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Several significant ultrastructural changes were caused by 100 μmol\u002FL Cr+Ni – deposition of electron dense material in cell walls; larger vacuolar precipitates surrounded by membranes inside vacuoles; increment of disintegrated organelles and high vacuolization in cytoplasm. The localization of the precipitates in which the metal ions were detected by electron energy loss spectroscopy (EELS) and electron spectroscopic imaging (ESI) was investigated. Chromium and nickel were localized in the electron dense precipitates of the root cells exposed to only 100 μmol\u002FL Cr+Ni. None were found in the root cells exposed to 10 μmol\u002FL Cr+Ni. Higher amounts of Cr+Ni were mainly accumulated in the cell walls and vacuoles of the fourth or fifth cortical layer.",{"EN":212,"VI":213},"Subcellular localization of chromium and nickel in root cells of Allium cepa by EELS and ESI","Định xứ dưới tế bào của crom và niken trong các tế bào rễ của Allium cepa bằng EELS và ESI",{"VOID":215},"Aoyama M, Tsuda M, Seki K, Doi S. Kurimoto Y, Tamura Y. Adsorption of Cr(VI) from dichromate solutions onto black locust leaves. Holzforschung. 2000;54:340–2.\nBarceló J, Poschenrieder C. Chromium in plants. In: Canali, S, Tittarelli, F, Sequi, P. (eds), Chromium environmental issues. Franco Angeli Publ: Milano; 1997:101–29.\nBourque G, Vittorio P, Weinberg P. Uptake of 51Cr as an indicator of metabolic change in wheat root tips. Can J Physiol Pharmacol. 1967;45:235–9.\nBücking H, Beckmann S, Heyser W, Kottke I. Elemental contents in vacuolar granules of ectomycorrhizal fungi measured by EELS and EDXS. A comparison of different methods and preparation techniques. Micron. 1998;29:53–61.\nCaridad-Cancela R, Abreu CA, Paz-González A. Total trace element contents in natural soil by two methods. Symposium no. 8, paper No. 1031, 17th World Congress of Soil Science, 14–21 August 2002, Thailand.\nCobbett CS. Phytochelatins and their roles in heavy metal detoxification. Plant Physiol. 2000;123:825–32.\nDixon NE, Gazzola C, Blakeley RL, Zerner B. Jack bean urease (E.C.3.5.1.5.) a metalloenzyme. A simple biological role for nickel? J Am Chem Soc. 1975;97:4131–3.\nGuo YL, Schulz R, Marschner H. Uptake, distribution and binding of cadmium and nickel in different plant species. J Plant Nutr. 1995;18:2691–706.\nHelmke PA. Soil chemistry: the chemical composition of soils. In: ME Sumner (ed), Handbook of soil science. CRC Press: Boca Raton, FL; 2000:B16–17.\nHuffman EWD, Allaway WH. Growth of plants in solution culture containing low levels of chromium. Plant Physiol. 1973;52:72–5.\nIrmer U, Wachholz I, Schäfer H, Lorch DW. Influence of lead on Chlamydomonas reinhardtii Danegard (Volvocales, Chlorophyta): accumulation, toxicity and ultrastructural changes. Environ Exp Bot. 1986;26:97–105.\nKabata-Pendias A, Pendias H. Trace elements in soils and plants. CRC Press: Boca Raton, FL; 2001:413.\nKrämer U, Pickering IJ, Prince RC, Raskin I, Salt DE. Subcelluar localization and speciation of nickel in hyper-accumulator and non-accumulator Thlaspi species. Plant Physiol. 2000;122:1343–53.\nKukkola E, Rautio P, Huttunen S. Stress indications in copper-and nickel-exposed Scots pine seedlings. Environ Exp Bot. 2000;43:197–210.\nLevan A. Cytological reactions induced by inorganic salt solutions. Nature. 1945;156:751.\nLiu DH, Jiang WS, Li MS. Effects of trivalent and hexavalent chromium on root growth and cell division of Allium cepa. Hereditas. 1992;117:23–9.\nLiu DH, Jiang WS, Guo L, Hao YQ, Lu C, Zhao FM. Effects of nickel sulfate on root growth and nucleoli in root tip cells of Allium cepa. Isr J Plant Sci. 1994;42:143–8.\nMertz W. Biological role of chromium. Fed Proc. 1967;26:186–93.\nMyttenaere C, Mousny JM. The distribution of chromium-51 in lowland rice in relation to the chemical form and the amount of stable chromium in the nutrient solution. Plant Soil. 1974;41:65–72.\nNassiri Y, Mansot JL, Wéry J, Ginsburger-Vogel T, Amiard JC. Ultrastructural and electron energy loss spectroscopy studies of sequestration mechanisms of Cd and Cu in the marine diatom Skeletonema costatum. Arch Environ Toxicol. 1997;33:147–55.\nRauser WE, Ackerley CA. Localization of cadmium in granules within differentiating and mature root cells. Can J Bot. 1986;65:643–6.\nRauser WE. Phytochelatins and related peptides. Structure, biosynthesis, and function. Plant Physiol. 1995;109:1141–9.\nRyan CA, Walker-Simmons M. Plant vacuoles. Meth Enzymol. 1983;96:580–9.\nSanità di Toppi L, Gabbrielli R. Response to cadmium in higher plants. Environ Expt Bot. 1999;41:105–30.\nSchlösser L. Einsatz von Aldehydkarbonsäure in der Chromgerbung. In: Cot J (ed), Compendium of advanced topics on leather technology, vol 2. Associación Quimica Española de la Industria del Cuero, Barcelona, 991:1017–26.\nSresty TVS, Madhava Rao KV. Ultrastructural alterations in response to zinc and nickel stress in the root cells of pigeonpea. Environ Expt Bot. 1999;41:3–13.\nSrivastava S, Prakash S, Srivastava MM. Studies on mobilization of chromium with reference to its plant availability -- role of organic acids. BioMetals. 1999;12:201–7.\nSpurr AR. A low-viscosity epoxy resin embedding medium for electron microscopy. J Ultrastruct Res. 1969;26:31-43.\nStephan UW, Prochazka Z, Physiological disorders of the nicotianamine-auxotroph tomato mutant chloronerva at different levels of iron nutrition. I. Growth characteristics and physiological abnormalities as related to iron and nicotianamine supply. Acta Bot Neerl. 1989;38:147–53.\nVázquez MD, Poschenrieder Ch, Barceló J. Chromium VI induced structural and ultrastructural changes in bush bean plants (Phaseolus vulgaris L.). Ann Bot. 1987;59:427–38.\nWoolhouse HW. Toxicity and tolerance in the responses of plants to metals. In: Lange OL, Nobel PS, Osmond CB, Ziegler H (eds), Physiological plant ecology. III. Responses to the chemical biological environment, Springer-Verlag: Berlin; 1983:246–300.\nYang X, Baligar VC, Martens DC, Clark RB. Plant tolerance to nickel toxicity I. Influx, transport, and accumulation of nickel in four species. J Plant Nutr. 1996;19:73–85.\nYang XE, Baligar VC, Foster JC, Martens DC. Accumulation and transport of nickel in relation to organic acid in ryegrass and maize growth with different nickel levels. Plant Soil. 1997;196:271–276.\nZheng ZQ, Feng WH, Bian SP, Zheng JM, Zhang LZ, Xing SL. Study on fate of pollutant chromium in the agro-ecosystem. J Environ Sci. 1987;8:14–19.",{"VOID":217},"10.1023\u002FB:CBTO.0000004984.87619.15","PUBLICATION","VERIFIED","2025-01-26T21:46:03.881+00:00","Auto Verify",[223],"VI","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1023\u002FB:CBTO.0000004984.87619.15",[226,251],{"id":227,"sortIndex":21,"researcher":20,"roles":228,"affiliations":230,"properties":248,"displayName":250,"givenName":20,"familyName":20},"a9be9e81-ebe0-464e-9828-5f1a94a8e8da",[229],"AUTHOR",[231,239],{"id":232,"sortIndex":21,"affiliation":233,"properties":20},"c1a1d3e8-7ce6-43b6-84e7-dca1cd5347d9",{"id":232,"createTime":20,"updateTime":20,"relativeEntities":234,"slug":20,"properties":235,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":238,"statistic":20},[],{"title":236},{"VI":237},"Department of Biology, College of Chemistry and Life Sciences, Tianjin Normal University, Tianjin, P.R. China",[],{"id":240,"sortIndex":138,"affiliation":241,"properties":247},"b3fca74c-7a0b-4b83-9bb2-31d337a5bca7",{"id":240,"createTime":20,"updateTime":20,"relativeEntities":242,"slug":20,"properties":243,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":246,"statistic":20},[],{"title":244},{"VI":245},"Botanisches Institut, Spezielle Botanik, Eberhard-Karls Universitaet Tübingen, Mykologie, Germany",[],{},{"title":249},{"VI":250},"D. 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First, we observed that PRE induces potent cytotoxic effects in MCF-7 cells. The cell death had features of cytoplasmic vacuolation, plasma membrane permeabilization, chromatin condensation, phosphatidylserine externalization, absence of executioner caspase activation, insensitivity to z-VAD-fmk (caspase inhibitor), increased accumulation of autophagic markers, and lysosomal membrane permeabilization (LMP). Both the inhibition of early stage autophagy flux and lysosomal cathepsins did not improve cell viability. The antioxidant, n-acetylcysteine, and the iron chelator, deferoxamine, failed to restore the lysosomal integrity indicating that PRE-induced LMP is independent of oxidative stress. This was corroborated with the absence of enhanced ROS production in PRE-treated cells. Chelation of both intracellular calcium and zinc promotes PRE-induced LMP. Geranylgeranylacetone, an inducer of Hsp70 expression, also had no significant protective effect on PRE-induced LMP. Moreover, we found that PRE induces endoplasmic reticulum (ER) stress and mitochondrial membrane depolarization in MCF-7 cells. The ER stress inhibitor, 4-PBA, did not restore the mitochondrial membrane integrity, whereas cathepsin inhibitors demonstrated significant protective effects. Collectively, our results suggest that PRE induces an autophagic block, LMP, ER stress, and mitochondrial dysfunction in MCF-7 cells. However, further studies are clearly warranted to explore the exact mechanism behind the anticancer activity of PRE in MCF-7 human breast cancer cells.",{"EN":335},"Pinus radiata bark extract induces caspase-independent apoptosis-like cell death in MCF-7 human breast cancer cells",{"VOID":337},"[\"835250845626194008\"]",{"VOID":339},"Aits S, Jäättelä M. Lysosomal cell death at a glance. J Cell Sci. 2013;126(Pt 9):1905–12.\nAmelio I, Melino G, et al. Cell death pathology: cross-talk with autophagy and its clinical implications. Biochem Biophys Res Commun. 2011;414(2):277–81.\nApel A, Herr I, et al. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 2008;68(5):1485–94.\nAppelqvist H, Wäster P, et al. The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol. 2013;5(4):214–26.\nBjørkøy G, Lamark T, et al. Monitoring autophagic degradation of p62\u002FSQSTM1. Methods Enzymol. 2009;452:181–97.\nBoya P, Kroemer G. Lysosomal membrane permeabilization in cell death. Oncogene. 2008;27(50):6434–51.\nChen X, Li Y, et al. Tea polyphenols induced apoptosis of breast cancer cells by suppressing the expression of survivin. Sci Rep. 2014;4:4416.\nCovarrubias L, Hernández-García D, et al. Function of reactive oxygen species during animal development: passive or active? Dev Biol. 2008;320(1):1–11.\nFilomeni G, De Zio D, et al. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22(3):377–88.\nHasima N, Ozpolat B. Regulation of autophagy by polyphenolic compounds as a potential therapeutic strategy for cancer. Cell Death Dis. 2014;5:e1509.\nHeymann D. Autophagy: a protective mechanism in response to stress and inflammation. Curr Opin Investig Drugs. 2006;7(5):443–50.\nHowell A. An early peak of relapse after surgery for breast cancer. Breast Cancer Res. 2004;6(6):255–7.\nKlionsky DJ, Elazar Z, et al. Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy. 2008;4(7):849–50.\nKomatsu M, Ichimura Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett. 2010;584(7):1374–8.\nKukic I, Kelleher SL, et al. Zn2+ efflux through lysosomal exocytosis prevents Zn2+-induced toxicity. J Cell Sci. 2014;127(Pt 14):3094–103.\nLee SJ, Koh JY. Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. Mol Brain. 2010;3(1):30.\nLee JW, Kim WH, et al. ER stress is implicated in mitochondrial dysfunction-induced apoptosis of pancreatic beta cells. Mol Cells. 2010;30(6):545–9.\nLeGendre O, Breslin PA, et al. (−)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization. Mol Cell Oncol. 2015;2(4):e1006077.\nLivesey KM, Tang D, et al. Autophagy inhibition in combination cancer treatment. Curr Opin Investig Drugs. 2009;10(12):1269–79.\nMena S, Rodríguez ML, et al. Pterostilbene-induced tumor cytotoxicity: a lysosomal membrane permeabilization-dependent mechanism. PLoS One. 2012;7(9):e44524.\nMoustapha A, Pérétout PA, et al. Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events. Cell Death Dis. 2015, Article number: 15017.\nNylandsted J, Rohde M, et al. Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci U S A. 2000;97(14):7871–6.\nNylandsted J, Gyrd-Hansen M, et al. Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med. 2004;200(4):425–35.\nOberle C, Huai J, et al. Lysosomal membrane permeabilization and cathepsin release is a Bax\u002FBak-dependent, amplifying event of apoptosis in fibroblasts and monocytes. Cell Death Differ. 2010;17(7):1167–78.\nOstenfeld MS, Fehrenbacher N, et al. Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res. 2005;65(19):8975–83.\nPoljsak B, Šuput D, et al. Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants. Oxid Med Cell Longev. 2013;2013:956792.\nRacoma IO, Meisen WH, et al. Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS One. 2013;8(9):e72882.\nRodríguez-Muela N, Hernández-Pinto AM, et al. Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa. Cell Death Differ. 2015;22(3):476–87.\nSamie MA, Xu H. Lysosomal exocytosis and lipid storage disorders. J Lipid Res. 2014;55(6):995–1009.\nSano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013;1833(12):3460–70.\nSong Q, Gou WL, et al. FAM3A attenuates ER stress-induced mitochondrial dysfunction and apoptosis via CHOP-Wnt pathway. Neurochem Int. 2016;94:82–9.\nSuganuma M, Kurusu M, et al. Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene. Int J Cancer. 2006;119(1):33–40.\nTerman A, Kurz T, et al. Lysosomal labilization. IUBMB Life. 2006;58(9):531–9.\nTrondl R, Flocke LS, et al. Triapine and a more potent dimethyl derivative induce endoplasmic reticulum stress in cancer cells. Mol Pharmacol. 2014;85(3):451–9.\nVillalpando Rodriguez GE, Torriglia A. Calpain 1 induce lysosomal permeabilization by cleavage of lysosomal associated membrane protein 2. Biochim Biophys Acta. 2013;1833(10):2244–53.\nWei T, Kang Q, et al. Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats. Exp Ther Med. 2015;9(2):476–82.\nWeng CJ, Yen GC. Chemopreventive effects of dietary phytochemicals against cancer invasion and metastasis: phenolic acids, monophenol, polyphenol, and their derivatives. Cancer Treat Rev. 2012;38(1):76–87.\nWiggins HL, Wymant JM, et al. Disulfiram-induced cytotoxicity and endo-lysosomal sequestration of zinc in breast cancer cells. Biochem Pharmacol. 2015;93(3):332–42.\nWu YT, Tan HL, et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem. 2010;285(14):10850–61.\nYadav RK, Chae SW, et al. Endoplasmic reticulum stress and cancer. J Cancer Prev. 2014;19(2):75–88.\nYu C, Huang X, et al. Lysosome dysfunction enhances oxidative stress-induced apoptosis through ubiquitinated protein accumulation in Hela cells. Anat Rec (Hoboken). 2013;296(1):31–9.\nZuo L, Zhou T, et al. Biological and physiological role of reactive oxygen species—the good, the bad and the ugly. Acta Physiol (Oxf). 2015;214(3):329–48.",{"VOID":341},"10.1007\u002Fs10565-016-9346-9","2024-05-16T21:39:46.341+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10565-016-9346-9",[345,362,375,391],{"id":346,"sortIndex":21,"researcher":20,"roles":347,"affiliations":348,"properties":357,"displayName":359,"givenName":20,"familyName":20},"3f4e3cb2-d618-4a82-b40f-9c0bff1cbd16",[229],[349],{"id":350,"sortIndex":21,"affiliation":351,"properties":20},"68e1e8ab-149b-4a05-a8c4-87bde7851a7c",{"id":350,"createTime":20,"updateTime":20,"relativeEntities":352,"slug":20,"properties":353,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":356,"statistic":20},[],{"title":354},{"EN":355},"Department of Forest Products and Biotechnology, College of Forest Science, Kookmin University, Seoul, South Korea",[],{"title":358,"gsAuthor":360},{"VI":359},"Thamizhiniyan 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examined the maintenance of functional and morphological integrity of precision-cut rat liver slices cultured in various incubation systems and conditions for 72 h. Slices were incubated (37°C) for 6, 24, 48, and 72 h in supplemented Williams E medium in 6-well plastic culture plates on a gyratory shaking platform (WPCS) or in a rotating organ culture system (ROCS) using 5% CO2–95% air (WPCS\u002Fair or ROCS\u002Fair) or 5% CO2–70% O2–25% N2 (WPCS\u002F O2 or ROCS\u002F O2). Biochemical and functional parameters of slices maintained in WPCS\u002Fair or WPCS\u002F O2 were almost totally inhibited after 24 h, in keeping with the extensive and diffuse coalescing coagulative necrosis typical of post-ischemic injury affecting almost all the slice surface after 48 h. As compared to freshly isolated slices, slices maintained in ROCS\u002Fair for 72 h showed stable ATP and GSH content, increased protein synthesis, and a slight steady decrease in GST activity, while ATP and GST activity remained stable and protein synthesis and GSH content increased in slices incubated in ROCS\u002F O2 for 72 h. The extent of coagulative necrosis was markedly lower in longitudinal sections from slices incubated for 72 h in ROCS\u002F O2 than in ROCS\u002Fair. Transversal sections from slices kept in ROCS\u002Fair for 72 h showed a thick central band of necrotic cells edged by two peripheral layers of viable hepatocytes, whereas most of the slice was composed of viable hepatocytes lined by two thin layers of necrotic cells after 72 h in ROCS\u002F O2. ROCS\u002F O2 emerged as the system best preserving the histological and functional integrity of rat liver slices in long-term culture.",{"EN":477},"Morphological and functional integrity of precision-cut rat liver slices in rotating organ culture and multiwell plate culture: Effects of oxygen tension",{"VOID":479},"[\"6485561371599356956\"]",{"VOID":481},"10.1023\u002FA:1007458408863","2024-05-04T09:26:00.549+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1023\u002FA:1007458408863",[485,500,513,526,539,553],{"id":486,"sortIndex":21,"researcher":20,"roles":487,"affiliations":488,"properties":497,"displayName":499,"givenName":20,"familyName":20},"90c719f9-6be8-4db8-835c-896330fd02ea",[229],[489],{"id":490,"sortIndex":21,"affiliation":491,"properties":20},"4eaeff0a-d8e3-47d8-83eb-e575febed3b6",{"id":490,"createTime":20,"updateTime":20,"relativeEntities":492,"slug":20,"properties":493,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":496,"statistic":20},[],{"title":494},{"VI":495},"Départment Sécurité du Médicament, Centre de Recherche de Vitry-Alfortville, Rhône-Poulenc Rorer S.A., Services de Toxicologie, Expérimentale et d'Anatomie Pathologique, Vitry sur Seine, France",[],{"title":498},{"VI":499},"H.J. 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Secondary bioenergetic hypoxia: inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low O2 concentrations. J Biol Chem. 1982;257: 8997–9004.","https:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs10440-022-00541-7",{"doi":637},"10.1007\u002Fs10440-022-00541-7",{"id":633,"text":639,"url":635,"identifiers":640},"Azri-Meehan S, Mata HP, Gandolfi AJ, Brendel K. The hepatotoxicity of chloroform in precision-cut rat liver slices. Toxicology. 1992a;73:239–50.",{"doi":637},{"id":633,"text":642,"url":635,"identifiers":643},"Azri S, Mata R, Reid LL, Gandolfi AJ, Brendel K. Further examination of the selective toxicity of CCl4 in rat liver slices. Toxicol Appl Pharmacol. 1992b;112:81–6.",{"doi":637},{"id":633,"text":645,"url":635,"identifiers":646},"Beamand JA, Price RJ, Cunninghame ME, Lake BG. Culture of precision-cut liver slices: effect of some peroxisome proliferators. Food Chem Toxicol. 1993;31:137–47.",{"doi":637},{"id":648,"text":649,"url":650,"identifiers":651},"6924db08-9f22-41b8-b6fd-03fb7e1257c8","Connors S, Rankin DR, Gandolfi AJ, Krumdieck CL, Koep LJ, Brendel K. Cocaine hepatotoxicity in cultured liver slices: a species comparison. Toxicology. 1990;61:171–83.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0300483X9090018C",{"doi":652},"10.1016\u002F0300-483x(90)90018-c",{"id":633,"text":654,"url":635,"identifiers":655},"Courjault-Gautier F, Hoet D, Leroy D, Toutain HJ. Dissimilar alterations of sodium-coupled uptake by platinum-coordination complexes in renal proximal tubular cells in primary culture. J Pharmacol Exp Ther. 1994;270:1097–104.",{"doi":637},{"id":20,"text":657,"url":20,"identifiers":658},"Dale O, Gandolfi AJ, Brendel K, Schuman S. Rat liver slices and diazepam metabolism: in vitro interactions with volatile anaesthetic drugs and albumin. Br J Anesth. 1988;60:692–6.",{},{"id":633,"text":660,"url":635,"identifiers":661},"Dogterom P. Development of a simple incubation system for metabolic studies with precision-cut liver slices. Drug Metab Dispos. 1993;21:699–704.",{"doi":637},{"id":20,"text":663,"url":20,"identifiers":664},"Dogteron P, Rothuizen J. A species comparison of tolbutamide metabolism in precision-cut liver slices from rats and dogs. Drug Metab Dispos. 1993;21:705–9.",{},{"id":633,"text":666,"url":635,"identifiers":667},"Ekins S. Past, present and future applications of precision-cut liver slices for in vitro xenobiotic metabolism. Drug Metab Rev. 1996;28:591–623.",{"doi":637},{"id":20,"text":669,"url":20,"identifiers":670},"Fisher RL, Smith PF, Sipes IG, Gandolfi AJ, Krumdieck CL, Brendel K. Toxicity of chlorobenzenes in cultured rat liver slices. In Vitro Toxicol. 1990;3:181–93.",{},{"id":633,"text":672,"url":635,"identifiers":673},"Fisher RL, Shaughnessy RP, Jenkins PM et al. Dynamic organ culture is superior to multiwell plate culture for maintaining precision-cut tissue slices: optimization of tissue slice culture, part I. Toxicol Methods. 1995;5:99–113.",{"doi":637},{"id":633,"text":675,"url":635,"identifiers":676},"Gandolfi AJ, Wijeweera J, Brendel K. Use of precision-cut liver slices as an in vitro tool for evaluating liver function. Toxicol Pathol. 1996;24:58–61.",{"doi":637},{"id":633,"text":678,"url":635,"identifiers":679},"Ganthous HN, Fernando J, Gandolfi AJ, Brendel K. Biotransformation of halothane in guinea pig liver slices. Drug Metab Dispos. 1990;18:514–8.",{"doi":637},{"id":633,"text":681,"url":635,"identifiers":682},"Gokhale MS, Bunton TE, Zurlo J, Yager JD. Cytochrome P-450 1A1\u002F1A2 induction, albumin secretion and histological changes in cultured rat liver slices. In Vitro Toxicol. 1995;8: 357–68.",{"doi":637},{"id":684,"text":685,"url":686,"identifiers":687},"c016fc08-56bf-40ba-9bd6-22415ae05bf9","Griffith OW. Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Anal Biochem. 1980;106:207–12.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0003269780901396",{"doi":688},"10.1016\u002F0003-2697(80)90139-6",{"id":633,"text":690,"url":635,"identifiers":691},"Guguen-Guillouzo C, Clement B, Baffet G et al. Maintenance and reversibility of active albumin secretion by adult rat hepatocytes co-cultured with another liver epithelial cell type. Exp Cell Res. 1983;143:47–63.",{"doi":637},{"id":20,"text":693,"url":20,"identifiers":694},"Habig WH, Pabst MJ, Jacoby WB. Glutathione-S-transferases: the first enzymatic step in mercapturic acid formation. J Biol Chem. 1974;249:7130–9.",{},{"id":633,"text":696,"url":635,"identifiers":697},"Harris JW, Rahman A, Bok-Ryang K, Guengerich FP, Collins JM. Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res. 1994;54:4026–35.",{"doi":637},{"id":699,"text":700,"url":701,"identifiers":702},"e3c729e4-db38-4c33-af94-1f7c9231ab2f","Krumdieck CL, dos Santos JE, Ho KJ. A new instrument for the rapid preparation of tissue slices. Anal Biochem. 1980; 104:118–23.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0003269780902845",{"doi":703},"10.1016\u002F0003-2697(80)90284-5",{"id":633,"text":705,"url":635,"identifiers":706},"Lerche C, Le Jossic C, Fautrel A et al. Rat liver epithelial cells express functional cytochrome P450 2E1. Carcinogenesis. 1996;17:1101–6.",{"doi":637},{"id":20,"text":708,"url":20,"identifiers":709},"Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–75.",{},{"id":633,"text":711,"url":635,"identifiers":712},"Matsui Y, Kitade H, Kamiya T. Adenylate energy charge of rat human cultured hepatocytes. In Vitro Cell Dev Biol. 1994; 30:609–14.",{"doi":637},{"id":633,"text":714,"url":635,"identifiers":715},"McGuinness S, Gandolfi AJ, Brendel K. Use of renal slices and renal tubule suspensions for in vitro toxicity studies. In Vitro Toxicol. 1993;6:1–24.",{"doi":637},{"id":633,"text":717,"url":635,"identifiers":718},"Miller MG, Beyer J, Hall GL, Degraffenreid LA, Adams PE. Predictive value of liver slices for metabolism and toxicity in vivo: use of acetominophen as a model hepatotoxicant. Toxicol Appl Pharmacol. 1993;122:108–16.",{"doi":637},{"id":720,"text":721,"url":722,"identifiers":723},"396dbd16-1d8c-4892-9775-86f7507bb03c","Okamoto T, Mitsuhashi M, Fujita I, Sindhu RK, Kikkawa Y. Induction of cytochrome P450 1A1 and 1A2 by hyperoxia. Biochem Biophys Res Commun. 1993;197:878–85.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0006291X83725611",{"doi":724},"10.1006\u002Fbbrc.1993.2561",{"id":633,"text":726,"url":635,"identifiers":727},"Page RA, Stowell KM, Hardman MJ, Kitson KE. The assessment of viability in isolated rat hepatocytes. Anal Biochem. 1992;200:171–5.",{"doi":637},{"id":633,"text":729,"url":635,"identifiers":730},"Parrish AR, Gandolfi AJ, Brendel K. Precision-cut tissue slices: applications in pharmacology and toxicology. Life Sci. 1995;21:1887–901.",{"doi":637},{"id":633,"text":732,"url":635,"identifiers":733},"Potter DW, Tran TB. Apparent rates of glutathione turnover in rat tissues. Toxicol Appl Pharmacol. 1993;120:186–92.",{"doi":637},{"id":735,"text":736,"url":737,"identifiers":738},"be55a516-9581-46a2-8c07-facf216b31e6","Shan X, Aw TY, Smith ER et al. Effect of chronic hypoxia on detoxication enzymes in rat liver. Biochem Pharmacol. 1992;43:2421–6.","https:\u002F\u002Flinkinghub.elsevier.com\u002Fretrieve\u002Fpii\u002F000629529290322A",{"doi":739},"10.1016\u002F0006-2952(92)90322-a",{"id":741,"text":742,"url":743,"identifiers":744},"81e0cb90-3ecb-46ce-b308-e6462bd169d9","Smith PF, Krack G, McKee RL et al. Maintenance of adult rat liver slices in dynamic organ culture. In Vitro Cell Dev Biol. 1986;22:706–12.","http:\u002F\u002Flink.springer.com\u002F10.1007\u002FBF02621087",{"doi":745},"10.1007\u002FBF02621087",{"id":747,"text":748,"url":749,"identifiers":750},"2ff2f989-535c-4663-bb0a-d498822ae5a3","Smith PF, Fisher R, Shubat PJ, Gandolfi AJ, Krumdieck CL, Brendel K. In vitro cytotoxicity of allyl alcohol and bromobenzene in a novel organ culture system. Toxicol Appl Pharmacol. 1987;87:509–22.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0041008X87902572",{"doi":751},"10.1016\u002F0041-008x(87)90257-2",{"id":633,"text":753,"url":635,"identifiers":754},"Toutain HJ, Sarsat JP, Bouant A, Hoet D, Leroy D, Moronvalle-Halley V. Precision-cut dog renal cortical slices in dynamic organ culture for the study of cisplatin nephrotoxicity. Cell Biol Toxicol. 1996;12:289–98.",{"doi":637},{"id":633,"text":756,"url":635,"identifiers":757},"Van Rossum GDV. The relation of sodium and potassium ion transport to the respiration and adenine nucleotide content of liver slices treated with inhibitors of respiration. Biochem J. 1972;129:427–38.",{"doi":637},{"id":633,"text":759,"url":635,"identifiers":760},"Vickers AEM, Fisher V, Connors S et al. Cyclosporin A metabolism in human liver, kidney and intestine slices: comparison to rat and dog slices and human cell lines. Drug Metab Dispos. 1992;20:802–9.",{"doi":637},{"id":762,"text":763,"url":764,"identifiers":765},"54c9f3ec-3ca3-4535-90ee-d652ed8fc878","Weinstein R, Wenc K. Growth factor responses of human arterial endothelial cells in vitro, In Vitro Cell Dev Biol. 1986;22:549–56.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002FBF02621142",{"doi":766},"10.1007\u002FBF02621142",{"id":768,"text":769,"url":770,"identifiers":771},"05e020c3-a942-4ef8-a8b9-30f37991da95","Zurlo J, Arterburn LM. Characterization of a primary hepatocyte culture system for toxicological studies. In Vitro Cell Dev Biol. 1996;32:211–20.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002FBF02722948",{"doi":772},"10.1007\u002FBF02722948",{"id":774,"createTime":775,"updateTime":776,"relativeEntities":777,"slug":778,"properties":779,"entityType":218,"verifyStatus":219,"verifyTime":790,"verifyNote":221,"languages":20,"translateLanguages":20,"viewCount":21,"primaryUrl":791,"fullTextUrl":20,"authors":792,"publicationType":264,"publisherRelationship":849,"citationCount":118,"citationInfo":905,"publishDate":908,"publishYear":906,"citationAnalyzeStatus":19,"lastCitationAnalyze":909,"indexDatabases":910,"openAccess":20,"references":20,"isForceReanalyzing":324},"858478bc-1d9b-4058-810c-f9a2240428ec","2024-02-07T15:06:55.610+00:00","2026-07-28T06:23:52.803+00:00",[],"Liver-cell-hydration",{"abstract":780,"title":782,"gsPaper":784,"references":786,"doi":788},{"EN":781},"Liver cells possess potent mechanisms to maintain their volume, i.e., their hydration state. These volume-regulatory mechanisms, however, are apparently not designed to maintain absolute cell volume constancy; they rather act as dampeners to prevent excessive cell volume deviations, which would otherwise result from cumulative substrate uptake or anisotonic stress. Furthermore, these volume-regulatory mechanisms can even be activated in the resting state by hormones and other stimuli, and by that means cell volume changes are affected secondarily. Thus, liver cell hydration can change within minutes under the influence of aniso-osmolarity, hormones, nutrients, and oxidative stress. Such short-term modulation of cell volume within a narrow range acts as an independent and potent signal which modifies hepatocellular metabolism and gene expression. 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Hepatology. 1991;14:551–66.\nNishida E, Gotoh Y. The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem Sci. 1993;18:128–31.\nNoe B, Schliess F, Wettstein M, Heinrich S, Häussinger D. Regulation of taurocholate excretion by a hypoosmolarity-activated signal transduction pathway in rat liver. Gastroenterology. 1996;110:858–65.\nOffensperger WB, Offensperger S, Stoll B, Gerok W, Häussinger D. Effects of anisoosmotic exposure on duck hepatitis B virus replication. Hepatology. 1994;20:1–7.\nParker JC. In defense of cell volume? Am J Physiol. 1993;265: C1191–200.\nPeak M, Al-Habori M, Agius L. Regulation of glycogen synthesis and glycolysis by insulin, pH and cell volume. Biochem J. 1992;282:797–805.\nSackin H. Stretch-activated ion channels. In: Strange K, ed. Cellular and molecular physiology of cell volume regulation. Boca Raton: CRC Press; 1994.\nSaha N, Stoll B, Lang F, Häussinger D. Effect of anisotonic cell volume modulation on gluathione-S-conjugate release, t-butylhydroperoxide metabolism and the pentose-phosphate shunt in perfused rat liver. Eur J Biochem. 1992;209:437–44.\nSaha N, Schreiber R, vom Dahl S, Lang F, Gerok W, Häus-singer D. Endogenous hyperperoxide formation, cell volume and cellular K+ balance in perfused rat liver. Biochem J. 1993;296:701–7.\nSchliess F, Schreiber R, Häussinger D. Activation of the extracellular signal related kinases Erk-1 and Erk-2 by cell swelling in H4IIE hepatoma cells. Biochem J. 1995;309:13–17.\nSchreiber R, Häussinger D. Characterization of the swelling-induced alkalinization of endocytotic vesicles in fluorescein isothiocyanate-dextran-loaded rat hepatocytes. Biochem J. 1995;309:19–24.\nSchrieber R, Stoll B, Lang F, Häussinger D. Effects of aniso-osmolarity and hydroperoxides on intracellular pH in isolated rat hepatocytes as assessed by (2',7')-bis(carboxy-ethyl)-5(6)-carboxyfluorescein and fluorescein isothiocyanate-dextran fluorescence. Biochem J. 1994;303:113–20.\nSchreiber R, Zhang F, Häussinger D. Regulation of pH in liver macrophages and parenchymal cells by ammonia and anisotonicity as assessed by FITC-dextran fluorescence. Biochem J. 1996;315:385–92.\nStoll B, Gerok W, Lang F, Häussinger D. Liver cell volume and protein synthesis. Biochem J. 1992;287:217–22.\nStrange K (ed.). Cellular and molecular physiology of cell volume regulation. Boca Raton: CRC Press; 1994.\nTakenaka M, Preston AS, Kwon HM, Handler JS. The tonicity-sensitive element that mediates increased transcription of the betaine transporter gene in response to hypertonic stress. J Biol Chem. 1994;269:29379–81.\nVan Dyke R. Acidification of rat liver lysosomes: quantitation and comparison with endosomes. Am J Physiol. 1993;265: C901–17.\nvom Dahl S, Häussinger D. Nutritional state and the swelling-induced inhbition of proteolysis in the perfused rat liver. J Nutr. 1996;126:395–402.\nvom Dahl S, Hallbrucker C, Lang F, Gerok W, Häussinger D. Regulation of liver cell volume and proteolysis by glucagon and insulin. Biochem J. 1991;278:771–7.\nvom Dahl S, Stoll B, Gerok W, Häussinger D. Inhibition of proteolysis by cell swelling in the liver requires intact microtubular structures. Biochem J. 1995;308:529–36.\nWarskulat U, Wettstein M, Häussinger D. Osmoregulated taurine transport in HYIIE hepatoma cells and perfused rat liver. Biochem J. 1997;321:683–90.\nWarskulat U, Zhang F, Häussinger D. Modulation of phagocytosis by anisoosmolarity and betaine in rat liver macro-phages (Kupffer cells) and RAW264.7 mouse macrophages. FEBS Lett. 1996;391:287–92.\nWaskiewicz AJ, Cooper JA. Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. Curr Opin Cell Biol. 1995;7:798–805.\nWondergem R, Davis J. Ethanol increases hepatocyte water volume. Alcoholism Clin Exp Res. 1994;18:1230–6.\nYancey PH, Clark ME, Hand SC, Bowlus RD, Somero GN. Living with water stress: evolution of osmolyte systems. Science. 1982;217:1214–22.\nZhang F, Wettstein M, Warskulat U et al. Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat Kupffer cells. Biochem J. 1995; 312:135–43.\nZhang F, Warskulat U, Wettstein M, Häussinger D. Identification of betaine as an osmolyte in rat liver macrophages. Gastroenterology. 1996a;110:1543–52.\nZhang F, Warskulat U, Häussinger D. Modulation of tumor necrosis factor-a release by anisoosmolarity and betaine in rat liver macrophages. FEBS Lett. 1996b;391:291–5.",{"VOID":789},"10.1023\u002FA:1007483324138","2024-06-24T19:39:10.240+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1023\u002FA:1007483324138",[793,810,823,836],{"id":794,"sortIndex":21,"researcher":20,"roles":795,"affiliations":796,"properties":805,"displayName":807,"givenName":20,"familyName":20},"71845602-0c07-4275-beca-3b101ab0f3f2",[229],[797],{"id":798,"sortIndex":21,"affiliation":799,"properties":20},"e052c2ae-ad4f-4722-ae6a-f437451a6673",{"id":798,"createTime":20,"updateTime":20,"relativeEntities":800,"slug":20,"properties":801,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":804,"statistic":20},[],{"title":802},{"VI":803},"Medizinische Universitätsklinik, Heinrich-Heine-University, Düsseldorf, Germany",[],{"title":806,"gsAuthor":808},{"VI":807},"D. 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improve long-term expression of drug biotransformation activities in hepatocytes, we have examined the suitability of several epithelial-like cell lines (MDCK, MS and L-132) for supporting functional co-cultures with rat hepatocytes. Cells were selected on the basis of their compatibility with hepatocytes, formation of stable monolayers in the absence of serum and lack of drug biotransformation activities. The expression of individual elements of the biotransformation system was evaluated in these co-cultures. Co-cultured hepatocytes remained viable and showed a characteristic polygonal shape for more than a week. Depending on the cell line used, levels of aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase activities of co-cultured hepatocytes oscillated between 24–47% of their initial value after 4 days in culture. The highest levels of monooxygenase activity were found in hepatocytes co-cultured with MS cells (41–47%). In contrast, these activities decreased to 6% when hepatocytes were maintained in pure culture for the same period. The activities of the conjugating enzymes UDP-glucuronyltransferase and glutathione S-transferase were maintained at nearly the initial levels during the complete period of study, both in pure and mixed-cultures, regardless of the cell line used. MS cells adapted themselves much better to serum-free culture conditions, and the co-culture with rat hepatocyte was technically easier. After one week, total cytochrome P450 and reduced glutathione in rat hepatocytes\u002FMS co-cultures were 31% and 127% respectively of the day O values, whereas they were undetectable in pure culture. A clear induction of monooxygenase activities by methylcholanthrene, phenobarbital and ethanol could be observed by the 5th day in MS cells\u002Fhepatocyte co-cultures. The fact that the results of our work show the suitability of MS cells, an epithelial-derived cell line, for improving the expression of biotransformation enzymes of cultured hepatocytes opens new possibilities of simplifying co-cultures for their use in drug-metabolism studies.","Để cải thiện sự biểu hiện lâu dài của các hoạt động chuyển hóa thuốc trong tế bào gan, chúng tôi đã khảo sát sự phù hợp của một số dòng tế bào tương tự biểu mô (MDCK, MS và L-132) để hỗ trợ các nuôi cấy đồng thời chức năng với tế bào gan chuột. Các tế bào được chọn dựa trên khả năng tương thích với tế bào gan, khả năng hình thành lớp tế bào đơn ổn định trong điều kiện không có huyết thanh và thiếu các hoạt động chuyển hóa thuốc. Sự biểu hiện của các yếu tố riêng lẻ trong hệ thống chuyển hóa được đánh giá trong các nuôi cấy đồng thời này. Tế bào gan được nuôi cấy đồng thời vẫn giữ được tính khả thi và có hình dạng đa giác điển hình trong hơn một tuần. Tùy thuộc vào dòng tế bào được sử dụng, mức độ hoạt động của aryl hydrocarbon hydroxylase và 7-ethoxycoumarin O-deethylase ở tế bào gan đồng nuôi biến đổi từ 24% đến 47% giá trị ban đầu sau 4 ngày nuôi cấy. Mức độ hoạt động monooxygenase cao nhất được phát hiện ở tế bào gan đồng nuôi với tế bào MS (41-47%). Ngược lại, các hoạt động này giảm xuống còn 6% khi các tế bào gan được duy trì trong nuôi cấy thuần khiết trong cùng thời gian. Các hoạt động của các enzyme kết hợp UDP-glucuronyltransferase và glutathione S-transferase được duy trì gần như ở mức ban đầu trong suốt thời gian nghiên cứu, cả trong nuôi cấy thuần và hỗn hợp, bất kể dòng tế bào được sử dụng. Tế bào MS thích nghi tốt hơn nhiều với điều kiện nuôi cấy không có huyết thanh, và việc nuôi cấy đồng thời với tế bào gan chuột cũng dễ thực hiện hơn về mặt kỹ thuật. Sau một tuần, tổng lượng cytochrome P450 và glutathione khử trong nuôi cấy đồng thời tế bào gan chuột\u002FMS đạt 31% và 127% tương ứng so với giá trị ngày O, trong khi chúng không thể phát hiện trong nuôi cấy thuần. Một sự kích thích rõ rệt về hoạt động monooxygenase do methylcholanthrene, phenobarbital và ethanol có thể được quan sát từ ngày thứ 5 trong các nuôi cấy đồng thời tế bào MS\u002Ftế bào gan. Thực tế rằng các kết quả của công việc của chúng tôi cho thấy sự phù hợp của tế bào MS, một dòng tế bào có nguồn gốc từ biểu mô, để cải thiện sự biểu hiện của các enzyme chuyển hóa của tế bào gan nuôi cấy mở ra những khả năng mới trong việc đơn giản hóa các nuôi cấy đồng thời để sử dụng trong nghiên cứu chuyển hóa thuốc.",{"EN":922,"VI":923},"Co-cultures of hepatocytes with epithelial-like cell lines: Expression of drug-biotransformation activities by hepatocytes","Nuôi cấy đồng thời tế bào gan với các dòng tế bào tương tự biểu mô: Biểu hiện hoạt động chuyển hóa thuốc của tế bào gan",{"VOID":925},"[\"2235396495522585533\"]",{"VI":927},"",{"VOID":929},"10.1007\u002FBF00121326","2024-04-29T23:25:06.025+00:00",[223],"https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002FBF00121326",[934,949,964],{"id":935,"sortIndex":21,"researcher":20,"roles":936,"affiliations":937,"properties":946,"displayName":948,"givenName":20,"familyName":20},"ab482582-d2c9-4f4c-b037-39613a61aa2c",[229],[938],{"id":939,"sortIndex":21,"affiliation":940,"properties":20},"fde2c01e-66f9-481a-91c5-76b7b32601f1",{"id":939,"createTime":20,"updateTime":20,"relativeEntities":941,"slug":20,"properties":942,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":945,"statistic":20},[],{"title":943},{"VI":944},"Unidad de Hepatología Experimental, Centro de Investigación, Hospital La Fe, Servicio Valenciano de Salud, Valencia, Spain",[],{"title":947},{"VI":948},"M. 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(1984). Prolonged maintenance of active cytochrome P-450 in adult rat hepatocyte co-cultured with another liver cell type. Hepatology 4:839–842.",{"doi":637},{"id":633,"text":1045,"url":635,"identifiers":1046},"BISSELL, D.M., ARENSON, D.M., MAHER, J.J. and ROLL, F.G. (1987). Support of cultured hepatocytes by a laminin-rich gel. Evidence for a functionally significant subendothelial matrix in normal rat liver. J. Clin. Invest. 79:801–812.",{"doi":637},{"id":1048,"text":1049,"url":1050,"identifiers":1051},"eb767a29-7f63-4623-8b39-3ad60b5e3d89","BISSELL, D.M. and GUZELIAN, P.S. (1979) Ascorbic acid deficiency and cytochrome P-450 in adult rat hepatocytes in primary monolayer culture. Arch. Biochem. 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Commun. 78:279–287.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0006291X77912517",{"doi":1061},"10.1016\u002F0006-291x(77)91251-7",{"id":633,"text":1063,"url":635,"identifiers":1064},"DICKINS, M., PETERSON, R.E. (1980). Effects of a hormone-supplemented medium on cytochrome P-450 content and monooxygenase activities of rat hepatocytes in primary culture. Biochem. Pharmacol. 29:1231–1238.",{"doi":637},{"id":633,"text":1066,"url":635,"identifiers":1067},"DONATO, M.T., CASTELL, J.V. and GOMEZ-LECHON, M.J. (1990). Prolonged expression of biotransformation activities of rat hepatocytes co-cultured with established cell lines. Toxic. In Vitro 4:461–466.",{"doi":637},{"id":20,"text":1069,"url":20,"identifiers":1070},"GOMEZ-LECHON, M.J. and CASTELL, J.V. (1983). The role of fetal calf serum during the first stages of hepatocyte culture. In: Hormonally defined media. A tool in cell biology (A. Fisher and R.J. Wieseer, eds.), pp. 340–343. Springer-Verlag, Berlin.",{},{"id":633,"text":1072,"url":635,"identifiers":1073},"GOMEZ-LECHON, M.J., LOPEZ, P. and CASTELL, J.V. (1984). Biochemical functionality recovery of hepatocytes after deep-freezing storage. In Vitro 20:826–832.",{"doi":637},{"id":633,"text":1075,"url":635,"identifiers":1076},"GOULET, F., NORMAND, C. and MORIN O. (1988). Cellular interactions promote tissue-specific function, biomatrix deposition and junctional communication of primary cultured hepatocytes. Hepatology 8:1010–1018.",{"doi":637},{"id":20,"text":1078,"url":20,"identifiers":1079},"GREENLEE, W.F. and POLAND, A. (1978). Mainitenance and reversibility of active albumin secretion by adult rat of hepatic enzyme activity in C547 BL\u002F6J and DBA\u002F2J mice by phenobarbital, 3-methylcholanthrene and 2,3,7,8-tetrachlorobenzo-p-dioxin. J. Pharmacol. Exp. Ther. 205:569–605.",{},{"id":633,"text":1081,"url":635,"identifiers":1082},"GUGUEN-GUILLOUZO, C., CLEMENT, B., BAFFET, G., BEAUMONT, C., MORELCHANY, E., GLAISE, D. and GUILLOUZO, A. (1983). Maintenance and reversibility of active albumin secretion by adult rat hepatocytes co-cultured with another liver epithelial cell type. Exptl. Cell. Res. 143:47–54.",{"doi":637},{"id":633,"text":1084,"url":635,"identifiers":1085},"GUZELIAN, P.S. and BISSELL, D.M. (1976) Effect of cobalt on synthesis of heme and cytochrome P-450 in the liver liver. Studies of adult rat hepatocytes in primary monolayer and in vivo. J. Biol. Chem. 251:4421–4427.",{"doi":637},{"id":633,"text":1087,"url":635,"identifiers":1088},"HABIG, W.H. and JAKOBY, W.B. (1981). Assays for differentiation of glutathione S-transferases. In: Methods in Enzymology (P.S. Colowick and N.O. Kaplan, eds.) vol. 77, pp. 398–405. Academic Press, New York.",{"doi":637},{"id":633,"text":1090,"url":635,"identifiers":1091},"HISSIN, P.J. and HILF, R. (1976). A fluorimetric method for determination of oxidized and reduced glutathione in tissues. Anal. Biochem. 274:214–226.",{"doi":637},{"id":633,"text":1093,"url":635,"identifiers":1094},"HOLME, J.A. (1985). Xenobiotic metabolism and toxicity in primary monolayer cultures of hepatocytes. NIPH Annals 8:49–63.",{"doi":637},{"id":633,"text":1096,"url":635,"identifiers":1097},"HOLME, J.A., SODERLUND, E. and DYDING, E. (1983). Drug metabolism activities of isolated rat hepatocytes in monolayer culture. Acta Pharmacol. Toxicol. 52:348–356.",{"doi":637},{"id":633,"text":1099,"url":635,"identifiers":1100},"JONGEN, W.M.F., SIJTSMA, S.R., ZWIJSEN, R.M.L. and TEMMINK, J.H.M. (1987). A co-cultivation system consisting of primary chick embryo heepatocytes and V79 Chinese hamster cells as a model for metabolic cooperation studies. Carcinogenesis 8:767–772.",{"doi":637},{"id":633,"text":1102,"url":635,"identifiers":1103},"KURI-HARCUCH, W. and MENDOZA-FIGUEROA, T. (1989). Cultivation of adult rat hepatocytes on 3T3 cells: expression of various liver differentiated functions. Differentiation 41:148–157.",{"doi":637},{"id":20,"text":1105,"url":20,"identifiers":1106},"LANGENBACH, R., MALICK, L., TOMPA, A., KUSZYNSKI, C., FREED, H., and HUBERMAN, E. (1979). Maintenance of adult rat hepatocytes on C3H\u002F1OT1\u002F2 cells. Cancer Res. 39:3509–3514.",{},{"id":633,"text":1108,"url":635,"identifiers":1109},"LILIENBLUM, W., WALI, A.K. and BOCK, K.W. (1982). Differential induction of rat liver microsomal UDP-glucuronyltransferase activities by various inducing agents. Biochem. Pharmacol. 31:907–913.",{"doi":637},{"id":20,"text":1111,"url":20,"identifiers":1112},"LOWRY, O.H., ROSENBROUGH, N.J., FARR, A.L. and RANDALL, R.J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275.",{},{"id":1114,"text":1115,"url":1116,"identifiers":1117},"d4e260a9-ff27-4981-bed4-0985ddbfb349","MAIER, P. (1988). Development of in vitro toxicity tests with cultures of freshly isolated rat hepatocytes. Experientia 44:807–817.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002FBF01941176",{"doi":1118},"10.1007\u002FBF01941176",{"id":633,"text":1120,"url":635,"identifiers":1121},"MICHALOPOULOS, G., SATTLER, G.L. and PITOT, H.C. (1976). Maintenance of microsomal cytochrome b5 and P-450 in primary cultures of parenchymal liver cells on collagen membranes. Life Sci. 18:1139–1144.",{"doi":637},{"id":1123,"text":1124,"url":1125,"identifiers":1126},"e6cfd036-d038-47bf-a819-b84599c049d1","MICHALOPOULOS, G., RUSELL, F. and BILES, C. (1979). Primary cultures of hepatocytes on human fibroblasts. In Vitro 15:796–806.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002FBF02618306",{"doi":1127},"10.1007\u002FBF02618306",{"id":633,"text":1129,"url":635,"identifiers":1130},"MORIN, O. and NORMAND, C. (1986). Lont-term maintenance of hepatocyte functional activity in co-culture: Requirements for sinusoidal endothelial cells and dexamethasone. J. Cell. Physiol. 129:103–110.",{"doi":637},{"id":633,"text":1132,"url":635,"identifiers":1133},"NEBERT, D.W. and GELBOIN, H.V. (1968). Substrate-inducible microsomal aryl hydroxylase in mammalian cell culture. J. Biol. Chem. 243:6242–6249.",{"doi":637},{"id":633,"text":1135,"url":635,"identifiers":1136},"OMURA, T. and SATO, R. (1964). The carbon monoxide-binding pigment of liver microsomes. J. Biol. Chem. 239:2370–2378.",{"doi":637},{"id":633,"text":1138,"url":635,"identifiers":1139},"PAINE, A.J. and HOCKIN, L. (1980). Nutrient imbalance causes the loss of cytochrome P-450 in liver cell culture: Formulation of culture media which maintain cytochrome P-450 at in vivo concentrations. Biochem. Pharmacol. 29:3215- 3218.",{"doi":637},{"id":633,"text":1141,"url":635,"identifiers":1142},"PAINE, A.J., VILLA, P. and HOCKIN, L. (1980). Evidence that ligand formation is a mechanism underlying the maintenance of cytochrome P-450 in rat liver cell culture. Potent maintenance by metyrapone. Biochem. J. 188:937–939.",{"doi":637},{"id":1144,"text":1145,"url":1146,"identifiers":1147},"dcf59e67-be5a-4b94-9c55-b605c0ab5c95","RAINE, A.J., WILLIAMS, L.J. and LEGG, R.F. (1979). Apparent maintenance of cytochrome P-450 by nicotinamide in primary cultures of rat hepatocytes. Life Sciences 24:2185–2192.","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002F0024320579901176",{"doi":1148},"10.1016\u002F0024-3205(79)90117-6",{"id":20,"text":1150,"url":20,"identifiers":1151},"REID, L.M., NARITA, M., FUJITA, M., MURRAY, Z., LIVERPOOL C. and ROSENBERG, L. (1986). Matrix and hormonal regulation in liver cultures. In: Research in isolated and Culture Hepatocytes (A. Guillouzo and C. Guguen-Guillouzo, eds.), pp. 225–258. John Libbey Eurotext Ltd.\u002FINSERM, London.",{},{"id":633,"text":1153,"url":635,"identifiers":1154},"SAWADA, N., TOMOMURA, A., SATTLER, C.A., SATTLER, G.L., KLEINMAN, H.K. and PITOT, H.C. (1987). Effects of extracellular matrix components on the growth and differentiation of cultured rat hepatocytes. In Vitro Cell. Dev. Biol. 23:267–273.",{"doi":637},{"id":633,"text":1156,"url":635,"identifiers":1157},"SCHUETZ, E.G., LI, D., OMIECINSKI, C.J., MULLER-EBERHARD, U., KLEINMAN, H.K., ELSWICK, B. and GUZELIAN, P.S. (1988). Regulation of gene expression in adult rat hepatocytes cultured on a basement membrane matrix. J. Cell. Physiol. 134:309–323.",{"doi":637},{"id":633,"text":1159,"url":635,"identifiers":1160},"SUOLINNA, E.M. (1982). Isolation and culture of liver cells and their use in the biochemical research of xenobiotics. Med. Biol. 60:237–254.",{"doi":637},{"id":633,"text":1162,"url":635,"identifiers":1163},"TURNER, N.A., WILSON, N.M., JEFCOATE, C.R. and PITOT, H.C. (1988). The expression and metabolic activity of cytochrome P-450 isozymes in control and phenobarbital-induced primary cultures of rat hepatocytes. Arch. Biochem. Biophys. 263:204–215.",{"doi":637},{"id":1165,"text":1166,"url":1167,"identifiers":1168},"11738c9d-c06f-48ac-b043-163a2ec54aec","VANDENBERGHE, Y., RATANASAVANH, D., GLAISE, D. and GUILLOUZO, A. (1988). Influence of medium composition and culture conditions on glutathione S-transferase activity in adult rat hepatocytes during culture. In Vitro Cell. Develop. Biol. 24:281–288.","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002FBF02628828",{"doi":1169},"10.1007\u002FBF02628828",{"id":633,"text":1171,"url":635,"identifiers":1172},"WARREN, M., FRY, J.R. and BALLS, M. (1985). The effect ofgglucose, insulin and dexamethasone upon 7-ethoxycoumarin O-deethylase activity of adult rat hepatocytes in primary culture. Xenobiotica 15:775–779.",{"doi":637},{"id":1174,"createTime":1175,"updateTime":1176,"relativeEntities":1177,"slug":1178,"properties":1179,"entityType":218,"verifyStatus":219,"verifyTime":1190,"verifyNote":221,"languages":20,"translateLanguages":20,"viewCount":21,"primaryUrl":1191,"fullTextUrl":20,"authors":1192,"publicationType":264,"publisherRelationship":1291,"citationCount":20,"citationInfo":20,"publishDate":1347,"publishYear":1348,"citationAnalyzeStatus":1349,"lastCitationAnalyze":1350,"indexDatabases":1351,"openAccess":20,"references":20,"isForceReanalyzing":324},"9b138d94-f70c-445c-8163-cafd9aa0bf47","2024-01-12T23:20:46.314+00:00","2026-07-22T12:04:54.835+00:00",[],"Induction-of-Sestrin2-by-pterostilbene-suppresses-ethanol-triggered-hepatocyte-senescence-by-degrading-CCN1-via-p62-dependent-selective-autophagy",{"abstract":1180,"title":1182,"gsPaper":1184,"references":1186,"doi":1188},{"EN":1181},"Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism. \n                  \n                    \n                      \n                    \n                  \n                ",{"EN":1183},"Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy",{"VOID":1185},"[]",{"VOID":1187},"Babuta M, Furi I, Bala S, Bukong TN, Lowe P, Catalano D, Calenda C, Kodys K, Szabo G. Dysregulated autophagy and lysosome function are linked to exosome production by Micro-RNA 155 in Alcoholic Liver Disease. Hepatology. 2019;70(6):2123–41.\nBian Z, Peng Y, You Z, Wang Q, Miao Q, Liu Y, et al. CCN1 expression in hepatocytes contributes to macrophage infiltration in nonalcoholic fatty liver disease in mice. J Lipid Res. 2013;54(1):44–54.\nChen J, Liu Z, et al. SIRT6 enhances telomerase activity to protect against DNA damage and senescence in hypertrophic ligamentum flavum cells from lumbar spinal stenosis patients. Aging (Albany NY). 2021;13:6025–40.\nChen Y, Zhang H, et al. Pterostilbene as a protective antioxidant attenuates diquat-induced liver injury and oxidative stress in 21-day-old broiler chickens. Poult Sci. 2020;99(6):3158–67.\nChen YT, Huang ZY, Tang HH, Kuo WT, Wu SY, Lan SH, et al. Pterostilbene sensitizes cisplatin-resistant human bladder cancer cells with oncogenic HRAS. Cancers (Basel). 2020a;12(10):1–25.\nDing WX, Li M, et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010;139(5):1740–52.\nDing WX, Manley S, Ni HM. The emerging role of autophagy in alcoholic liver disease. Exp Biol Med (Maywood). 2011;236(5):546–56.\nDong R, Wang X, Wang L, Wang C, Huang K, Fu T, et al. Yangonin inhibits ethanol-induced hepatocyte senescence via miR-194\u002FFXR axis. Eur J Pharmacol. 2021;890:173653.\nFeng M, Peng H, Yao R, Zhang Z, Mao G, Yu H, et al. Inhibition of cellular communication network factor 1 (CCN1)-driven senescence slows down cartilage inflammaging and osteoarthritis. Bone. 2020;139:115522.\nFeng T, Meng J, Kou S, Jiang Z, Huang X, Lu Z, Zhao H, Lau LF, Zhou B, Zhang H. CCN1-Induced cellular senescence promotes heart regeneration. Circulation. 2019;139(21):2495–8.\nGómez-Zorita S, Milton-Laskíbar I, Aguirre L, Fernández-Quintela A, Xiao J, Portillo MP. Effects of pterostilbene on diabetes, liver steatosis and serum lipids. Curr Med Chem. 2021;28(2):238–52.\nGorojod RM, Alaimo A, Porte Alcon S, Pomilio C, Saravia F, Kotler ML. The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions. Free Radic Biol Med. 2015;87:237–51.\nHabiballa L, Salmonowicz H, Passos JF. Mitochondria and cellular senescence: Implications for musculoskeletal ageing. Free Radic Biol Med. 2019;132:3–10.\nHe S, Sharpless NE. Senescence in health and disease. Cell. 2017;169(6):1000–11.\nHuang X, Cai H, Zhou H, Li T, Jin H, Evans CE, Cai J, Pi J. Cobalt oxide nanoparticle-synergized protein degradation and phototherapy for enhanced anticancer therapeutics. Acta Biomater. 2021;121:605–20.\nIwai-Kanai E, Yuan H, Huang C, Sayen MR, Perry-Garza CN, Kim L, Gottlieb RA. A method to measure cardiac autophagic flux in vivo. Autophagy. 2008;4(3):322–9.\nJin H, Lian N, Bian M, Zhang C, Chen X, Shao J, et al. Oroxylin A inhibits ethanol-induced hepatocyte senescence via YAP pathway. Cell Prolif. 2018;51(3):e12431.\nKang KY, Shin JK, Lee SM. Pterostilbene protects against acetaminophen-induced liver injury by restoring impaired autophagic flux. Food Chem Toxicol. 2019;123:536–45.\nLiu X, Yang X, Han L, Ye F, Liu M, Fan W, et al. Pterostilbene alleviates polymicrobial sepsis-induced liver injury: Possible role of SIRT1 signaling. Int Immunopharmacol. 2017;49:50–9.\nLiu Z, Wang J, Zhang Y, Wu D, Li S, Jiang A, et al. Pterostilbene exerts hepatoprotective effects through ameliorating LPS\u002FD-Gal-induced acute liver injury in mice. Inflammation. 2020;44:525–35.\nLu C, Xu W, Shao J, Zhang F, Chen A, Zheng S. Nrf2 Activation is required for ligustrazine to inhibit hepatic steatosis in alcohol-preferring mice and hepatocytes. Toxicol Sci. 2017;155(2):432–43.\nLu C, Xu W, Shao J, Zhang F, Chen A, Zheng S. Nrf2 induces lipocyte phenotype via a SOCS3-dependent negative feedback loop on JAK2\u002FSTAT3 signaling in hepatic stellate cells. Int Immunopharmacol. 2017b;49:203–11.\nLu C, Xu W, Zhang F, Shao J, Zheng S. Nrf2 knockdown attenuates the ameliorative effects of ligustrazine on hepatic fibrosis by targeting hepatic stellate cell transdifferentiation. Toxicology. 2016a;365:35–47.\nLu C, Xu W, Zhang F, Shao J, Zheng S. 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Hepatology. 2013;58(3):995–1010.\nWang YJ, Chen YY, Hsiao CM, Pan MH, Wang BJ, Chen YC, Ho CT, Huang KC, Chen RJ. Induction of autophagy by pterostilbene contributes to the prevention of renal fibrosis via attenuating NLRP3 Inflammasome activation and epithelial-mesenchymal transition. Front Cell Dev Biol. 2020;8:436.\nWu J, Li M, He J, Lv K, Wang M, Guan W, et al. Protective effect of pterostilbene on concanavalin A-induced acute liver injury. Food Funct. 2019;10(11):7308–14.\nWu R, Wang X, Shao Y, Jiang Y, Zhou Y, Lu C. NFATc4 mediates ethanol-triggered hepatocyte senescence. Toxicol Lett. 2021;350:10–21.\nYao R, Ren C, Xia Z, Yao Y. Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy. 2021;17:385–401.\nYu CL, Yang SF, Hung TW, Lin CL, Hsieh YH, Chiou HL. Inhibition of eIF2alpha dephosphorylation accelerates pterostilbene-induced cell death in human hepatocellular carcinoma cells in an ER stress and autophagy-dependent manner. Cell Death Dis. 2019;10(6):418.\nZhang H, Chen Y, Chen Y, Ji S, Jia P, Xu J, et al. Pterostilbene attenuates liver injury and oxidative stress in intrauterine growth-retarded weanling piglets. Nutrition. 2021a;81:110940.\nZhang L, Zheng J, Tie X, Lin T, Yang W, Li Z, et al. Pterostilbene and its nicotinate derivative ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of sirtuin 1. Can J Physiol Pharmacol. 2021b;2:1–10.\nZhou Y, Jin H, Wu Y, Chen L, Bao X, Lu C. Gallic acid protects against ethanol-induced hepatocyte necroptosis via an NRF2-dependent mechanism. Toxicol in Vitro. 2019;57:226–32.",{"VOID":1189},"10.1007\u002Fs10565-021-09635-8","2024-06-26T23:07:12.319+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10565-021-09635-8",[1193,1208,1221,1236,1249,1264,1277],{"id":1194,"sortIndex":21,"researcher":20,"roles":1195,"affiliations":1196,"properties":1205,"displayName":1207,"givenName":20,"familyName":20},"7c141600-d44b-43ab-9a27-4061f25a7d3f",[229],[1197],{"id":1198,"sortIndex":21,"affiliation":1199,"properties":20},"6200a0ff-5f2a-4370-9760-1a2e59d336cc",{"id":1198,"createTime":20,"updateTime":20,"relativeEntities":1200,"slug":20,"properties":1201,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1204,"statistic":20},[],{"title":1202},{"VI":1203},"School of Pharmacy, Nantong University, Nantong, China",[],{"title":1206},{"VI":1207},"Yiming 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steatohepatitis (NASH) is a highly prevalent, chronic liver disease characterized by hepatic lipid accumulation, inflammation, and concomitant fibrosis. Up to date, no anti-NASH drugs have been approved. In this study, we reproduced key NASH characteristics in vitro by exposing primary human hepatocytes (PHH), human skin stem cell-derived hepatic cells (hSKP-HPC), HepaRG and HepG2 cell lines, as well as LX-2 cells to multiple factors that play a role in the onset of NASH. The obtained in vitro disease models showed intracellular lipid accumulation, secretion of inflammatory chemokines, induced ATP content, apoptosis, and increased pro-fibrotic gene expression. These cell systems were then used to evaluate the anti-NASH properties of eight peroxisome proliferator-activated receptor (PPAR) agonists (bezafibrate, elafibranor, fenofibrate, lanifibranor, pemafibrate, pioglitazone, rosiglitazone, and saroglitazar). PPAR agonists differently attenuated lipid accumulation, inflammatory chemokine secretion, and pro-fibrotic gene expression. Based on the obtained readouts, a scoring system was developed to grade the anti-NASH potencies. The in vitro scoring system, based on a battery of the most performant models, namely PHH, hSKP-HPC, and LX-2 cultures, showed that elafibranor, followed by saroglitazar and pioglitazone, induced the strongest anti-NASH effects. These data corroborate available clinical data and show the relevance of these in vitro models for the preclinical investigation of anti-NASH compounds.",{"EN":1362},"Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists",{"VOID":1364},"[\"2981907981470193949\"]",{"VOID":1366},"Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–9.\nBierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-κB. 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The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.\nChi KR. The NASH drug dash. Nat Rev Drug Discov. 2015;14:447–8.\nDash A, Figler RA, Blackman BR, Marukian S, Collado MS, Lawson MJ, et al. Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol Vitr. 2017;39:93–103.\nDorn C, Engelmann JC, Saugspier M, Koch A, Hartmann A, Müller M, et al. Increased expression of c-Jun in nonalcoholic fatty liver disease. Lab Investig. 2014;94:394–408.\nEkstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–54.\nEstes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123–33.\nFeaver RE, Cole BK, Lawson MJ, Hoang SA, Marukian S, Blackman BR, et al. Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. J Clin Invest. 2016;1:e90954.\nFernández-Miranda C, Pérez-Carreras M, Colina F, López-Alonso G, Vargas C, Solís-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis. 2008;40:200–5.\nFrades I, Andreasson E, Mato JM, Alexandersson E, Matthiesen R, Martínez-Chantar ML. Integrative genomic signatures of hepatocellular carcinoma derived from nonalcoholic fatty liver disease. PLoS One. 2015;10:e0124544.\nFrancque S, Verrijken A, Caron S, Prawitt J, Paumelle R, Derudas B, et al. PPAR-α gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015;63:164–73.\nFranko A, Neschen S, Rozman J, Rathkolb B, Aichler M, Feuchtinger A, et al. Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice. Mol Metab. 2017;6:256–66.\nFriedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–22.\nGarbacz WG, Lu P, Miller TM, Poloyac SM, Eyre NS, Mayrhofer G, et al. Hepatic overexpression of CD36 improves glycogen homeostasis and attenuates high-fat diet-induced hepatic steatosis and insulin resistance. Mol Cell Biol. 2016;36:2715–27.\nGross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017;13:36–49.\nHaas JT, Vonghia L, Mogilenko DA, Verrijken A, Molendi-Coste O, Fleury S, et al. Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution. Nat Metab. 2019;1:604–14.\nHan J, Hajjar DP, Tauras JM, Feng J, Gotto AM, Nicholson AC. Transforming growth factor-β1 (TGF-β1) and TGF-β2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-γ. J Biol Chem. 2000;275:1241–6.\nHeikkinen S, Auwerx J, Argmann CA. PPARγ in human and mouse physiology. Biochim Biophys Acta—Mol Cell Biol Lipids. 2007;1771:999–1013.\nHolden PR, Tugwood JD. Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences. J Mol Endocrinol. 1999;22:1–8.\nHonda Y, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Fujita K, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep. 2017;7:1–11.\nIshibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol. 2018;12:173–84.\nJain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, et al. Dual PPARα\u002Fγ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 2018;38:1084–94.\nKanmani P, Kim H. Protective effects of lactic acid bacteria against TLR4 induced inflammatory response in hepatoma HepG2 cells through modulation of toll-like receptor negative regulators of mitogen-activated protein kinase and NF-κB signaling. Front Immunol. 2018;9:1537.\nKleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.\nKücükoglu Ö, Labenz C, Sydor S, Schlattjan M, Best J, Gerken G, et al. Free fatty acids enhance CD36 knockdown in primary human hepatocytes and abrogate PTEN expression—recapitulation of NASH-associated HCC. J Hepatol. 2017;66:S464.\nLeBleu VS, O’Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation to promote metastasis. Nat Cell Biol. 2014;16:992–1003.\nLópez-Riera M, Conde I, Tolosa L, Zaragoza Á, Castell JV, Gómez-Lechón MJ, et al. New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease. Front Pharmacol. 2017;8:1–12.\nMandard S, Müller M, Kersten S. Peroxisome proliferator-activated receptor α target genes. Cell Mol Life Sci. 2004;61:393–416.\nMannaerts I, Leite SB, Verhulst S, Claerhout S, Eysackers N, Thoen LFR, et al. The hippo pathway effector YAP controls mouse hepatic stellate cell activation. J Hepatol. 2015;63:679–88.\nMarchesini G, Day CP, Dufour JF, Canbay A, Nobili V, Ratziu V, et al. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402.\nMaréchal L, Laviolette M, Rodrigue-Way A, Sow B, Brochu M, Caron V, et al. The CD36-PPARγ pathway in metabolic disorders. Int J Mol Sci. 2018;19:1–16.\nMarra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147:577–94.\nMiquilena-Colina ME, Lima-Cabello E, Sánchez-Campos S, García-Mediavilla MV, Fernández-Bermejo M, Lozano-Rodríguez T, et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut. 2011;60:1394–402.\nMoylan CA, Pang H, Dellinger A, Suzuki A, Garrett ME, Guy CD, et al. Hepatic gene expression profiles differentiate pre-symptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology. 2014;59:471–82.\nOhashi T, Tanabe J, Ishikawa T, Okumura A, Sato K, Ayada M, et al. Inflammatory cytokines modulate chemokine production patterns of HepG2 cells toward initially inclined direction. Hepatol Res. 2009;39:510–9.\nRatziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology. 2008;135:100–10.\nRatziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51:445–53.\nRatziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–59.\nRodrigues RM, De Kock J, Branson S, Vinken M, Meganathan K, Chaudhari U, et al. Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals. Stem Cells Dev. 2014;23:44–55.\nRodrigues RM, Branson S, De Boe V, Sachinidis A, Rogiers V, De Kock J, et al. In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol. 2016a;90:677–89.\nRodrigues RM, Heymans A, De Boe V, Sachinidis A, Chaudhari U, Govaere O, et al. Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems. Toxicol Lett. 2016b;240:50–9.\nRogue A, Lambert C, Jossé R, Antherieu S, Spire C, Claude N, et al. Comparative gene expression profiles induced by PPARγ and PPARα\u002Fγ agonists in human hepatocytes. PLoS One. 2011;6:e18816.\nRogue A, Anthérieu S, Vluggens A, Umbdenstock T, Claude N, De la Moureyre-Spire C, et al. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells. Toxicol Appl Pharmacol. 2014;276:73–81.\nSanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.\nSato O, Kuriki C, Fukui Y, Motojima K. Dual promoter structure of mouse and human fatty acid translocase\u002FCD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor α and γ ligands. J Biol Chem. 2002;277:15703–11.\nScarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta. 2011;1813:1269–78.\nSumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD\u002FNASH. J Gastroenterol. 2018;53:362–76.\nTacke F, Zimmermann HW, Trautwein C, Schnabl B. CXCL5 plasma levels are decreased in patients with chronic liver disease. J Gastroenterol Hepatol. 2011;26:523–9.\nTarek I, Tamini A-R, Elgouhari HM, Alkhouri N, Yerian LM, Berk MP, et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. J Hepatol. 2011;54:1224–9.\nTen RM, Paya CV, Israel N, Le Bail O, Mattei MG, Virelizier JL, et al. The characterization of the promoter of the gene encoding the p50 subunit of NF-κB indicates that it participates in its own regulation. EMBO J. 1992;11:195–203.\nThomas E, Gonzalez VD, Li Q, Modi AA, Chen W, Noureddin M, et al. HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons. Gastroenterology. 2012;142:978–88.\nTong L, Wang L, Yao S, Jin L, Yang J, Zhang Y, et al. PPAR δ attenuates hepatic steatosis through autophagy-mediated fatty acid oxidation. Cell Death Dis. 2019;10:1–14.\nVaidyanathan S, Maboudian M, Warren V, Yeh C, Dieterich HA, Howard D, et al. A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects. Curr Med Res Opin. 2008;24:2313–26.\nVarga ZV, Ferdinandy P, Liaudet L, Pacher P. Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol—Heart Circ Physiol. 2015;309:1453–67.\nWettstein G, Luccarini J-M, Poekes L, Faye P, Kupkowski F, Adarbes V, et al. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol Commun. 2017;1:524–37.\nXu L, Hui AY, Albanis E, Arthur MJ, Blaner WS, Mukherjee P, et al. Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut. 2005;54:142–51.\nYan F, Wang Q, Xu C, Cao M, Zhou X, Wang T, et al. Peroxisome proliferator-activated receptor α activation induces hepatic steatosis, suggesting an adverse effect. PLoS One. 2014;9:e99245.\nYang L, Roh YS, Song J, Zhang B, Liu C, Loomba R, et al. TGF-β signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism. Hepatology. 2014;59:483–95.\nYounossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. 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acid (OA), produced by dinoflagellates during harmful algal blooms (HAB), belongs to the Diarrheic Shellfish Poisoning toxins that cause gastrointestinal symptoms in humans after consumption. In the present work, Ruditapes decussatus haemocytes were selected to evaluate the effect of OA on cell viability, enzymatic status and immune capacity through the measure by flow cytometry of apoptosis–cell death, non-specific esterase activity and phagocytosis. In order to compare different exposure conditions, two experiments were developed: in vitro exposure to OA and HAB simulation by feeding clams with the OA producer, Prorocentrum lima. Apoptosis was not OA dose-dependent and cell death increased in both assays. Phagocytosis of latex beads and esterase activity decreased in haemocytes incubated with OA. In contrast, esterases increased during the feeding with P. lima. Our results showed that OA and the simulated HAB caused damages on haemocyte functions and viability.",{"EN":1593},"Effect of okadaic acid on carpet shell clam (Ruditapes decussatus) haemocytes by in vitro exposure and harmful algal bloom simulation assays",{"VOID":1595},"[\"10462761278696105772\"]",{"VOID":1597},"Ahn KH, Kim YS, Kim SY, Hub Y, Park C, Jeong JW. Okadaic acid protects human neuroblatoma SH-SY5Y cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis. Neurosci Lett. 2009;449:93–7.\nAllam B, Ford SE. Effects of the pathogenic Vibrio tapetis on defence factors of susceptible and non-susceptible bivalve species: I. Haemocyte changes following in vitro challenge. Fish Shellfish Immunol. 2006;20:374–83.\nAllam B, Ashton-Alcox KA, Ford SE. Flow cytometric comparison of haemocytes from three species of bivalve mollusks. Fish Shellfish Immunol. 2002;13:141–58.\nBetti M, Ciacci C, Lorusso LC, Canonico B, Falcioni T, Gallo G, et al. Effects of tumour necrosis factor α (TNFα) on Mytilus haemocytes: role of stress-activated mitogen-activated protein kinases (MAPKs). Biol Cell. 2006;98:233–44.\nBinelli A, Cogni D, Parolini M, Riva C, Provini A. In vivo experiments for the evaluation of genotoxic and cytotoxic effects of Triclosan in Zebra mussel hemocytes. Aquat Toxicol. 2009;91:238–44.\nBiolojan C, Takai A. Inhibitory effect of a marine-sponge toxin okadaic acid on protein phosphatases. Specificity and kinetics. Biochem J. 1988;256:283–90.\nBlanco J, Moroño A, Fernández ML. Toxic episodes in shellfish produced by lipophilic phycotoxins: an overiew. Revista Galega de Recursos Mariños. 2005;1:1–70.\nBoudreau RT, Conrad DM, Hoskin DW. Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase. Cell Signal. 2007;19:139–51.\nBravo I, Fernández ML, Ramilo I, Martínez A. Toxin composition of the toxic dinoflagellate Prorocentrum lima isolated from different locations along the Galician coast (NW Spain). Toxicon. 2001;39:1537–45.\nCabado AG, Leira F, Vieytes MR, Vieites JM, Botana LM. Cytoskeletal disruption is the key factor that triggers apoptosis in okadaic acid-treated neruroblastoma cells. Arch Toxicol. 2004;78:74–85.\nCanesi L, Pruzzo C, Tarsi R, Gallo G. Surface interactions between Escherichia coli and hemocytes of the Mediterranean mussel Mytilus galloprovincialis Lam leading to efficient bacterial clearance. Appl Environ Microbiol. 2001;67:464–8.\nCarvalho Pinto-Silva CR, Ferreira JF, Costa RHR, Belli Filho P, Creppy EE, Matias WG. Micronucleus induction in mussels exposed to okadaic acid. Toxicon. 2003;41:93–7.\nCarvalho Pinto-Silva CR, Creppy EE, Matias WC. Micronucleus test in mussels Perna perna fed with the toxic dinoflagellate Prorocentrum lima. Arch Toxicol. 2005;79:422–6.\nComesaña-Losada M, Leão JM, Gago-Martínez A, Rodríguez-Vázquez JA, Quilliam MA. Further studies on the analysis of DSP toxin profiles in galician mussels. J Agric Food Chem. 1999;47:618–21.\nCosta MM, Prado-Alvarez M, Gestal C, Li H, Roch P, Novoa B, et al. Functional and molecular immune response of Mediterranean mussel (Mytilus galloprovincialis) haemocytes against pathogen-associated molecular patterns and bacteria. Fish Shellfish Immunol. 2009;26:515–23.\nda Silva PM, Hégaret H, Lambert C, Wikfors GH, Goïc NL, Shumway SE, et al. Immunological responses of the Manila clam (Ruditapes philippinarum) with varying parasite (Perkinsus olseni) burden, during a long-term exposure to the harmful alga, Karenia selliformis, and possible interactions. Toxicon. 2008;51:563–73.\nDickey RW, Bobzin SC, Faulkner DJ, Bencsath FA, Andrzejewski D. Identification of okadaic acid from a Caribbean dinoflagellate, Prorocentrum concavum. Toxicon. 1990;28:371–7.\nDizer H, Fischer B, Harabawy AS, Hennion MC, Hansen PD. Toxicity of domoic acid in the marine mussel Mytilus edulis. Aquat Toxicol. 2001;55:149–56.\nFeng SY. Cellular defense mechanisms of oysters and mussels. Am Fish Soc Spec Publ. 1988;18:153–68.\nFernández MT, Zitko V, Gascón S, Novelli A. The marine toxin okadaic acid is a potent neurotoxin for cultured cerebellar neurons. Life Sci. 1991;49:157–62.\nFernández-Sánchez MT, García-Rodríguez A, Díaz-Trelles R, Novelli A. Inhibition of protein phosphatases induces IGF-1-blocked neurotrophin-insensitive neuronal apoptosis. FEBS Lett. 1996;398:106–12.\nFerraz-Mello D, de Oliveira Proença LA, Barracco MA. Comparative study of various immune parameters in three bivalve species during a natural bloom of Dinophysis acuminata in Santa Catarina Island, Brazil. Toxins. 2010;2:1166–78.\nFlórez-Barrós F, Prado-Alvarez M, Méndez J, Fernández-Tajes J. Evaluation of genotoxicity in gills and hemolymph of clam Ruditapes decussatus fed with the toxic dinoflagellate Prorocentrum lima. J Toxicol Environ Health Part A. 2011;74:971–9.\nFranchini A, Malagoli D, Ottaviani E. Targets and effects of yessotoxin okadaic acid and palytoxin: a differential review. Mar Drugs. 2010;8:658–77.\nGagnaire B, Thomas-Guyon H, Renault T. In vitro effects of cadmium and mercury on Pacific oyster, Crassostrea gigas (Thunberg), haemocytes. Fish Shellfish Immunol. 2004;16:501–12.\nGagnaire B, Thomas-Guyon H, Burgeot T, Renault T. Pollutant effects on Pacific oyster, Crassostra gigas (Thunberg), hemocytes: screening of 23 molecules using flow cytometry. Cell Biol Toxicol. 2006;22:1–14.\nGalimany E, Place AR, Ramón M, Jutson M, Pipe RK. The effects of feeding Karlodinium veneficum (PLY # 103; Gymnodinium veneficum Ballantine) to the blue mussel Mytilus edulis. Harmful Algae. 2008a;7:91–8.\nGalimany E, Sunila I, Hégaret H, Ramón M, Wikfors GH. Pathology and immune response of the blue mussel (Mytilus edulis L.) after an exposure to the harmful dinoflagellate Prorocentrum minimum. Harmful Algae. 2008b;7:630–8.\nGalimany E, Sunila I, Hégaret H, Ramón M, Wikfors GH. Experimental exposure of the blue mussel (Mytilus edulis, L.) to the toxic dinoflagellate Alexandrium fundyense: histopathology, immune responses, and recovery. Harmful Algae. 2008c;7:702–11.\nGarcía C, Pruzzo M, Rodríguez-Unda N, Contreras C, Lagos N. First evidence of Okadaic acid acyl-derivative and Dinophysistoxin-3 in mussel samples collected in Chiloe Island, Southern Chile. J Toxicol Sci. 2010;35:335–44.\nGarcía-García E, Prado-Alvarez M, Novoa B, Figueras A, Rosales C. Immune responses of mussel haemocyte subpopulations are differentially regulated by enzymes of the PI 3K, PKC and ERK kinase families. Dev Comp Immunol. 2008;32:637–53.\nGestal C, Costa M, Figueras A, Novoa B. 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Hemocyte responses of Manila clam, Ruditapes philippinarum, with varying parasite, Perkinsus olseni, severity to toxic-algal exposures. Aquat Toxicol. 2007;84:469–79.\nHégaret H, Smolowitz RM, Sunila I, Shumway SE, Alix J, Dixon M, et al. Combined effects of a parasite, QPX, and the harmful-alga, Prorocentrum minimum on northern quahogs, Mercenaria mercenaria. Mar Environ Res. 2010;69:337–44.\nHégaret H, da Silva PM, Wikfors GH, Haberkorn H, Shumway SE, Soudant P. In vitro interactions between several species of harmful algae and haemocytes of bivalve molluscs. Cell Biol Toxicol. 2011;27:249–66.\nJayaraj R, Gupta N, Lakshamana Rao PV. Multiple signal transduction pathways in okadaic acid induced apoptosis in HeLa cells. Toxicology. 2009;256:118–27.\nKuchel RP, Raftos DA. In vitro effects of noradrenaline on Akoya pearl oyster (Pinctada imbricata) haemocytes. Fish Shellfish Immunol. 2011;31:365–72.\nLago J, Santaclara F, Vieites JM, Cabado AG. 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Toxicol In vitro. 2002;16:23–31.\nLeira F, Alvarez C, Cabado AG, Vieites JM, Vieytes MR, Botana LM. Development of a F actin-based live-cell fluorimetric microplate assay for diarrhetic shellfish toxins. Anal Biochem. 2003;317:129–35.\nMalagoli D, Casarini L, Ottaviani E. Effect of the marine toxins okadaic acid and palytoxin on mussel phagocytosis. Fish Shellfish Immunol. 2008;24:180–6.\nNarain AS. The amoebocytes of lamellibranch molluscs, with special reference to the circulating amoebocytes. Malacol Rev. 1973;6:1–12.\nNuydens R, de Jong M, Van Den Kieboom G, Heers C, Dispersyn G, Cornelissen F, et al. Okadaic acid-induced apoptosis in neuronal cells: evidence for an abortive mitotic attempt. J Neurochem. 1998;70:1124–33.\nPrado-Alvarez M, Gestal C, Novoa B, Figueras A. Differentially expressed genes of the carpet shell clam Ruditapes decussatus against Perkinsus olseni. Fish Shellfish Immunol. 2009;26:72–83.\nPrado-Alvarez M, Flórez-Barrós F, Sexto-Iglesias A, Méndez J, Fernandez-Tajes J. Effects of okadaic acid on haemocytes from Mytilus galloprovincialis: a comparison between field and laboratory studies. Mar Environ Res. 2012a;81:90–3.\nPrado-Alvarez M, Romero A, Balseiro P, Dios S, Novoa B, Figueras A. Morphological characterization and functional immune response of the carpet shell clam (Ruditapes decussatus) haemocytes after bacterial stimulation. Fish Shellfish Immunol. 2012b;32:69–78.\nRiordan FA, Foroni L, Hoffbrand AV, Mehta AB, Wickremasinghe GR. Okadaic acid-induced apoptosis of HL60 leukemia cells is preceded by destabilization of bcl-2 mRNA and downregulation of bcl-2 protein. FEBS Lett. 1998;435:195–8.\nRossini GP, Sgarbi N, Malaguti C. The toxic responses induced by okadaic acid involve processing of multiple caspase isoforms. Toxicon. 2001;39:763–70.\nSantaclara F, Lago J, Vieites JM, Cabado AG. Effect of okadaic acid on integrins and structural proteins in BE(2)-M17 cells. Arch Toxicol. 2005;79:582–6.\nSvensson S, Förlin L. Intracellular effects of okadaic acid in the blue mussel Mytilus edulis and rainbow trout Oncorhynchus mykiss. Mar Environ Res. 1998;46:449–52.\nSvensson S, Särngren A, Förlin L. Mussel blood cells, resistant to the cytotoxic effects of okadaic acid, do not express cell membrane p-glycoprotein activity (multixenobiotic resistance). Aquat Toxicol. 2003;65:27–37.\nTraoré A, Baudrimont I, Ambaliou S, Dano SD, Creppy EE. DNA breaks and cell cycle arrest induced by okadaic acid in Caco-2 cells, a human colonic epithelial cell line. Arch Toxicol. 2001;75:110–7.\nValdiglesias V, Méndez J, Pásaro E, Cemeli E, Anderson D, Laffon B. Assessment of okadaic acid effects on cytotoxicity, DNA damage and DNA repair in human cells. Mutat Res. 2010;689:74–9.\nVale C, Botana LM. Marine toxins and cytoskeleton: okadaic acid and dinophysistoxins. FEBS J. 2008;275:6060–6.\nVermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled Annexin V. J Immunol Methods. 1995;184:39–51.\nVon Zezschwitz C, Vorwerk H, Tergau F, Steinfelder HJ. Apoptosis induction by inhibitors of Ser\u002FThr phosphatases 1 and 2A is associated with transglutaminase activation in two different human epithelial tumour lines. FEBS Lett. 1997;413:147–51.\nXue QG, Renault T, Chilmonczyk S. Flow cytometric assessment of haemocyte sub-populations in the European flat oyster, Ostrea edulis, haemolymph. Fish Shellfish Immunol. 2001;11:557–67.\nYasumoto T, Murata M, Oshima Y, Sano M, Matsumoto GK, Clardy J. Diarrhetic shellfish toxins. Tetrahedron. 1985;41:1019–25.",{"VOID":1599},"10.1007\u002Fs10565-013-9246-1","2024-05-06T20:02:38.308+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10565-013-9246-1",[1603,1618,1631,1646],{"id":1604,"sortIndex":21,"researcher":20,"roles":1605,"affiliations":1606,"properties":1615,"displayName":1617,"givenName":20,"familyName":20},"85590bd9-2edc-462e-8d13-965e8b0465b9",[229],[1607],{"id":1608,"sortIndex":21,"affiliation":1609,"properties":20},"6c685337-5a4f-4245-8f5b-2c68e5eba8e3",{"id":1608,"createTime":20,"updateTime":20,"relativeEntities":1610,"slug":20,"properties":1611,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1614,"statistic":20},[],{"title":1612},{"VI":1613},"Department of Cell and Molecular Biology, Faculty of Sciences, University of A Coruña, A Coruña, Spain",[],{"title":1616},{"VI":1617},"Maria 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causes vasoconstriction in the liver when present at high concentrations, an action that is strictly Ca2+-dependent. Diltiazem is also active on energy metabolism. This toxic action could be partly a consequence of hemodynamic effects. In the absence of Ca2+, the hemodynamic effects are no longer present and, consequently, Ca2+-free experiments are useful for distinguishing between hemodynamics-dependent and hemodynamics-independent effects. The experimental system used was the hemoglobin-free perfused rat liver from fed and fasted rats. Diltiazem was infused at various concentrations in the presence and absence of Ca2+. Several metabolic parameters were measured: lactate and pyruvate production (glycolysis), glycogenolysis, oxygen uptake, gluconeogenesis, and the cellular levels of lactate, pyruvate, glucose, AMP, ADP, and ATP. The effects of diltiazem can be divided into three groups: (1) Effects that are strictly dependent on the Ca2+-mediated hemodynamic action. This group comprises inhibition of oxygen uptake at all concentrations (50–500 μmol\u002FL) inhibition of lactate, pyruvate, and glucose release at high concentrations; the decrease in cellular ATP; the increase in cellular AMP; and the cellular accumulation of glucose and lactate. (2) Effects that are independent of the hemodynamic action. The most relevant effect of this type is inhibition of gluconeogenesis. (3) Effects that are influenced by Ca2+ but are independent of the hemodynamic effects. This is the typical case of lactate and glucose release from endogenous glycogen, whose stimulation by low diltiazem concentrations is more pronounced in the presence of Ca2+ than in its absence.",{"EN":1731},"The role of Ca2+ and hemodynamics in the action of diltiazem on hepatic energy metabolism",{"VOID":1733},"[\"9043540288507981852\"]",{"VOID":1735},"Bergmeyer HU, Bernt E. Glucose determination with glucose oxidase and peroxidase. In: Bergmeyer HU, ed. Methods of enzymatic analysis. New York: Academic Press, 1974:1205–15.\nBracht A, Schmeisch AP, Sampaio E, Pagadigorria C, Constantin J, D'Avila RB. The hemodynamic effects of diltiazem in the isolated perfused rat liver are Ca2+-dependent. Liver. 1999;19:145–50.\nBuckley MMT, Grant SM, Goa KL, McTavish D, Sorkin EM. Diltiazem. A reappraisal of its pharmacological properties and therapeutic use. Drugs. 1990;39:757–806.\nCzok R, Lamprecht W. Pyruvate, phosphoenolpyruvate and glycerate-2-phosphate. In: Bergmeyer HU, ed. Methods of enzymatic analysis. New York: Academic Press, 1974:1446–51.\nDahl S, Wettstein M, Gerok W, Häussinger D. Stimulation of release of prostaglandin D2 and thromboxane B2 from perfused rat liver by extracellular adenosine. Biochem J. 1990;270:39–44.\nFaller J, Irving H, Fox H. Ethanol-induced hyperuricemia. Evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med. 1982;23:1598–602.\nFarre AJ, Colombo M, Fort M, Gutierrez B. Differential effects of various Ca2+ antagonists. Gen Pharmacol. 1991;22:177–81.\nFleckenstein A. Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxicol. 1977;17:149–66.\nGutmann I, Wahlefeld A W. (+)Lactate determination with lactate dehydrogenase and NAD+. In: Bergmeyer HU, ed. Methods of enzymatic analysis. New York: Academic Press, 1974:1464–68.\nJaworek D, Gruber W, Bergmeyer U. Adenosine 5′-diphosphate and adenosine 5′-monophoshate. In: Bergmeyer HU. ed. Methods of enzymatic analysis. New York: Academic Press, 1974:2127–31.\nKarlsberg RP. Calcium channel blockers for cardiovascular disorders. Arch Intern Med. 1982;142:452–55.\nKelmer-Bracht AM, Ishii EL, Andrade PVM, Bracht A. Construction of a liver perfusion apparatus for studies on metabolic regulation and mechanisms of drug action. Arq Biol Tecnol. 1984;27:419–38.\nKimura S, Koide Y, Tada R, Abe J, Ogata E. Inhibitory effect of calcium channel blockers on α-adrenergic activation of glycogenolysis and calcium efflux in perfused rat liver. Endocrinol Jpn. 1981;28:69–78.\nLamprecht W, Trautschold I. Adenosine-5′-triphosphate. Determination with hexokinase and glucose-6-phosphate dehydrogenase. In: Bergmeyer HU, ed. Methods of enzymatic analysis. New York: Academic Press, 1974:2101–10.\nMarques-Silva AC, D'avila RB, Ferrari RB, Kelmer-Bracht AM, Constantin J, Bracht A. Ca2+ dependence of gluconeogenesis stimulation by glucagon at different cytosolic NAD+-NADH redox potentials. Braz J Med Biol Res. 1997;30:827–36.\nMatsumura T, Kashiwagi T, Meren H, Thurman RG. Gluconeogenesis predominates in periportal regions of the liver lobule. Eur J Biochem. 1984;144:409–15.\nNishiyama P, Ishii-Iwamoto EL, Kelmer-Bracht AM, Bracht A. Concentration dependence of the metabolic effects of diltiazem in the isolated perfused rat liver. 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