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Putrescine Treatment Reverses Α-Tocopherol-Induced

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Putrescine Treatment Reverses Α-Tocopherol-Induced Sánchez‑Sevilla et al. J Transl Med (2016) 14:307 DOI 10.1186/s12967-016-1062-y Journal of Translational Medicine RESEARCH Open Access Putrescine treatment reverses α‑tocopherol‑induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration Lourdes Sánchez‑Sevilla, Edgar Mendieta‑Condado and Rolando Hernández‑Muñoz* Abstract Background: The pre-treatment with α-tocopherol inhibits progression of rat liver proliferation induced by partial hepatectomy (PH), by decreasing and/or desynchronizing cyclin D1 expression and activation into the nucleus, activation and nuclear translocation of STAT-1 and -3 proteins and altering retinoid metabolism. Interactions between retinoic acid and polyamines have been reported in the PH-induced rat liver regeneration. Therefore, we evaluated the effect of low dosage of α-tocopherol on PH-induced changes in polyamine metabolism. Methods: This study evaluated the participation of polyamine synthesis and metabolism during α-tocopherol- induced inhibition of rat liver regeneration. In PH-rats (Wistar) treated with α-tocopherol and putrescine, parameters indicative of cell proliferation, lipid peroxidation, ornithine decarboxylase expression (ODC), and polyamine levels, were determined. Results: Pre-treatment with α-tocopherol to PH-animals exerted an antioxidant effect, shifting earlier the increased ODC activity and expression, temporally affecting polyamine synthesis and ornithine metabolism. Whereas admin‑ istration of putrescine induced minor changes in PH-rats, the concomitant treatment actually counteracted most of adverse actions exerted by α-tocopherol on the remnant liver, restituting its proliferative potential, without changing its antioxidant effect. Putrescine administration to these rats was also associated with lower ODC expression and activ‑ ity in the proliferating liver, but the temporally shifting in the amount of liver polyamines induced by α-tocopherol, was also “synchronized” by the putrescine administration. The latter is supported by the fact that a close relationship was observed between fluctuations of polyamines and retinoids. Conclusions: Putrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased retinoid levels induced by α-tocopherol. Therefore interactions between polyamines and retinol, mediated by the oxidant status, should be taken into consideration in the development of new therapeutic strategies for pathologies occurring with liver cell proliferation. Keywords: Cell proliferation, Ornithine decarboxylase, Putrescine, Lipid peroxidation, Citrulline Background tocopherol (α > β > γ > δ) [1]; however, γ-tocopherol, but The α-tocopherol is the predominant form of vitamin E not α-tocopherol, has anti-inflammatory properties [2]. in the human plasma, and the most effective antioxidant As to the effects of α-tocopherol in the diseased liver, efforts have been made to evaluate the impact of vita- min E (VE) on hepatocellular carcinoma (for review, see *Correspondence: [email protected] Hernández-Muñoz et al., Ref. [3]). Several vitamins such Departamento de Biología Celular y Desarrollo, Instituto de Fisiología as retinoic acid, ascorbic acid, vitamin D and E are known Celular, Universidad Nacional Autónoma de México (UNAM), Apdo. Postal 70‑243, 04510 Mexico City, DF, Mexico to prevent the development and progression of breast © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sánchez‑Sevilla et al. J Transl Med (2016) 14:307 Page 2 of 11 cancer [4]; indeed, retinoic acid and α-tocopherol act [20]. In this context, perioperative oral polyamine admin- synergistically in inhibiting human breast cancer cell pro- istration attenuates liver ischemia-reperfusion injury and liferation, upregulating antioxidant enzymes and proteins promotes liver regeneration [21]. involved in apoptosis [5]. Moreover, VE plays a protective Moreover, there is evidence pointing out interactions effect against cigarette smoke extract-induced cytotoxic- between retinoic acid and polyamines. The transglutami- ity in mouse embryonic lung cells, apparently involving nase activity (or transamidation function) can cross-link the mitochondrial pathway of cytochrome c-mediated polyamines to target proteins, and retinoic acid increases caspase activation [6]. In the same context, abdominal expression/activation of transglutaminase [22]. Depletion obesity is a risk factor associated with enhanced oxidative of transglutaminase activity by cadaverine enhances tox- stress; it has proved that this condition has relationships icity of retinoids [23], which can be counteracted by poly- with dietary vitamin E and A intake and genetic variants amines in several tissues [24]. of thioredoxin and catechol-O-methyltransferase [7]. In Based on the aforementioned, we sought that the this regard, we have demonstrated that the oxidant status inhibitory effect of α-tocopherol on rat liver regeneration can control the progression of partial hepatectomy (PH)- could be linked to altered ODC expression and polyam- induced rat liver regeneration [8, 9], and treatment with ine synthesis and metabolism, in a similar fashion that the α-tocopherol promotes an early termination of prim- involves disturbed ADH-mediated retinoid metabolism ing cell events, culminating in a partial inhibition of rat [12]. Therefore, it is likely that putrescine administration liver regeneration [10]. can partial or completely rescue the adverse effects of The proliferating liver after PH is highly sensible to α-tocopherol on rat liver regeneration. small dosing of α-tocopherol, which alters the pattern of signal transducer and activator of transcription (STAT) Methods protein activation, and blunts retinoic acid formation by Animals and treatments decreasing alcohol dehydrogenase (ADH) activity [11, Male Wistar rats weighing 240–270 g (3 months old 12], probing that reactive oxygen species (ROS) partici- n = 120), were housed with free access to food and water. pate in changing the cell redox state during liver cell pro- Animals were randomly divided into two groups: rats liferation [11]. Retinoic acid is synthesized in the liver receiving a daily intragastric administration of 6 IU/kg and can interact with retinoid receptors which control of α-tocopherol (approximately 4 mg/kg of VE) diluted expression of a large number of genes involved in hepatic in peanut oil (1 mL/rat), and those receiving only the processes [13]. We have demonstrated that interactions α-tocopherol vehicle [10]. After completing the treatment between α-tocopherol and retinoid compounds (retinol, with α-tocopherol, animals were again divided accord- retinal, and retinoic acid) are important for impacting rat ing to their surgical status. The 70 % PH was performed liver regeneration after PH. In this context, an anti-tumor according to the previously described [8] and sham-oper- effect of VE might be attributed to a kind of disruption ated animals provided a surgical control. Another set of of signal transduction [14], as we have already explored sham- and PH-rats, treated or not with α-tocopherol, [10, 15]. In this regard, it has been highlighted the role of received an intraperitoneally single dose of 40 mg/kg of STAT3 signaling in liver injury, steatosis, inflammation, body (0.3 mmol/kg of b.w.) of putrescine, as previously regeneration, fibrosis, and hepato-carcinogenesis, pro- reported [19]. Afterwards, rats were euthanized under posing that cytokines and small molecules that activate sodium pentobarbital anesthesia and liver samples were STAT3 in hepatocytes may readily have therapeutic ben- obtained. All manipulations were done according to our efits to treat liver diseases, including cancer [16]. Institutional Guide for Animal Experimentation and As well as retinoid metabolism, the polyamines are also Care (National University of Mexico). required for animal cell proliferation, since activation of polyamine catabolism invariably leads to growth inhibi- Liver histology and mitotic index tion [17]. The PH-induced rat liver regeneration is closely Hepatic samples from each group (after 48 h of surgery) linked to synthesis and metabolism of polyamines, and were used for light microscopy stained with hematoxylin- its inhibition resulted in decreased hepatic DNA synthe- eosin. Evaluated criteria for the analysis of morphological sis [18], which is reversed by supplementing the polyam- abnormalities were the same as previously reported [25]: ine putrescine [19]. Cellular polyamine concentrations fatty infiltration, degree of inflammation, and hepatocel- are highly regulated, since enhanced levels of these mol- lular disorganization. Mitotic index corresponded to the ecules can dysregulate polyamine homeostasis leading to number of mitotic cells in 10 microscopic fields with a toxic cellular effects. In turn, low levels of polyamines can 40× objective, and expressed as number of mitosis per inhibit
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