Vincamine alleviates intrahepatic cholestasis in rats through modulation of NF-kB/PDGF/klf6/PPARγ and PI3K/Akt pathways.
Apoptosis
Intrahepatic cholestasis
NF-kB
Oxidative stress
PI3K/Akt
PPARγ
Vincamine
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
18 May 2024
18 May 2024
Historique:
received:
19
01
2024
accepted:
24
04
2024
medline:
18
5
2024
pubmed:
18
5
2024
entrez:
18
5
2024
Statut:
aheadofprint
Résumé
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, PPARγ, catalase, heme-oxygenase-1, NTCP, and BSEP were evaluated using ELISA. mRNA levels of NF-kB, IL-1β, IL-6, TNFα, PDGF, klf6, PPARγ, and P53 were examined using qRT-PCR. PI3K, Akt and cleaved caspase-3 proteins were assessed using western blotting. Histopathological analyses were performed using hematoxylin & 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, TNFα, IL-6, IL-1β, and PDGF, and the expression of NF-kB at the genetic and protein level and suppressed the anti-inflammatory genes, klf6 and PPARγ. 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 P53 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 NF-kB, TNFα, IL-6, IL-1β and PDGF and activated the expression of klf6 and PPARγ. Furthermore, vincamine reduced MDA levels and induced GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway. Additionally, it inhibited expression of P53 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/PPARγ and PI3K/Akt pathways.
Identifiants
pubmed: 38761209
doi: 10.1007/s00210-024-03119-2
pii: 10.1007/s00210-024-03119-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
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
pubmed: 36907325
doi: 10.1016/j.lfs.2023.121562
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-α, IL-1β and IL-6) via TLRs following NF-κB and MAPKs in bovine mastitis. Acta Trop 207:105458
pubmed: 32243879
doi: 10.1016/j.actatropica.2020.105458
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
pubmed: 34946711
pmcid: 8708443
doi: 10.3390/molecules26247629
Alaaeldin R, Abuo-Rahma GE-DA, Zhao Q-L, Fathy M (2021b) Modulation of apoptosis and epithelial-Mesenchymal transition E-cadherin/TGF-β/Snail/TWIST pathways by a new ciprofloxacin chalcone in breast cancer cells. Anticancer Res 41:2383–2395
pubmed: 33952463
doi: 10.21873/anticanres.15013
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 36:160–170
pubmed: 34268806
doi: 10.1111/fcp.12708
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-β/MAPK/Snai1 Pathway. Molecules 28:4665
pubmed: 37375218
pmcid: 10303541
doi: 10.3390/molecules28124665
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
pubmed: 33450545
doi: 10.1016/j.bioorg.2021.104626
Alvarez L, Jara P, Sánchez-Sabaté E, Hierro L, Larrauri J, Díaz MC, Camarena C, De la Vega A, Frauca E, López-Collazo E, Lapunzina P (2004) Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum Mol Genet 13:2451–2460
pubmed: 15317749
doi: 10.1093/hmg/ddh261
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 34:776–784
pubmed: 17162535
doi: 10.1080/01926230600918892
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 21:389–395
pubmed: 15769908
doi: 10.1152/physiolgenomics.00025.2005
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
pubmed: 37908315
pmcid: 10615573
doi: 10.1155/2023/6767735
Boyer JL (2007) New perspectives for the treatment of cholestasis: lessons from basic science applied clinically. J Hepatol 46:365–371
pubmed: 17223219
doi: 10.1016/j.jhep.2006.12.001
Boyer JL, Soroka CJ (2021) Bile formation and secretion: An update. J Hepatol 75:190–201
pubmed: 33617926
doi: 10.1016/j.jhep.2021.02.011
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 72:248–254
pubmed: 942051
doi: 10.1016/0003-2697(76)90527-3
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 179:197–207
pubmed: 26723467
doi: 10.1016/j.jep.2015.12.033
Copple BL, Jaeschke H, Klaassen CD (2010) Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis 30:195–204
pubmed: 20422501
doi: 10.1055/s-0030-1253228
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
doi: 10.2741/3981
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 110:47–60
pubmed: 19407337
pmcid: 2696329
doi: 10.1093/toxsci/kfp094
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 590:377–386
pubmed: 18590720
doi: 10.1016/j.ejphar.2008.06.044
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-γ/CD44 cells inflammatory cascade. Life Sci 272:119224
pubmed: 33610575
doi: 10.1016/j.lfs.2021.119224
Fathy M, Nikaido T (2013) In vivo modulation of iNOS pathway in hepatocellular carcinoma by Nigella sativa. Environ Health Prev Med 18:377–385
pubmed: 23609474
pmcid: 3773091
doi: 10.1007/s12199-013-0336-8
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
pubmed: 34639009
pmcid: 8508698
doi: 10.3390/ijms221910669
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
pubmed: 35209172
pmcid: 8879001
doi: 10.3390/molecules27041383
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-κB, and NLRP3/IL-1β signaling pathways. Life Sci 314:121343
pubmed: 36592787
doi: 10.1016/j.lfs.2022.121343
Geier A, Wagner M, Dietrich CG, Trauner M (2007) Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta 1773:283–308
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 16:2793–2801
pubmed: 12456800
doi: 10.1210/me.2002-0020
Greenfield EA (2013) Antibodies: a laboratory manual. Cold Spring Harbor Laboratory Press
Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 26:173–179
pubmed: 21199529
doi: 10.1111/j.1440-1746.2010.06592.x
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
pubmed: 31262200
pmcid: 6766645
doi: 10.1096/fj.201900867RR
Kosters A, Karpen SJ (2010) The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis 30(2):186–194
pubmed: 20422500
pmcid: 3746018
doi: 10.1055/s-0030-1253227
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):125–133
pubmed: 20422495
pmcid: 3008346
doi: 10.1055/s-0030-1253222
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-γ signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J 277:1543–1550
pubmed: 20163460
doi: 10.1111/j.1742-4658.2010.07581.x
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 261:1–12
pubmed: 27601294
doi: 10.1016/j.toxlet.2016.09.002
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
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 63:826–831
pubmed: 23770272
doi: 10.1016/j.neuint.2013.06.004
Mehendale H, Roth R, Gandolfi AJ, Klaunig J, Lemasters JJ, Curtis L (1994) Novel mechanisms in chemically induced hepatotoxicity 1. FASEB J 8:1285–1295
pubmed: 8001741
doi: 10.1096/fasebj.8.15.8001741
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
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-κB signaling cascade. Int Immunopharmacol 108:108773
pubmed: 35453074
doi: 10.1016/j.intimp.2022.108773
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-κB signaling cascade. Int Immunopharmacol 108:108773
doi: 10.1016/j.intimp.2022.108773
Rodríguez-Garay EA (2003) Cholestasis: human disease and experimental animal models. Ann Hepatol 2:150–158
pubmed: 15115953
doi: 10.1016/S1665-2681(19)32126-X
Roth RA, Dahm LJ (1997) Neutrophil-and glutathione-mediated hepatotoxicity of α-naphthylisothiocyanate. Drug Metab Rev 29:153–165
pubmed: 9187516
doi: 10.3109/03602539709037578
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-κB Activity and Metastatic Ability of Breast Cancer Cells. Biol Pharm Bull 45:1564–1571
pubmed: 36184517
doi: 10.1248/bpb.b22-00508
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
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 43:7–16
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 49:1671–1678
pubmed: 18385090
doi: 10.1167/iovs.07-1099
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 9:1751–1761
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
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 PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma. Acta Pharmacol Sin 36:171–178
pubmed: 25619395
pmcid: 4326789
doi: 10.1038/aps.2014.128
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
pubmed: 35267563
pmcid: 8909759
doi: 10.3390/cancers14051255
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 β-protein via the PI3K/Akt/Bad/BclXL-regulated mitochondrial apoptotic pathway. Eur J Pharmacol 672:45–55
pubmed: 21978835
doi: 10.1016/j.ejphar.2011.09.177
Zhao X, Zhang Y, Strong R, Grotta JC, Aronowski J (2006) 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-γ, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 26:811–820
pubmed: 16208315
doi: 10.1038/sj.jcbfm.9600233
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 37:339–357
pubmed: 18569074
doi: 10.1080/08820130802111589
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 50:61–72
pubmed: 30466993
doi: 10.1016/j.phymed.2018.09.184