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WO2008037740A2 - Boisson appropriée pour retarder la dégénérescence cellulaire qui accompagne le vieillissement - Google Patents

Boisson appropriée pour retarder la dégénérescence cellulaire qui accompagne le vieillissement Download PDF

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Publication number
WO2008037740A2
WO2008037740A2 PCT/EP2007/060216 EP2007060216W WO2008037740A2 WO 2008037740 A2 WO2008037740 A2 WO 2008037740A2 EP 2007060216 W EP2007060216 W EP 2007060216W WO 2008037740 A2 WO2008037740 A2 WO 2008037740A2
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WO
WIPO (PCT)
Prior art keywords
carnosine
beverage
beverage according
ageing
epigallocatechin gallate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2007/060216
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English (en)
Other versions
WO2008037740A3 (fr
Inventor
Sara Bernasconi
Ivano Bertini
Isidoro Lucciola
Claudio Luchinat
Alessandro Quattrone
Giovanni Scapagnini
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GENALTA Srl
Original Assignee
GENALTA Srl
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Publication date
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Publication of WO2008037740A2 publication Critical patent/WO2008037740A2/fr
Publication of WO2008037740A3 publication Critical patent/WO2008037740A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to the general field of the prevention of chronic pathologies related to ageing, including central nervous system disorders and cardiovascular pathologies.
  • the invention relates to a beverage the formulation of which contains a mixture of compounds capable of specifically activating a family genes and proteins having an anti-oxidant and anti-inflammatory action, generically known as vitagenes.
  • the beverage object of the present patent application is effective in promoting the viability of cells, tissues and of the organism and is particularly effective in protecting the central and peripheral nervous system cells and the endothelial cells from deterioration, from death related to degenerative processes and to ageing in general.
  • vitagenes genes which are activated to promote cell viability, and thus the viability of tissues and of the entire organism, have recently been named vitagenes, the 'genes of life', the 'genes of youth' (Calabrese V, Butterfield DA, Scapagnini G; Stella AM, Maines MD (2006) Antiredox Redox Signal. 8 (3-4): 444-477).
  • the class of vitagenes includes inducible genes coding for proteins having an antioxidant action, such as superoxide dismutase-2 (SOD-2) or heme oxygenase-1 (HO-1 ), an antitumor action, such as type 2 detoxifying enzymes, or a damaged protein restructuring activity, such as Heat Shock Proteins (Calabrese V., Scapagnini G., Colombrita C, Ravagna A., Pennisi G., Giuffrida, Stella AM, GaIIi
  • Beverages containing substances which confer additional properties to their hydration ability alone are known.
  • saline integrators used by athletes to facilitate re-hydration and avoid hyponatremia during physical effort are very common on the market.
  • these beverage also contain rapid-absorption sugars with the purpose of providing a ready available source of energy.
  • the applicant has now developed a beverage, drinkable by anyone without restriction of quantity nor particular contraindications, having a preventive effect, on the long term of systematic intake, in retarding and partially preventing cellular degeneration due to ageing.
  • Such a beverage is based on an original formulation characterized in that it comprises epigallocathechin gallate (EGCG) and L-carnosine, possibly associated with other active components.
  • EGCG epigallocathechin gallate
  • L-carnosine possibly associated with other active components.
  • EGCG and L-carnosine in aqueous solution, have unexpectedly shown the capability to activate in a synergic manner and specifically the system of vitagenes, so increasing the cellular defenses.
  • Figure 1 is a diagram of cell viability of mouse cortical neurons treated for 12h with 15, 25, 50 and 100 ⁇ M of EGCG or L-carnosine. * P ⁇ 0.01.
  • Figure 2 is a diagram of cell viability of mouse cortical neurons exposed for 2 h. into 50 mU/ml glucose oxydase after treatment for 12 h. with 25 ⁇ M of EGCG, L-carnosine or EGCG + L-carnosine. * P ⁇ 0.01 ; ** P ⁇ 0,001.
  • Figure 3 is a diagram of HO-1 and Hsp72 mRNA steady state levels of mouse cortical neurons treated with 5, 15, 25, 50 or 100 ⁇ M of EGCG or L- carnosine. * P ⁇ 0.01.
  • Figure 4 is a diagram of heme oxygenase activity of mouse cortical neurons treated with 5, 15, 25, 50 or 100 ⁇ M of EGCG or L-carnosine. * P ⁇ 0.01.
  • Figure 5 is a diagram of cell viability of mouse cortical neurons exposed for 2 h. into 50 mU/ml glucose oxydase after treatment for 12 h. with 25 M of EGCG, L-carnosine, EGCG + L-carnosine or 10 ⁇ M ZnPP. * P ⁇ 0.01 ; * * P ⁇ 0,001 •
  • Figure 6 is a diagram of protein levels of HO-1 estimated by densitometry of bands of western blot. Neurons were treated with 25 ⁇ M of EGCG or L- carnosine and with, 25 or 50 ⁇ M of EGCG + L-carnosine. Levels of HO-1 are normalized to ⁇ -actin. * P ⁇ 0.01. ** P ⁇ 0.001.
  • the object of the present invention is a beverage consisting of an aqueous solution comprising epigallocatechin gallate and L-carnosine.
  • the applicant has found that when the beverage of the present invention is used in a systematic manner, for example in replacement of normal mineral water, a preventive protective effect on the degenerative processes induced by ageing is observed. Moreover, such a preventive effect is more effective if the administration starts before the ageing process begins.
  • the use of the beverage of the present invention is recommended to individuals of all ages, not only the elderly.
  • EGCG and L-carnosine are undoubtedly among the most interesting natural bioactive compounds for which antiaging properties have been proposed in the last years, with in vivo and in vitro data reported in hundreds of scientific publications.
  • Drug synergism occurs when two drugs interact in ways that enhance or magnify one or more effects, or side effects, of them. In other words, two drugs that produce overtly similar effects will sometimes produce exaggerated or diminished effects when used concurrently, and a quantitative assessment is necessary to distinguish these cases from simply additive action (Tallarida RJ. Drug synergism: its detection and applications. J Pharmacol Exp Ther. 2001 Sep;298(3):865-72).
  • the biological effects on which we are focusing are positive modulation of neuronal survival and positive modulation of neuronal repair and plasticity, both in terms of single neurons and of neuronal populations.
  • synergism when translated in terms of molecular events, relates often to the ability of the two bioactive substances producing synergism to enhance cell functions by eliciting pathways which are originally distinct but converge at the higher levels in elementary cell activities concurring to the same major cell program.
  • a and B there are two ways for a cell to avoid death controlled by two unrelated or minimally related pathways A and B, enhancement of only A or B by two compounds is likely to produce at the highest doses saturation of the pathway, and therefore a combined effect which is less than additive.
  • ROS reactive oxygen species
  • Applicant therefore decided to use the combination of the two compounds both at 25 ⁇ M before exposing the cells for 2 h in to glucose oxydase (50 mU/ml).
  • the glucose oxidase oxidant system generates hydrogen peroxide at a constant rate and it is known to produce cellular injury in vitro.
  • cells were washed and exposed to complete medium containing 1 % Alamar blue for 5 h according to manufacturers' instruction in order to assess cell viability. After the incubation period, optical density in the medium of each well was measured using a plate reader.
  • the assay is based on detection of the metabolic activity of living cells using a redox indicator, which changes from oxidized (blue) to reduced (red) form.
  • the intensity of the red colour is proportional to the viability of cells.
  • Treatment of cells for 2 h with glucose oxidase resulted in 27% of residual cell viability (Fig. 2).
  • Exposure of cells for 12 h to EGCG 25 ⁇ M reduced glucose oxidase-mediated damage, rising cell viability to 51 % (24% more than the control).
  • L-carnosine at 25 ⁇ M concentration was less effective in protecting cells by oxidative damage, giving a viability of 33% (7% more than the control).
  • the association of the two compounds protected cells in a synergistic way, giving a rate of neuronal survival of 76% (49% more than the control, which is over the expected additive effect of 31 %).
  • Fig. 3 shows HO-1 and Hsp72 mRNA steady state levels following administration of increasing doses of EGCG and L-carnosine.
  • EGCG elicits a dose-dependent increase of HO-1 mRNA, measured with respect to the not-inducible HO-2 paralog gene, which reaches the maximum (about 8 fold) at 25 ⁇ M, and decreases subsequently at 50 and 100 ⁇ M.
  • L-carnosine is instead much less active in inducing HO-1 gene expression at the same concentrations, and reaches the maximum again at 25 ⁇ M.
  • Hsp72 gene expression which is normalized on the levels of the paralog, not-inducible gene Hsc70.
  • EGCG administration gives a dose-dependent enhancement till the last concentration, 100 ⁇ M, at which we know that cell viability is decreased of 25% (see Fig. 1 ).
  • the 25 ⁇ M dose known to have no effects on cell viability, does not enhance Hsp72 gene expression in a statistically significant way.
  • L-carnosine at the same concentration, induces an increase of hsp72 of about 8-fold.
  • HO-1 gene expression measured at the mRNA level corresponded to an equivalent increase of heme oxygenase activity, it was measured this activity at the same EGCG and L-carnosine doses after 6 and 24 hours from the administration.
  • the pattern of increase of activity was comparable to the results obtained looking at the cellular mRNAs, confirming the functional significance of the data obtained by the real time PCR determinations (Fig. 4).
  • L-carnosine could be also in terms of cooperative increase in the levels of HO-1 , which is primarily induced by EGCG.
  • the aforesaid components are preferably contained in the beverages according to the invention in the following concentrations: epigallocatechin gallate 50-70 mg/L
  • the beverage of the present invention further contains also folic acid 0.1 -0.15 mg/L
  • Zn 2+ is contained in the beverage of the present invention in the form of zinc citrate.
  • Mg 2+ is contained in the beverage of the present invention as magnesium gluconate.
  • the new beverage may also contain pyridoxine, preferably in the form of hydrochloride, in addition to the aforesaid components.
  • pyridoxine is contained in the beverage in a concentration from 1 .0 to
  • a particularly preferred formulation of the beverage of the present invention comprises: epigallocatechin gallate 60 mg/L L-carnosine 100 mg/L folic acid 0.1 mg/L
  • the beverage according to the present invention may further comprise ascorbic acid, preferably in a concentration from 60 to 90 mg/L.
  • the beverage of the present invention may contain components which make it specifically intended for male or female consumers, given the different and specific causes of ageing in the two cases.
  • the beverage of the present invention is intended for use in a female population, it will preferably further contain biotin, preferably in a concentration from 0.07 to 0.1 1 mg/L and ferulic acid, preferably in concentration from 60 to 125 mg/L, in addition to the aforesaid components.
  • biotin preferably in a concentration from 0.07 to 0.1 1 mg/L
  • ferulic acid preferably in concentration from 60 to 125 mg/L, in addition to the aforesaid components.
  • a particularly preferred formulation of this type of beverage intended for female consumers comprises: epigallocatechin gallate 60 mg/L
  • beverage of the present invention is intended for use in a male population, it will further contain K + , preferably in the form of potassium citrate, and selenium, preferably in the form of selenomethionine.
  • K + is contained in a concentration from 2.5 to 20 mg/L and selenium is contained in a concentration from 0.02 to 0.05 mg/L.
  • a particularly preferred formulation of this type of beverage intended for male consumers comprises: epigallocatechin gallate 60 mg/L
  • the beverage of the present invention may further contain food-grade excipients. Basing on the preliminary studies which have demonstrated the synergic effect between EGCG and L-carnosine the applicant has conducted a wide research on cultured rat astroglial and endothelial cells, by exposing them to various concentrations (10, 50 and 100 ⁇ l/ml) of the aforesaid beverage according to the invention for 6, 12 and 24 hours. The study has shown the ability of the beverage according to the invention to strongly induce the expression of heme oxygenase-1 (HO-1 ), a highly active protein in oxidative stress defense (Poon HF, Calabrese V, Scapagnini G, Butterfield DA (2004) J.
  • HO-1 heme oxygenase-1
  • Heme oxygenase is the main enzyme for the catabolism of heme which is degraded into biliverdin-bilirubin, carbon monoxide (CO) and iron.
  • CO carbon monoxide
  • biliverdin and bilirubin have powerful anti-oxidant properties (Scapagnini G, D'Agata V, Calabrese V, Pascale A, Colombrita C, Alkon D, Cavallaro S. (2002) Brain Res.
  • CO performs fundamental signaling functions and behaves as a gaseous modulator in vessel function
  • Abraham NG Scapagnini G, Kappas A. (2003) J Cell Biochem. 90(6):1098-11 1 1
  • iron is a known gene regulator (Smith M. A., Wehr K., Harris P. L R., Siedlak S. L, Connor J. R., and Perry G. (1998) Brain Res. 788, 232-236).
  • HO-1 decreases the levels of heme which is intrinsically a powerful inducer of lipid peroxidation and formation of free radicals.
  • the beverage according to the invention was capable of considerably activating the expression of Hsp70, a heat shock protein involved in the regeneration of damaged proteins.
  • the preparation of the beverage of the present invention displayed considerable difficulties related to the instability of its components in water. It is therefore a further aspect of the present invention to provide the preparation procedure of a beverage adapted to retard the cellular degeneration which accompanies ageing, consisting of an aqueous solution comprising epigallocatechin gallate, L-carnosine, and in case other active components as above indicated characterized by methods which allow to solubilize the aforesaid sensitive substances either avoiding or limiting their contact with oxygen, with light and with degradation reaction catalyzing metals.
  • Mg 2+ (as gluconate) 100 mg/L citric acid 1 ,000 mg/L
  • the commercial product TEAVIGO ® (RES PHARMA) was used as epigallocatechin gallate.
  • the preparation of the aforesaid beverage was made according to the steps of the procedure described hereinafter.
  • the impurities of the transition metals were removed from the water by means of an appropriate process and/or the use of a chelating agent.
  • the water treated in this manner was then placed inside a closed system away from light.
  • L-carnosine, folic acid, zinc citrate and magnesium gluconate were added to the solution.
  • the mixture was mixed until all of the components where completely dissolved and then citric acid was added.
  • Epigallocatechin gallate was finally added and, upon complete solubilisation, the water was sterilised by micro-filtration.
  • Mg 2+ (as gluconate) 100 mg/L pyridoxine (as hydrochloride) 1 mg/L biotin 0.075 mg/L ferulic acid 125 mg/L
  • the commercial product TEAVIGO ® (RES PHARMA) was used as epigallocatechin gallate.
  • Mg 2+ (as gluconate) 100 mg/L pyridoxine (as hydrochloride) 1 mg/L
  • the commercial product TEAVIGO ® (RES PHARMA) was used as epigallocatechin gallate.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nutrition Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Botany (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Non-Alcoholic Beverages (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Tea And Coffee (AREA)

Abstract

La présente invention a pour objet une boisson appropriée pour retarder la dégénérescence cellulaire qui accompagne le vieillissement, ladite boisson comportant du gallate d'épigallocatéchine et de la L-carnosine, le cas échéant associés à d'autres composants actifs.
PCT/EP2007/060216 2006-09-28 2007-09-26 Boisson appropriée pour retarder la dégénérescence cellulaire qui accompagne le vieillissement Ceased WO2008037740A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2006A001854 2006-09-28
IT001854A ITMI20061854A1 (it) 2006-09-28 2006-09-28 Bevanda atta a rallentare la degenerazione cellulare che accompagna l'invecchiamento

Publications (2)

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WO2008037740A2 true WO2008037740A2 (fr) 2008-04-03
WO2008037740A3 WO2008037740A3 (fr) 2008-05-15

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IT (1) ITMI20061854A1 (fr)
WO (1) WO2008037740A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014114496A3 (fr) * 2013-01-28 2014-12-24 Unilever N.V. Composition de soins de peau
WO2015191533A1 (fr) * 2014-06-13 2015-12-17 East Carolina University Méthodes d'utilisation de carnosinol et d'analogues de celui-ci
US9579347B2 (en) 2012-10-04 2017-02-28 Abbott Laboratories Methods for enhancing the effect of EGCg on mitigating skeletal muscle loss
FR3056381A1 (fr) * 2016-09-26 2018-03-30 Futur Optimal Composition comprenant de la carnosine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005527234A (ja) * 2002-05-31 2005-09-15 スオメン・ラビットセムスインスティトゥーティ・オイ 飲料組成物及び飲料の製造方法
DE10326822A1 (de) * 2003-06-11 2005-01-05 Herzpharma Vita-Check Diagnosegeräte GmbH Mittel zur Nahrungsergänzung, dieses Mittel enthaltende pharmazeutische Präparate und Verwendungen des Mittels
EP1667699B1 (fr) * 2003-10-03 2010-08-18 Green Meadows Research. LLC. Compositions contenant des extraits de lotus et des donneurs de méthyle
WO2006026713A2 (fr) * 2004-08-31 2006-03-09 Tracie Martyn International, Llc Compositions topiques contenant de la benfotiamine et de la pyridoxamine
CA2546464A1 (fr) * 2005-05-04 2006-11-04 Richard Wachsberg Application sequentielle de formulations orales et topiques pour traiter les rides et autres dommages subis par la peau

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9579347B2 (en) 2012-10-04 2017-02-28 Abbott Laboratories Methods for enhancing the effect of EGCg on mitigating skeletal muscle loss
WO2014114496A3 (fr) * 2013-01-28 2014-12-24 Unilever N.V. Composition de soins de peau
EA028472B1 (ru) * 2013-01-28 2017-11-30 Юнилевер Н.В. Композиция по уходу за кожей
WO2015191533A1 (fr) * 2014-06-13 2015-12-17 East Carolina University Méthodes d'utilisation de carnosinol et d'analogues de celui-ci
FR3056381A1 (fr) * 2016-09-26 2018-03-30 Futur Optimal Composition comprenant de la carnosine

Also Published As

Publication number Publication date
ITMI20061854A1 (it) 2008-03-29
WO2008037740A3 (fr) 2008-05-15

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