neuint.2013.06.004","volume":"63","author":"Y Luo","year":"2013","unstructured":"Luo Y, Yang X, Zhao S, Wei C, Yin Y, Liu T, Jiang S, Xie J, Wan X, Mao M (2013) Hydrogen sulfide prevents OGD\/R-induced apoptosis via improving mitochondrial dysfunction and suppressing an ROS-mediated caspase-3 pathway in cortical neurons. Neurochem Int 63:826\u2013831","journal-title":"Neurochem Int"},{"key":"3119_CR36","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1096\/fasebj.8.15.8001741","volume":"8","author":"H Mehendale","year":"1994","unstructured":"Mehendale H, Roth R, Gandolfi AJ, Klaunig J, Lemasters JJ, Curtis L (1994) Novel mechanisms in chemically induced hepatotoxicity 1. FASEB J 8:1285\u20131295","journal-title":"FASEB J"},{"key":"3119_CR37","first-page":"A14426","volume":"126","author":"K Nakamura","year":"2012","unstructured":"Nakamura K, Akagi S, Matsubara H, Ogawa A, Miura A, Miura D, Miyoshi T, Nagase S, Morita H, Kohno K (2012) PDGF-BB activates inflammatory signaling in pulmonary arterial smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Am Heart Assoc 126:A14426","journal-title":"Am Heart Assoc"},{"key":"3119_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.108773","volume":"108","author":"A Patangrao Renushe","year":"2022","unstructured":"Patangrao Renushe A, Kumar Banothu A, Kumar Bharani K, Mekala L, Mahesh Kumar J, Neeradi D, Durga Veera Hanuman D, Gadige A, Khurana A (2022) Vincamine, an active constituent of Vinca rosea ameliorates experimentally induced acute lung injury in Swiss albino mice through modulation of Nrf-2\/NF-\u03baB signaling cascade. Int Immunopharmacol 108:108773","journal-title":"Int Immunopharmacol"},{"key":"3119_CR39","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.108773","volume":"108","author":"AP Renushe","year":"2022","unstructured":"Renushe AP, Banothu AK, Bharani KK, Mekala L, Kumar JM, Neeradi D, Hanuman DDV, Gadige A, Khurana A (2022) Vincamine, an active constituent of Vinca rosea ameliorates experimentally induced acute lung injury in Swiss albino mice through modulation of Nrf-2\/NF-\u03baB signaling cascade. Int Immunopharmacol 108:108773","journal-title":"Int Immunopharmacol"},{"key":"3119_CR40","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/S1665-2681(19)32126-X","volume":"2","author":"EA Rodr\u00edguez-Garay","year":"2003","unstructured":"Rodr\u00edguez-Garay EA (2003) Cholestasis: human disease and experimental animal models. Ann Hepatol 2:150\u2013158","journal-title":"Ann Hepatol"},{"key":"3119_CR41","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3109\/03602539709037578","volume":"29","author":"RA Roth","year":"1997","unstructured":"Roth RA, Dahm LJ (1997) Neutrophil-and glutathione-mediated hepatotoxicity of \u03b1-naphthylisothiocyanate. Drug Metab Rev 29:153\u2013165","journal-title":"Drug Metab Rev"},{"key":"3119_CR42","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1248\/bpb.b22-00508","volume":"45","author":"RT Sabra","year":"2022","unstructured":"Sabra RT, Abdellatef AA, Abdel-Sattar E, Fathy M, Meselhy MR, Hayakawa Y (2022) Russelioside A, a Pregnane Glycoside from Caralluma tuberculate, Inhibits Cell-Intrinsic NF-\u03baB Activity and Metastatic Ability of Breast Cancer Cells. Biol Pharm Bull 45:1564\u20131571","journal-title":"Biol Pharm Bull"},{"key":"3119_CR43","doi-asserted-by":"crossref","unstructured":"Shytaj IL, Fares M, Gallucci L, Lucic B, Tolba MM, Zimmermann L, Adler JM, Xing N, Bushe J, Gruber AD, Ambiel I, Taha Ayoub A, Cortese M, Neufeldt CJ, Stolp B, Sobhy MH, Fathy M, Zhao M, Laketa V, Diaz RS, Sutton RE, Chlanda P, Boulant S, Bartenschlager R, Stanifer ML, Fackler OT, Trimpert J, Savarino A, Lusic M (2022) The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters. mBio 13:e0370521","DOI":"10.1128\/mbio.03705-21"},{"key":"3119_CR44","first-page":"7","volume":"43","author":"Z Singh","year":"2014","unstructured":"Singh Z, Karthigesu IP, Singh P, Rupinder K (2014) Use of malondialdehyde as a biomarker for assessing oxidative stress in different disease pathologies: a review. Iran J Public Health 43:7\u201316","journal-title":"Iran J Public Health"},{"key":"3119_CR45","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1167\/iovs.07-1099","volume":"49","author":"L Wang","year":"2008","unstructured":"Wang L, Chen Y, Sternberg P, Cai J (2008) Essential roles of the PI3 kinase\/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Invest Ophthalmol vis Sci 49:1671\u20131678","journal-title":"Invest Ophthalmol vis Sci"},{"key":"3119_CR46","first-page":"1751","volume":"9","author":"P Wang","year":"1850","unstructured":"Wang P, Peng X, Wei Z-F, Wei F-Y, Wang W, Ma W-D, Yao L-P, Fu Y-J (1850) Zu Y-G (2015) Geraniin exerts cytoprotective effect against cellular oxidative stress by upregulation of Nrf2-mediated antioxidant enzyme expression via PI3K\/AKT and ERK1\/2 pathway. Biochim Biophys Acta 9:1751\u20131761","journal-title":"Biochim Biophys Acta"},{"key":"3119_CR47","first-page":"2195","volume":"10","author":"L Wu","year":"2018","unstructured":"Wu L, Ye M, Zhang J (2018) Vincamine prevents lipopolysaccharide induced inflammation and oxidative stress via thioredoxin reductase activation in human corneal epithelial cells. Am J Trans Res 10:2195","journal-title":"Am J Trans Res"},{"key":"3119_CR48","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/aps.2014.128","volume":"36","author":"J Xu","year":"2015","unstructured":"Xu J, Zhu Y-t, Wang G-z, Han D, Wu Y-y, Zhang D-x, Liu Y, Zhang Y-h, Xie X-m, Li S-j (2015) The PPAR\u03b3 agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma. Acta Pharmacol Sin 36:171\u2013178","journal-title":"Acta Pharmacol Sin"},{"key":"3119_CR49","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.3390\/cancers14051255","volume":"14","author":"MYW Zaki","year":"2022","unstructured":"Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S (2022) Innate and Adaptive Immunopathogeneses in Viral Hepatitis Crucial Determinants of Hepatocellular Carcinoma. Cancers 14:1255","journal-title":"Cancers"},{"key":"3119_CR50","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ejphar.2011.09.177","volume":"672","author":"K-W Zeng","year":"2011","unstructured":"Zeng K-W, Wang X-M, Ko H, Kwon HC, Cha JW, Yang HO (2011) Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid \u03b2-protein via the PI3K\/Akt\/Bad\/BclXL-regulated mitochondrial apoptotic pathway. Eur J Pharmacol 672:45\u201355","journal-title":"Eur J Pharmacol"},{"key":"3119_CR51","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/sj.jcbfm.9600233","volume":"26","author":"X Zhao","year":"2006","unstructured":"Zhao X, Zhang Y, Strong R, Grotta JC, Aronowski J (2006) 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-\u03b3, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 26:811\u2013820","journal-title":"J Cereb Blood Flow Metab"},{"key":"3119_CR52","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1080\/08820130802111589","volume":"37","author":"L Zhao","year":"2008","unstructured":"Zhao L, Zhang S-L, Tao J-Y, Jin F, Pang R, Guo Y-J, Ye P, Dong J-H, Zheng G-H (2008) Anti-inflammatory mechanism of a folk herbal medicine, Duchesnea indica (Andr) Focke at RAW264. 7 cell line. Immunol Invest 37:339\u2013357","journal-title":"Immunol Invest"},{"key":"3119_CR53","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.phymed.2018.09.184","volume":"50","author":"S Zhao","year":"2018","unstructured":"Zhao S, Liu Z, Wang M, He D, Liu L, Shu Y, Song Z, Li H, Liu Y, Lu A (2018) Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies. Phytomedicine 50:61\u201372","journal-title":"Phytomedicine"}],"container-title":["Naunyn-Schmiedeberg's Archives of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-024-03119-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00210-024-03119-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-024-03119-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T13:07:09Z","timestamp":1727960829000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00210-024-03119-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,18]]},"references-count":53,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["3119"],"URL":"https:\/\/doi.org\/10.1007\/s00210-024-03119-2","relation":{},"ISSN":["0028-1298","1432-1912"],"issn-type":[{"value":"0028-1298","type":"print"},{"value":"1432-1912","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,18]]},"assertion":[{"value":"19 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Animal care and study protocols were followed according to the guidelines approved by The Research Ethics Committee and Experimental Animal Center, Minia University, Minia, Egypt (Approval No: ES09\/2021).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}