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    • 专利摘要:
    The invention relates to the use of Selenium as sodium selenite, of formula (Na 2 SeO 3 ) which is the most common inorganic form of nutritional supplement, derivatives or any of its combinations in the preparation of a nutritional supplement, drink and/or medication for the prevention or repair of cell damage, specifically the prevention of DNA damage caused by alcohol. It has its application in the pharmaceutical sector, specifically in that of functional foods. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2664444A1
    申请号:ES201600901
    申请日:2016-10-19
    公开日:2018-04-19
    发明作者:Maria Luisa OJEDA MURILLO；Fátima NOGALES BUENO；Javier DIAZ CASTRO；Maria Luisa MURILLO TARAVILLO；Olimpia CARRERAS SÁNCHEZ
    申请人:Universidad de Sevilla；
    IPC主号:
    专利说明:

     Use of sodium selenite to make a nutritional supplement, a drink or a medicine to repair the damage in the ONA caused by excessive consumption of acute alcohol. Object of the invention The invention relates to the use of Selenium as sodium selenite, of the formula (Na2Se03) which is the most common inorganic form of nutritional supplement, derivatives or any combination thereof in the preparation of a nutritional supplement, beverage and / or medicament for the prevention or repair of cellular damage, specifically 10 of the prevention of ONA damage caused by alcohol. It has its application in the pharmaceutical sector, specifically in that of functional foods. State of the art The term binge drinking (BO) or bottle, in Spain, is associated with an acute alcohol intake of 4 (women) or 6 (men) drinks, in a time of 4-6 hours, 15 reaching levels of 0.08 gIL blood alcohol, this pattern being interspersed for a few days of withdrawal. This pattern of consumption produces numerous social consequences and is related to various pathologies, including alterations in the central nervous system and various cardiovascular diseases, some of them related to oxidative stress. 20 The body has three pathways through which alcohol metabolism occurs: alcohol dehydrogenase (AOH), the microsomal oxidative system of ethanol (SMOE) and catalase (CAT) (1), each of these pathways leads to formation of reactive oxygen species (EROs) and, therefore, to the imbalance of the oxidative state (2). In the acute consumption type BO there is a greater activation of the cytochrome P450 2E1 (CYP2E1), isoform of the SMOE, which induces a greater production of free radicals that saturates the body's antioxidant systems, favoring the oxidation of the biomolecules and leading to finally in cellular damage (3), altering the synthesis and methylation of ONA (4). Specifically, our research group (CTS-193) has found an imbalance of hepatic glutathione (GSH) 30 and a decrease in the activity of glutathione peroxidase (GPx), increases in CAT and superoxide dismutase (SO O) and a increase in NAPH oxidase in a new model of adolescent rats exposed to BO (5). We have also proven that chronic alcohol "per se '; and not only malnutrition, producesSelenium deficiency (Se), because when generating reactive oxygen species (ROS) the body consumes Se to synthesize the antioxidant enzyme GPx (6). Selenium (Se) is an essential micronutrient, present in numerous foods that have been given an important role as an antioxidant since it is part of more than 5 of 25 selenoproteins, among which is the glutathione peroxidase family (GPx) (7). It is postulated that the oxidative stress is modulated, mainly, through the different GPxs, reducing the levels of hydrogen peroxide, lipids and hydroperoxides phospholipids (8). For this reason, among others, the deficiency of Se has been related to various alterations, such as cancer, the deterioration of immune functions, the development of cardiovascular diseases and alcoholic disease (9), among others. Some of them related to oxidative stress and stability of ONA. Oe fact, an increase in genomic instability, inherent or induced by some exogenous factor has been considered as one of the main factors that lead to a neoplastic transformation (10). 15 In this context, recently, this research group has shown that in adolescent rats that consume alcohol in the form of SO, there is a decrease in ONA stability, in addition to Se homeostasis is also altered, without malnutrition in these rats. Thus a depletion of Se in serum and liver is observed proportional to a lower activity of GPx3 in serum and GPx1 in liver. 20 All this could be related to the low expression of NFKS in the liver, a transcriptional factor that plays a very important role in inflammatory and apoptotic processes (11). Few studies refer to the problem of the "bottle" phenomenon of young adolescents on the state of Se and selenoproteins, and its antioxidant action against alcohol. After reviewing the literature we have not found studies that indicate a supplement of Se to young people with bottle alcohol consumption, and even less there is no evidence that the action is taken to prevent cell damage, specifically damage to the ONA, avoiding rupture of the double helix of the ONA caused by an acute consumption type SO, with the consequent benefit that society would suppose this economic and effective supplementation to the young people who make the bottle, which could, finally, avoid an organic damage in adolescence submitted to the bottle, being able to be beneficial for the rest of your life. In the literature consulted, we have found only 4 patents related to the methods of administration of Se. However, we have not found any patent dedicated to the selenium supplement andthe intake of acute alcohol type bottle. As for the published works, there are some who report that the neuroprotective effect has been carried out and others that conclude that the oxidative stress caused by alcohol is prevented, increasing antioxidant enzymes. The difference of these works with the one presented in the Report, 5 is that the form and route of administration of alcohol as well as the dose used is very different from that used by our group in this acute consumption "bottle type", and that none of these works measures the damage of the ONA and even less how a supplement of Se to young people can reverse this damage in the ONA, caused by the bottle, through an increase in the antioxidant enzyme GPx, which decreases the 10 EROs, and / or through glutathione (GSH), of the methionine cycle. All the other works found, that work with this supplement and the state of acute alcohol, have been those published and signed by our group (5,6,11,12-18) For all this in this Invention we present the supplement of Se, in the form of sodium selenite, as a therapeutic alternative against oxidative damage in 15 biomolecules and, mainly, in the prevention or repair of cellular damage, manifested by the instability of ONA caused by excessive consumption of acute alcohol, which could have an impact on organic damage References 20 1. Lieber CS. Alcohol and hepatitis C. Alcohol Res Health. 2001; 25 (4): 245-54. 2. Zima T, Fialová L, Mestek O, Janebová M, Crkovská J, Malbohan 1, Stípek S, Mikulíková L, Popov P. Oxidative stress, metabolism of ethanol and alcohol-related diseases. J Biomed Sci. 2001 Jan-Feb; 8 (1): 59-70 3. Artun BC, Küskü-Kiraz Z, Güllüoglu M, Cevikba§ U, Kor; ak-Toker N, Uysal M. The 25 effect of carnosine pretreatment on oxidative stress and hepatotoxicity in binge ethanol administered rats. Hum Exp Toxicol 2010; 29: 659-665. 4. Halsted CH, Villanueva JA, Devlin AM. Folate deficiency, methionine meta bolism, and alcoholic liver disease. Alcohol. 2002 Jul; 27 (3): 169-72. 5. Nogales F, Rua RM, Ojeda ML, Murillo ML, Carreras O. Oral or intraperitoneal binge 30 drinking and oxidative balance in adolescent rats. Chem Res Toxicol 2014; 27: 1926-1933.6. Ojeda ML, Nogales F, Vázquez B, Delgado MJ, Murillo ML, Carreras O (2009) Alcohol, gestation and breastfeeding: selenium as an antioxidant therapy. Alcohol Alcohol 2009; 44: 272-277. 7. Carreras O, Ojeda ML, Nogales F. Selenium Dietary Supplementation and Oxidative 5 Balance in Alcoholism. In. Molecular aspect of Alcohol and Nutrition., Edited by Vinood B. Patel, PhD Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK Academic Press, 2016. 8. Rayman MP. The import ce of selenium to human health. Lancet 2000 Jul 15; 356 (9225): 233-41. 10 9 Tinggi U. Selenium: its role as antioxidant in human health. Environ Health Prev Med. 2008 Mar, '13 (2): 1 02-8. 10. EI-Bayoumy K. The protective role of selenium on genetic damage and on cancer. Mutat Res. 2001 Apr 18; 475 (1-2): 123-39. 11. Ojeda ML, Rua RM, Murillo ML, Carreras O, Nogales F. Binge drinking during 15 adolescence disrupts Se homeostasis and its main hepatic selenoprotein expression. Alcohol Clin Exp Res. 2015 May; 39 (5): 818-26. 12. Jotty K, Ojeda ML, Nogales F, Murillo ML, Carreras O. Selenium dietary supplementation as a mechanism to restore hepatic selenoprotein regulation in rat pups exposed to alcohol. Alcohol 2013; 47: 545-552. 20 13. Nogales F, Ojeda ML, Fenutría M. Murillo ML, Carreras o. Role of selenium and glutathione peroxidase on development, growth, and oxidative balance in rat offspring. Reproduction 2013 Oct 29; 146 (6): 659-67. 14. Ojeda ML, Nogales F, Murillo ML, Carreras O. Selenium or selenium plus folic acid-supplemented diets ameliorate renal oxidation in ethanol-exposed pups. Alcohol Clin 25 Exp Res. 2012 Nov; 36 (11): 1863-72. 15. Nogales F, Ojeda ML, Delgado MJ, Jotfy K, Diaz Castro J, Murillo ML, Carreras O. Effects of antioxidant supplementation on duodenal Se-Met absorption in ethanol-exposed rat offspring in vivo. J Reprod Dev. 2011 Dec; 57 (6): 708-14. 16. Delgado MJ, Nogales F, Ojeda ML, Murillo ML, Carreras o. Effect of dietary 30 selenite on development and intestinal absorption in offspring rats. Life Sci. 2011 Jan 17; 88 (3-4): 150-5. 35 17. Ojeda ML, Jotfy K, Nogales F, Murillo ML, Carreras O. Selenium or selenium plus folic acid intake improves the detrimental effects of ethanol on pups' selenium balance. Food Chem Toxicol. 2010 Dec; 48 (12): 3486-91.18. Jotty K, Ojeda ML, Nogales F, Rubio JM, Murillo ML, Carreras O. Selenium tissue distribution changes after ethanol exposure during gestation and lactation: selenite as a therapy. Food Chem Toxic. 20090ct; 47 (10): 2484-9. 5 Description of the figures Figure 1. Kinds of possible Comets (Or for absence of damage and 4 for maximum damage). Figure 2. Effects of the Selenium Supplement on the Percent of Fluorescence in the Head of COMET (representing the percentage of ONA in the head) in 10 peripheral blood lymphocytes after Binge drinking. The results are expressed as the mean ± SEM. Statistical significance: A vs C: *** P <0.001; ASE vs A: +++ P <0.001 Figure 3. Effects of the Selenium Supplement on the Percentage of Fluorescence in Tail (representing the percentage of ONA in the tail) in peripheral blood lymphocytes after Binge drinking. The results are expressed as the mean ± SEM. 15 Statistical significance: A vs C: *** P <0.001; ASE vs A: +++ P <0.001 Figure 4. Effects of Selenium Supplement on OTM in peripheral blood lymphocytes after Binge drinking. The results are expressed as the mean ± SEM. Statistical significance: A vs C: *** P <0.001; ASE vs A: +++ P <0.001 Figure 5. Effects of Selenium Supplement on hepatic Glutathione 20 (GSH) levels (iJmol / g tissue) after Binge drinking. The results are expressed as the mean ± SEM. Statistical significance: A vs C: *** P <0.001; ASE vs A: +++ P <0.001 Figure 6. Simplified version of the effects produced by Binge drinking and Selenium on methionine metabolism. Binge drinking inhibits 5-methyltetrahydrofolate, Homocysteine, Cystathionine and GSH and inhibits the passage of 25 methionine to S-adenosylmethionine. Selenium (Se) favors the production of GSH. Description of the invention The invention relates to the use of sodium selenite, Na2Se03. for the preparation of a nutritional supplement, a drink and / or a medicine to combat damage in theSomatic DNA that accompanies excessive consumption of acute alcohol, especially in adolescents. Selenium, in the form of sodium selenium, is considered as an essential micronutrient or trace element, because it cannot be synthesized by the organism but is essential for its normal functioning. Selenium is found in a wide range of dietary sources and its main function is to protect the body against oxidative damage, since it is part of Glutathione peroxidase (GPx). However, in certain pathologies in which there is selenium deficiency, among others the consumption of chronic or acute alcohol, supplementation with this micronutrient is justified since these deficiencies affect the antioxidant enzymes and can cause damage at the level of lipid peroxidation , protein and even in DNA stability, with double helix rupture, which is one of the most severe types of DNA damage. In the invention presented, it has been supplemented with sodium selenite (Na2Se03) concomitantly with an acute consumption of alcohol, the bottle, reversing the oxidative damage caused by the bottle, in DNA. Specifically, the DNA rupture returns to control values at the level of the head of the DNA (Head% DNA), of the tail (Tail% DNA) and of the Olive Moment of the OTM tail (Olive Tail Moment), avoiding cell damage and Future organic damage. The mechanism of action could be related to the increase of the GPx antioxidant enzyme, which decreases EROs, and / or the methionine cycle through glutathione (GSH). 20 Supplementation with Se, in the form of sodium selenite, simultaneous with an acute consumption of binge drinking or bottle type, decreases the percentage of fluorescence measured in the tail (Tail) and in the OTM of blood lymphocytes at control levels and increases the percentage of the head (Head) demonstrating that Selenium has a great preventive power in the deleterious effect of alcohol on the stability of DNA, being able to reverse the breakage of the double helix of DNA and with it the cellular damage, finally being able to avoid organic damage, of worse consequences. Specifically, this effect could be related to the increase in GPx or the role that is played in the methionine cycle and DNA methylation, since it affects the levels of hepatic GSH, an intermediary of this cycle. The supplement is increased by 30 levels of hepatic GSH favoring DNA methylation. Thus, a first aspect of the invention relates to the use of Selenium as sodium selenite of formula (Na2Se03) which is the most common inorganic form of nutritional supplement, derivatives or any combination thereof in the preparation of anutritional supplement, drink or medicine for the prevention or repair of cell damage, in particular the prevention of DNA damage caused by alcohol. The term "derivative" includes both pharmaceutically acceptable compounds, that is derivatives of the formula (Na2Se03), which can be used for the preparation of a medicament, as well as pharmaceutically unacceptable derivatives that can be used in the preparation of pharmaceutically derived derivatives. acceptable. In the present invention the term "nutritional supplement" would correspond to that substance ingested that the organism would need to supplement the diet. The term "medicine" refers to any substance or combination of substances that is presented as having properties for the treatment or prevention of diseases or that can be used or administered to humans in order to restore, correct or modify physiological functions (LAW 29/2006, of July 26, on guarantees and rational use of medicines and health products. BOE 178,2006) By "cellular damage" in the invention refers to any functional or structural abnormality of diverse etiology that affects to the stability of biomolecules between them, DNA and that could eventually lead to organic damage so far not studied. Sodium selenium, nutritional supplement, derivatives or the like, can be administered in a pure form to a mammal and preferably to a human, or it can be administered as part of a more complex composition, where the amount would be that which would show the desired effect, being in this case an effective amount, from 0.25 to DA ppm of Selenium, although preferably DA ppm. For all this, a person who needs sodium selenium can ingest it in the form of a pharmaceutical composition or as part of a dietary supplement or as a food matrix in which this compound or its derivatives are added in an effective amount. This is the case of: Brazil nuts, sunflower seeds, fish (tuna, sardines, sole, salmon), shellfish, meats or viscera, eggs, mushrooms, grains, onions, etc. The nutritional requirements of Selenium are directly related to the 30 adverse consequences of overexposure and deficiency of selenium in body metabolism, being of great relevance for the need to saturate its antioxidant capacity, as well as other metabolic disorders such as imbalances ofthyroid hormones, cardiovascular diseases, cancer or HIV or alcoholic disease. The nutritional requirement of Selenium is based on the recommendations of daily intake of Selenium, which in animal models, the North American Research Council 5 (NRC) 2007, has established an intake between 0.1 ppm to 0.15 ppm of selenium as necessary to maintain the maximum performance of hepatic glutathione peroxidase activity and support the optimal growth of laboratory rats. 10 Embodiment of the invention An example is detailed below by tests carried out on how the consumption of selenium in the form of selenite is able to prevent damage or breakage of the DNA associated with the bottle. For this, integrity in eukaryotic cell gene expression with identical properties to other somatic cells has been studied from the evaluation of integrity in DNA. Thus the effects that alcohol and selenium supplements cause on the lymphocyte DNA may reflect and represent, to some extent, the effects of ethanol and Se on the body. It is a technique widely used in the scientific community to evaluate the genotoxicity of alcohol and is also used to monitor possible DNA damage in epidemiological studies. The invention was carried out by designing a prospective experimental study, in which for the performance of the work the animals (rats) were distributed, randomly, in four experimental groups: C: adolescent rat fed ad libitum with yagua food and intraperitoneal (IP) administration of isotonic saline (SSI); A: adolescent rat fed ad libitum with food and water and on its corresponding days a solution of 20% (v / v) IP ethanol in isotonic saline (3g / Kg / day) is administered; CSE: adolescent rat fed ad libitum with diet supplemented with Se and water and on the corresponding days IP is given an SSI; ASE: adolescent rat fed ad libitum with diet supplemented with Se and water and on its corresponding days a solution of 20% (v / v) IP ethanol in isotonic saline (3g / Kg / day) is administered.The food supplied to the animals consisted of a semi-synthetic basic diet (2014 Teklad Global 14% Protein Rodent Maintenance Diet, Harlan Laboratories, Barcelona, Spain) that covered all nutritional and energy needs, containing 0.23 ppm of Se and which was supplied ad libitum The S groups supplemented with Se (CSe and ASe) received selenium, in the drinking water, in the form of sodium selenite pentahydrate until reaching 0.4 ppm of Se throughout the experimental period. The alcoholization method used has been intraperitoneal administration, three days per week and for three weeks, of ethanol (3 g / kg) in 20% saline solution (v / v). At the end of the procedure, 28% w / v urethane (0.5 ml / 100 g weight) is anesthetized and the peripheral blood is extracted by puncturing the caudal vein. The alkaline Comet variant was used to determine the DNA damage. The procedure consists in preparing glass slides with agarose (1% HMP with distilled H202). Subsequently, lymphocytes were isolated by treatment of the peripheral blood sample of the caudal vein with phosphate buffered saline (PBS). Histopaque was deposited at the bottom of the eppendorf and centrifuged to obtain a pink phase that was treated by resuspending it in a second batch of eppendorffs to eliminate the Histopaque that proved to be toxic to the cell. Finally, samples are centrifuged until obtaining isolated lymphocytes. 20 These are resuspended in 1% LMP agarose in PBS whereby the cells are embedded in agarose and lysis of the plasmatic membranes is carried out, with lysis solution and Triton X, so that the nucleoid with the material is exposed genetic, where possible damage was assessed. And an electrophoresis (alkaline solution) was carried out, neutralization, to stop the basic attack and fluorescent staining with a fluorescent marker or 4 ', 6-diamino-2-phenylindole (DAPI) and observation with the Leika DMLS fluorescence microscope. To finally proceed to its quantification, where 100 comets were counted for each gel, framing them within each of the 5 classes of possible Comets (Or for absence of damage and 4 for maximum damage (Figure 1). A greater number of fragments of DNA in the tail indicated a greater damage in this biomolecule 30. Still, for a more reliable analysis the Hitachi camera was used using the Kinetic Imaging Komet 5.5 imaging software, which allowed us to use the following parameters for the quantification of DNA damage : the percentage of fluorescence in the tail of the comet (representing the fraction of DNA in it), percentage of DNA in the head (representing the fraction of genetic material in thesame) and the Olive Tail Moment (defined as the product of the tail length of the comet and the fraction of ONA in it). OTM = [Average of the tail-half of the head] x% of ONA in tail / 100 The results were analyzed by a statistical program (GraphPad InStat 3, CA, 5 USA) by analysis of variance. Once the one-way ANOVA was performed, a p <0.001 was obtained for the three parameters studied. Subsequently, for the multiple comparisons between the means, the Tukey-Kramer test is performed. Figure 2 shows a decrease in the percentage of ONA in the head (% Head ONA) in animals subjected to excessive consumption of acute alcohol with respect to their controls. However, a Se concomitant supplement to the bottle restores these% Head ONA values. As can be seen in Figures 3 and 4, the percentage of ONA in the tail (% Tail ONA) increases after alcohol exposure, with respect to its controls. The Olive Tail Moment (OTM) was also extremely increased in the alcohol group, in relation to the controls. We have also verified as a selenium selenium supplement, binge drinking or bottle, can revert the% of ONA in the tail and the OTM to control values. This index is particularly useful, since it provides the most stable measure to determine the damage in the ONA in relative terms, because it presents a greater degree of uniformity in 20 quartile dispersions. In addition, glutathione (GSH) was determined as an endogenous antioxidant and methylation product, showing that the supplement of Se concomitantly with an intake of bottle-type alcohol increases glutathione levels (Figure 5). In conclusion, it is revealed that the excess consumption of acute alcohol, alters the stability of the genetic material, at different levels related to the methionine cycle (Figure 6), causing damage to the ONA and therefore increases the frequency of breakage in the double helix, which increases the percentage of ONA in the tail. The intake of alcohol, binge drinking or bottle type, and a simultaneous selenium supplement could reverse the instability of the genetic material, with the corresponding breakage of the ONA, thus decreasing the breakage in the double helix which causes the ONA percentage to decrease in the queue. So Se, in the form of sodium selenite, has a beneficial effect on the stability of ONA in animals5 10 15 20 25 with binge drinking or bottle alcohol intake probably due to its direct antioxidant action or to favor DNA methylation through GSH synthesis (Figure 6). 
    权利要求:
    Claims (4)
    [1]
    5 10 15 20 25 Claims 1. Use of Sodium Selenite containing from 0.25 to 0.4 ppm of Selenium, to prepare a composition to treat the damage in ONA caused by excessive acute alcohol consumption.
    [2]
    2. Use of sodium selenite containing from 0.25 to 0.4 ppm of selenium, to make a composition according to claim 1, where composition 1 is a nutritional supplement.
    [3]
    3. Use of sodium selenite containing from 0.25 to 0.4 ppm of selenium, to make a composition according to claim 1, where composition 1 is a drink.
    [4]
    4. Use of sodium selenite containing from 0.25 to 0.4 ppm of selenium, to make a composition according to claim 1, where composition 1 is a medicine.
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