ITRM20120368A1 - COMPOSITION ABLE TO ACT ON THE MYOD MUSCLE REGULATOR AND OSTEOBLASTI PROLIFERATION - Google Patents
COMPOSITION ABLE TO ACT ON THE MYOD MUSCLE REGULATOR AND OSTEOBLASTI PROLIFERATION Download PDFInfo
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/20—Milk; Whey; Colostrum
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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Description
DESCRIZIONE DESCRIPTION
CAMPO DELL'INVENZIONE FIELD OF THE INVENTION
L'invenzione nel campo della chimica-farmaceutica descrive una composizione per aumentare contemporaneamente il numero di molecole di RNA messaggero di geni codificanti il fattore miogenico 1 (MyoD) e contemporaneamente il numero di osteoblasti. La presente invenzione rientra nel campo dei prodotti chimici naturali che possono trovare applicazione farmaceutica, nutrizionistica e dietetica, nutraceutica e alimentare. The invention in the field of pharmaceutical chemistry describes a composition for simultaneously increasing the number of messenger RNA molecules of genes encoding myogenic factor 1 (MyoD) and simultaneously the number of osteoblasts. The present invention falls within the field of natural chemicals which can find pharmaceutical, nutritional and dietetic, nutraceutical and food applications.
STATO DELL'ARTE STATE OF THE ART
Negli stati di affaticamento fisico e psìchico, cioà ̈ l'incapacità di mantenere lo sforzo fisico, scatta un meccanismo di difesa contro i danni a muscoli e cervello. Si possono distinguere due tipi di sforzo, una a carico del sistema periferico che coinvolge i muscoli e l'altro a livello centrale cioà ̈ cerebrale. In tutti questi casi si osserva una diminuzione, della fosfocreatina muscolare, un accumulo di idrogenioni (H<+>), un esaurimento di glicogeno a livello muscolare e una ipoglicemia derivante dall'aumento della frazione libera di triptofano (1). In states of physical and mental fatigue, ie the inability to maintain physical effort, a defense mechanism is triggered against damage to muscles and brain. Two types of effort can be distinguished, one on the peripheral system which involves the muscles and the other on the central level, ie the brain. In all these cases there is a decrease in muscle phosphocreatine, an accumulation of hydrogen ions (H <+>), a depletion of glycogen in the muscles and a hypoglycemia resulting from the increase in the free fraction of tryptophan (1).
Tutte queste attività richiedono consumo di ATP aerobico per esempio in caso di lunghe marce la richiesta può arrivare fino al 100% di consumo. Anche la senilità , la sedentarietà , le malattie vascolari e le infezioni virali hanno lo stesso risultato. All these activities require aerobic ATP consumption, for example in the case of long journeys the demand can reach up to 100% consumption. Senility, sedentary, vascular disease and viral infections also have the same result.
L'ipoglicemia induce il senso di stanchezza anche cerebrale per la mancanza di glucosio al cervello. L'ipoglicemia stimala l'uso di acidi grassi aumentando la rimozione dai siti di accumulo. La rimozione anomala induce l'aumento dei livelli di triptofano cerebrale, che non si lega all'albumina e induce il senso di stanchezza fisica. Hypoglycemia also induces a sense of brain fatigue due to a lack of glucose in the brain. Hypoglycemia stimulates the use of fatty acids by increasing removal from accumulation sites. The abnormal removal induces an increase in the levels of brain tryptophan, which does not bind to albumin and induces a sense of physical fatigue.
Per quanto riguarda l'attività fisica, specie di uno sportivo, occorre una dieta in grado di fornire le quantità adeguate di acqua, calorie, proteine, grassi, carboidrati, vitamine e minerali. La richiesta energetica dovrebbe essere modulata per ogni tipo di atleta e per il tipo di sforzo che egli compie. Per quanto riguarda l'uso delle proteine, bisogna ricordare che i protidi sono sostanze ad alto contenuto energetico che vengono trasformate in aminoacidi, alfa-chetoacidi e alla fine in C02+ H20 NH3+ ATP sostanze varie. Allora sono importanti la qualità e la quantità dell'alimento che in generale deve contenere il 10-12% di proteine in grado di provvedere un adeguato apporto di aminoacidi essenziali. Se l'alimentazione à ̈ sbagliata il soggetto sotto sforzo fisico ne può risentire, ciò à ̈ sicuramente vero per gli atleti che ne possono risentire anche in tempi brevi. Negli sforzi prolungati la richiesta di proteine à ̈ massima, per esempio negli atleti professionisti soggetti ad un intenso sforzo rapido la richiesta di proteine ammonta ad 1.2-1.7 g/kg di peso corporeo/die mentre in un atleta sottoposto a resistenza la richiesta in proteine si riduce a 1.2-1.4 g/kg di peso corporeo/die. Questa richiesta energetica può essere soddisfatta attraverso una dieta più abbondante e con derivati proteici come gli aminoacidi a catena ramificata (BCAA) che contengono leucina, vaiina e isoleucina. Questi sono aminoacidi essenziali assorbiti bene che non subiscono modificazioni a livello epatico, da dove vengono inviati ai muscoli per essere trasformati nei corrispondenti alfa-chetoacidi. Questi ritornano al fegato per la formazione di acetilcoenzima A, molecola essenziale nella formazione di ATP (1). Il passaggio fegato-muscolifegato coinvolge il glicogeno, che si trasforma in glucosio il quale attraverso il sangue arriva ai muscoli dove viene convertito per produrre alanina che ritorna al fegato. Nel fegato l'alanina viene in parte convertita in urea ed in altra parte ritorna al fegato sotto forma di piruvato. Quando c'à ̈ carenza di proteine sono utilizzate quelle dei muscoli con effetto di diminuirne la massa. L'aumento di un surplus di proteine con un alto contenuto di aminoacidi ramificati essenziali, può comportare l'aumento delle proteine contrattili muscolari e un miglior recupero fisico in fase di inattività . In queste condizioni l'integrazione proteica può essere utile, se opportunamente bilanciata, anche in sportivi amatoriali. Il bilanciamento può essere favorito ma non sostituito dagli integratori alimentari anche quando questi rivendicano di essere completi, sicuramente quelli monocomposti, incluso gli integratori proteici, necessitano dì essere razionati. As far as physical activity is concerned, especially for a sportsman, a diet is needed that is capable of providing adequate quantities of water, calories, proteins, fats, carbohydrates, vitamins and minerals. The energy demand should be modulated for each type of athlete and for the type of effort he makes. As for the use of proteins, it must be remembered that proteins are substances with a high energy content that are transformed into amino acids, alpha-keto acids and eventually into C02 + H20 NH3 + ATP various substances. Then the quality and quantity of the food are important, which in general must contain 10-12% of proteins capable of providing an adequate supply of essential amino acids. If the diet is wrong, the subject under physical effort can be affected, this is certainly true for athletes who can also be affected in a short time. In prolonged efforts the demand for protein is maximum, for example in professional athletes subject to intense rapid effort the demand for protein amounts to 1.2-1.7 g / kg of body weight / day while in an athlete subjected to resistance the demand for protein it is reduced to 1.2-1.4 g / kg of body weight / day. This energy demand can be satisfied through a more abundant diet and with protein derivatives such as branched chain amino acids (BCAAs) which contain leucine, goine and isoleucine. These are well absorbed essential amino acids that do not undergo changes in the liver, from where they are sent to the muscles to be transformed into the corresponding alpha-keto acids. These return to the liver for the formation of acetylcoenzyme A, an essential molecule in the formation of ATP (1). The liver-muscle liver passage involves glycogen, which is transformed into glucose which through the blood reaches the muscles where it is converted to produce alanine which returns to the liver. In the liver, alanine is partly converted into urea and in another part returns to the liver in the form of pyruvate. When there is a lack of proteins, those of the muscles are used with the effect of decreasing their mass. The increase of a protein surplus with a high content of essential branched amino acids, can lead to the increase of muscle contractile proteins and a better physical recovery in the phase of inactivity. In these conditions, protein supplementation can be useful, if properly balanced, even in amateur sports. Balancing can be favored but not substituted by food supplements even when they claim to be complete, certainly the mono-compound ones, including protein supplements, need to be rationed.
I prodotti per gli anziani suscitano grande interesse poiché i processi di sintesi proteica e le richieste energetiche sono state recentemente associate all'invecchiamento. Nell'anziano ci sono problemi legati alle diminuite capacità di assorbimento, alla malnutrizione e a fattori sociali che possono influenzarne la qualità della vita dell'anziano. Indubbiamente con il progredire dell'invecchiamento si ha una riduzione dell'esigenze caloriche giornaliere ma si ha anche una progressiva diminuzione della massa magra, soprattutto muscolare, con un ritmo di circa 0,6% / anno (2). Products for the elderly are of great interest as protein synthesis processes and energy demands have recently been associated with aging. In the elderly there are problems related to decreased absorption capacity, malnutrition and social factors that can influence the quality of life of the elderly. Undoubtedly, with the progress of aging there is a reduction in the daily caloric needs but there is also a progressive decrease in lean mass, especially muscle, with a rate of about 0.6% / year (2).
Tra i vari fabbisogni quello proteico non cambia in modo fondamentale con il passare dell'età ma l'apporto in proteine può variare in base a stati fisiopatologici più che all'età . In realtà con l'età si riduce l'utilizzazione dell'azoto tissutale e diminuiscono alcune albumine con il conseguente accumulo piasmatico di sostanze tossiche di origine proteica. Nell'anziano l'apporto medio proteico dovrebbe coprire il 12-15% dell'apporto calorico totale. Le osservazioni LARN stabiliscono che à ̈ necessario un apporto proteico pari ad almeno 0,6g / kg di peso corporeo/ die che può essere aumentato fino a l,5g/ kg di peso corporeo/ die. Da queste analisi emerge la necessità di assicurare a sportivi e anziani una dieta ricca di proteine ad elevato contenuto di amminoacidi essenziali. Le proteine vengono trasformate in aminoacidi e si à ̈ osservato che proteine differenti forniscono aminoacidi in tempi diversi (3). Among the various needs, the protein requirement does not change fundamentally with the passing of age but the protein intake can vary based on physiopathological states rather than age. In reality, with age, the use of tissue nitrogen decreases and some albumins decrease with the consequent piasmatic accumulation of toxic substances of protein origin. In the elderly, the average protein intake should cover 12-15% of the total calorie intake. LARN observations establish that a protein intake of at least 0.6g / kg body weight / day is required which can be increased up to 1.5g / kg body weight / day. From these analyzes it emerges the need to ensure a diet rich in proteins with a high content of essential amino acids for athletes and the elderly. Proteins are transformed into amino acids and different proteins have been observed to supply amino acids at different times (3).
Le proteine dal siero di latte costituiscono un valido aiuto nutrizionale ma non si poteva evincere dallo stato dell'arte quello che à ̈ il contenuto della presente invenzione: le proteine del latte associate a L-carnitina, argina alfa-chetoglutarato e L-carnosina hanno contemporaneamente un effetto specifico sulla trascrizione dei geni codificanti per la proteina MyoD (fattore di trascrizione miogenico) e sulla proliferazione degli osteoblasti. The whey proteins are a valid nutritional aid but the content of the present invention could not be deduced from the state of the art: the milk proteins associated with L-carnitine, argine alpha-ketoglutarate and L-carnosine have simultaneously a specific effect on the transcription of the genes coding for the MyoD protein (myogenic transcription factor) and on the proliferation of osteoblasts.
Ci sono molti usi brevettati di formulazioni contenenti WP che hanno varia applicazioni nel campo della muscolatura e del controllo del peso corporeo. Per esempio il brevetto US2012178673(A1) rivendica le proprietà di una composizione a base di WP idrolizzate in modo particolare e che hanno l'effetto di sopprimere l'accumulazione di grassi, il brevetto NZ585619 (A) rivendica le proprietà sui neonati di una composizione a base di WP e di altre sostanze (lipidi e carboidrati). Il brevetto WO2012081982 (A2) rivendica le proprietà di preparati a base di proteine globulari che sono utili per stimolare la sintesi proteica nei mammiferi ma indica una particolare funzione come quella di aumentare la trascrizione dei geni codificanti per MyoD. There are many proprietary uses of WP-containing formulations that have various applications in the field of musculature and body weight control. For example the patent US2012178673 (A1) claims the properties of a composition based on WP hydrolyzed in a particular way and which have the effect of suppressing the accumulation of fats, the patent NZ585619 (A) claims the properties on newborns of a composition based on WP and other substances (lipids and carbohydrates). The patent WO2012081982 (A2) claims the properties of preparations based on globular proteins which are useful for stimulating protein synthesis in mammals but indicates a particular function such as that of increasing the transcription of genes encoding MyoD.
Il brevetto US2012141445 (Al) rivendica ie proprietà di un preparato comprendente WP, BCAA liberi e probiotici per stimolare la forza muscolare negli anziani ma non si trattano le ossa. The patent US2012141445 (A1) claims the properties of a preparation comprising WP, free BCAAs and probiotics to stimulate muscle strength in the elderly but do not treat the bones.
Il brevetto NZ572802(A) rivendica le proprietà di un idrolizzato enzimatico di WP che ha le proprietà di aumentare il recupero dei muscoli danneggiati ma non si citano gli osteoblasti. Patent NZ572802 (A) claims the properties of an enzymatic hydrolyzate of WP which has the properties of increasing the recovery of damaged muscles but osteoblasts are not mentioned.
II brevetto W02012055371(A1) rivendica le proprietà di una bevanda a base di WP, elettroliti e frammenti idrolitici che combattono il senso di fatica e l'ipossia. Patent W02012055371 (A1) claims the properties of a drink based on WP, electrolytes and hydrolytic fragments that fight the sense of fatigue and hypoxia.
Il brevetto US2012082760(A1) rivendica le proprietà della caseina enzimaticamente idrolizzata, per controllare l'enzima mTOR e quindi il controllo del peso corporeo. Patent US2012082760 (A1) claims the properties of enzymatically hydrolyzed casein, to control the mTOR enzyme and therefore control body weight.
Il brevetto AU2009332369(A1) rivendica una composizione di un preparato a base di WP idrolizzate che à ̈ in grado di aumentare i muscoli ma non si fa riferimento alle ossa. Patent AU2009332369 (A1) claims a composition of a preparation based on hydrolyzed WP which is able to increase muscles but does not refer to bones.
Nessuno dei presenti brevetti à ̈ una combinazione di WP in grado di agire sia sulla proliferazione cellulare degli osteoblasti e promuovere la sintesi del fattore di controllo MyoD. La presente composizione à ̈ inventiva e innovativa, combina le WP in una composizione che ha usi fin qui mai descritti proponendo un intervallo di dosaggio efficace e mostra invece che un sovradosaggio di proteine o un'assunzione di una quantità arbitraria polirebbero inibire la crescita cellulare. None of the present patents is a combination of WP able to act both on the cell proliferation of osteoblasts and promote the synthesis of the control factor MyoD. The present composition is inventive and innovative, it combines the WPs in a composition that has uses hitherto never described by proposing an effective dosage range and instead shows that an overdose of proteins or an intake of an arbitrary quantity would inhibit cell growth.
La presente invenzione permette di regolare positivamente la miogenesi e la proliferazione di osteoblasti attraverso una somministrazione predosata. The present invention allows to positively regulate the myogenesis and the proliferation of osteoblasts through a pre-dosed administration.
Esempio 1. La composizione e la proliferazione cellulare degli osteoblasti. Le proteine di siero di latte (Whey Protein o WP) sono molto utilizzate per l'integrazione proteica in quanto sono caratterizzate da un elevato valore nutrizionale come mostrato in TABI (2, 4). Example 1. The composition and cell proliferation of osteoblasts. Whey proteins (Whey Protein or WP) are widely used for protein supplementation as they are characterized by a high nutritional value as shown in TABI (2, 4).
TABI: contenuto medio whey proteins TABI: medium whey proteins content
alcuni aminoacidi essenziali some essential amino acids
sorgente Proteine Leucina Lisina Isoleucina Leucina BCAA (E) (E) (g) (g) % % WP 24,00 2,53 2,23 1,57 10,54 26,38 Assumendo che una persona ha un peso corporeo medio di 70 kg à ̈ stato eseguito uno screening source Protein Leucine Lysine Isoleucine Leucine BCAA (E) (E) (g) (g)%% WP 24.00 2.53 2.23 1.57 10.54 26.38 Assuming that a person has an average body weight of 70 kg Screened
di varie molecole per scegliere quelle interessanti e la dose ottimale d'uso. In accordo con l'idea di of various molecules to choose the interesting ones and the optimal dose of use. In accordance with the idea of
ottenere una formulazione dosabile e attiva per quei soggetti che hanno necessità di assumere obtain a dosable and active formulation for those subjects who need to take
proteine perché sottoposte ad un intenso sforzo muscolare oppure perché si trovano in uno stato proteins because they are subjected to intense muscular effort or because they are in a state
in cui muscoli e ossa sono debilitati. Le proteine hanno sicuramente un ruolo importante e hanno where muscles and bones are weakened. Protein certainly plays an important role and has
un effetto proliferativo su alcune cellule ma ci sono differenze nel modo in cui le varie proteine a proliferative effect on some cells but there are differences in the way the various proteins
vengono idrolizzate e quindi assorbite. C'à ̈ differenza tra proteine WP e caseina: a parità di they are hydrolyzed and then absorbed. There is a difference between WP protein and casein: a par
concentrazione à ̈ stato evidenziato che esse hanno un differente effetto sul bilancio netto tra concentration It has been shown that they have a different effect on the net balance between
sintesi delle proteine nei muscoli (MPS) e digestione delie proteine nei muscoli (MPB). La caseina muscle protein synthesis (MPS) and muscle protein digestion (MPB). Casein
à ̈ considerata una proteina "slow" nel senso che l'assorbimento degli aminoacidi à ̈ molto lento It is considered a "slow" protein in the sense that the absorption of amino acids is very slow
rispetto alle WP che sono considerate "fast" (6). Le WP possono stimolare un rapido compared to WPs which are considered "fast" (6). WPs can stimulate rapid
assorbimento degli aminoacidi, allora à ̈ importante avere la possibilità di prendere pìccole dosi a absorption of amino acids, then it is important to be able to take small doses a
intervalli di 1-2 ore a seconda del tipo di dieta che si segue e del risultato che si intende 1-2 hour intervals depending on the type of diet you follow and the result you intend
raggiungere. Nella composizione preferita sono state usate le proteine di siero di latte isolate reach. Whey protein isolate was used in the preferred composition
(WPI) che sono quelle a più alto contenuto in proteine (in media circa il 86,6%) come mostrato (WPI) which are the ones with the highest protein content (on average about 86.6%) as shown
nella tabella 2 e nella tabella 3. in Table 2 and Table 3.
TAB2: contenuto medio di aminoacidi essenziali ramificati TAB2: average content of essential branched amino acids
alcuni aminoacidi essenziali some essential amino acids
valore medio average value
sorgente Proteine Leucina Lisina Isoleucina Leucina BCAA source Protein Leucine Lysine Isoleucine Leucine BCAA
(g) (g) (g) (g) % % (g) (g) (g) (g)%%
WP 24,00 2,53 2,23 1,57 10,54 26,38 WP 24.00 2.53 2.23 1.57 10.54 26.38
Le WP non hanno un valore calorico diverso da altre proteine (4kcal/g) ma le WPI hanno più WPs have no different caloric value from other proteins (4kcal / g) but WPIs have more
elevato valore nutrizionale tra le proteine e solo il 98% del peso à ̈ Furosina che può avere effetti avversi, nella tabella 3 si vede il confronto del contenuto di Furosina tra alcune proteine WP e high nutritional value among proteins and only 98% of weight is Furosine which can have adverse effects, in table 3 we see the comparison of the Furosine content between some WP proteins and
caseina (7). casein (7).
TAB3: confronto del contenuto di Furosina tra varie sorgenti proteiche TAB3: comparison of the Furosine content between various protein sources
Sorgente di Contenuto medio in proteine Contenuto medio in Source of Average protein content Average content of
Proteine (g/100g di prodotto) Furosina Protein (g / 100g of product) Furosine
(mg/100g) di proteine (mg / 100g) of protein
WPC 13,4 588,4 WPC 13.4 588.4
WPI 86,6 97,8 WPI 86.6 97.8
caseine 82,7 29,1 caseins 82.7 29.1
Nella presente composizione le proteine sono state miscelate con arginina alfa-chetoglutarato, L- In the present composition the proteins were mixed with arginine alpha-ketoglutarate, L-
carnitina ed L-carnosina. L'arginina à ̈ un aminoacido semi-essenziale, interviene nel metabolismo carnitine and L-carnosine. Arginine is a semi-essential amino acid, it intervenes in the metabolism
dell'urea ed ha un effetto fisiologico sulle naturali difese del'organismo e interviene nella of urea and has a physiological effect on the natural defenses of the organism and intervenes in the
produzione di ossido nitrico (8). L'arginina alfa-chetoglutato à ̈ una forma di arginina che production of nitric oxide (8). Arginine alpha-ketoglutate is a form of arginine that
interviene nell'anabolismo come prodotto del ciclo di krebs. Fornire questa forma di arginina può intervenes in anabolism as a product of the krebs cycle. Providing this form of arginine can
risultare utile in uno stato in cui il ciclo dell'acido citrico à ̈ rallentato in una fase immediata di be useful in a state where the citric acid cycle is slowed down in an immediate phase
recupero muscolare ma non sembra aumentare la resistenza muscolare. Tuttavia l'argìnina alfa- muscle recovery but does not appear to increase muscle endurance. However, arginine alpha-
chetoglutarato partecipa attraverso i suoi derivati metabolici alla crescita degli osteoblasti delle ketoglutarate participates through its metabolic derivatives in the growth of osteoblasts of
ossa su cui sono legati i muscoli scheletrici (9}. Non ci sono particolari limiti all'uso di questa bones on which the skeletal muscles are linked (9}. There are no particular limits to its use
sostanza se non in quelli generali per gli aminoacidi. substance except in the general ones for amino acids.
La L-Carnitina negli integratori si può somministrare fino a 1000 mg / kg di peso corporeo/die L-Carnitine in supplements can be administered up to 1000 mg / kg of body weight / day
poiché à ̈ coinvolta nel trasporto degli acidi grassi all'interno del mitocondrio dove ha un effetto as it is involved in the transport of fatty acids into the mitochondrion where it has an effect
fisiologico sul metabolismo dei grassi. La carnitina à ̈ stata mostrata avere un ruolo protettivo physiological on fat metabolism. Carnitine has been shown to have a protective role
contro la eccessiva produzione di ammonio dovuto a sforzo fisico (10). against excessive ammonium production due to physical exertion (10).
La L-Carnosina può essere usata sino a 500 mg/ kg di peso corporeo/die à ̈ un dipeptide con vari L-Carnosine can be used up to 500 mg / kg body weight / day is a dipeptide with various
effetti fisiologici tra cui quello di antiossidante in quanto l'istidina presente à ̈ in grado di strappare physiological effects including that of antioxidant as the histidine present is able to tear
un elettrone a radicali dell'ossigeno e in questo senso ha anche un effetto tampone rispetto an electron to oxygen radicals and in this sense also has a buffering effect compared
all'aumento di ioni H<+>al'interno del muscolo e comunque essendo piuttosto abbondante nel muscolo e nel cervello ha un importante effetto sul trofismo muscolare. La carnosina à ̈ stata indicata come fattore importante per la sua attività biologica sull'enzima mTOR che interviene nei processi di invecchiamento. to the increase of H <+> ions inside the muscle and in any case being quite abundant in the muscle and brain, it has an important effect on muscle trophism. Carnosine has been indicated as an important factor for its biological activity on the mTOR enzyme that intervenes in the aging process.
In una tipica realizzazione della presente composizione si sono scelti 4 elementi e si à ̈ fissato il totale del formulato a 1000 mg. i 4 elementi devono avere un'azione benefica sui muscoli e sulle ossa su cui sono attaccati i muscoli scheletrici. Con 4 elementi che si possono combinare tra loro fino a 1000 mg ci sono miliardi di possibili combinazioni, l'idea à ̈ quella di utilizzare un sistema per trovare quella miscela che cambia le sue proprietà al crescere del dosaggio e può servire ad uno sportivo o ad un anziano con problemi di recupero dell'apparato muscolo-scheletrico (5). In a typical embodiment of the present composition, 4 elements were selected and the total of the formulation was fixed at 1000 mg. the 4 elements must have a beneficial action on the muscles and bones on which the skeletal muscles are attached. With 4 elements that can be combined with each other up to 1000 mg there are billions of possible combinations, the idea is to use a system to find that mixture that changes its properties as the dosage increases and can be used by a sportsman or to an elderly person with recovery problems of the musculoskeletal system (5).
In un prodotto miscelato ad altre sostanze il contenuto medio di ciascuna sostanza si diluisce nelle altre, il contenuto di sostanza di partenza à ̈ allora importante; per questo nella realizzazione della presente composizione sono state scelte WP isolate ad elevata concentrazione. Durante il processo di purificazione delle proteine si sviluppa una reazione di Maillard (MR) per effetto dell'aumento della temperatura. Questa reazione si verifica tra gli ammino gruppi liberi della lisina e/o altri aminoacidi e i gruppi carbonilìci degli zuccheri riducenti come glucosio e maltosio. La lisina à ̈ l aminoacido più reattivo durante l'MR ed à ̈ molto importante nei cibi in cui diventa carente per effetto della sua reattività . La quantità di Furosina (e-N-(furoylmethyl)-L-Lysina) che si forma durante l'idrolisi adda di Amadori della fructosyllysina e lactusyllysina. Quanto maggiore à ̈ la quantità di furosina tanta più degradata sarà la proteina. Da questo punto di vista la Caseina sarebbe più indicata tuttavia ci sono altri effetti metabolici che fanno propendere per l'uso delle WPI. In a product mixed with other substances the average content of each substance is diluted in the others, the content of starting substance is then important; for this reason, high concentration isolated WPs have been chosen in the realization of the present composition. During the protein purification process a Maillard (MR) reaction develops due to the increase in temperature. This reaction occurs between the free amino groups of lysine and / or other amino acids and the carbonyl groups of reducing sugars such as glucose and maltose. Lysine is the most reactive amino acid during MR and is very important in foods where it becomes deficient due to its reactivity. The amount of Furosina (e-N- (furoylmethyl) -L-Lysina) that is formed during the adda hydrolysis of Amadori of fructosyllysina and lactusyllysina. The greater the amount of furosine, the more degraded the protein will be. From this point of view, Casein would be more suitable, however, there are other metabolic effects that suggest the use of WPIs.
Negli studi eseguiti si à ̈ variato il rapporto tra le varie proteine nella concentrazione mostrando che à ̈ possibile ottenere dei risultati utili agendo nei seguenti intervalli: proteine concentrate dal siero di latte tra il 75 % e il 78%; arginina alfa-chetoglutarato tra il 7% e il 10%; L-carnitina e o suoi derivati tra il 10% e il 15%; L-carnosina tra il 3% e il 5%. In the studies carried out, the ratio between the various proteins in the concentration has varied, showing that it is possible to obtain useful results by acting in the following ranges: concentrated proteins from whey between 75% and 78%; arginine alpha-ketoglutarate between 7% and 10%; L-carnitine and its derivatives between 10% and 15%; L-carnosine between 3% and 5%.
Nella presente composizione si à ̈ partiti da un dosaggio base con dosi definite e usate a varie concentrazioni per valutate l'effetto sulla proliferazione cellulare. Le cellule usate sono osteoblasti umani SAOS-2, queste cellule non sono trasformate e sono un buon modello di osteoblasti (11) e per alcuni aspetti di fibroblasti (12). Nella figura 1 si vede l'effetto di vari dosaggi della miscela scelta sulla proliferazione di osteoblasti. Tra questi dosaggi la composizione preferita à ̈ quella in cui c'à ̈ un aumento della proliferazione cellulare degli osteoblasti, che in una situazione di elevata attività osteoclastica oppure di osteopenia à ̈ particolarmente utile. Si noti che un dosaggio eccessivo della miscela à ̈ controproducente. (FIGURA 1) In the present composition we started from a basic dosage with defined doses and used at various concentrations to evaluate the effect on cell proliferation. The cells used are human SAOS-2 osteoblasts, these cells are not transformed and are a good model of osteoblasts (11) and in some aspects of fibroblasts (12). Figure 1 shows the effect of various dosages of the chosen mixture on the proliferation of osteoblasts. Among these dosages, the preferred composition is that in which there is an increase in the cell proliferation of osteoblasts, which is particularly useful in a situation of high osteoclastic activity or osteopenia. Note that excessive dosage of the mixture is counterproductive. (FIGURE 1)
Lo studio della proliferazione cellulare à ̈ stato fatto usando il metodo di esclusione del Trypan Blue. Le cellule vengono seminate e lasciate crescere per 3 giorni, poi viene aggiunta la miscela da analizzare e dopo 24 h si procede ai conteggio delle cellule vive. Per if conteggio delle cellule sono usati 20 Î1⁄4l di Trypan blue 0,1% e 20 Î1⁄4l di sospensione cellulare. Al microscopio ottico vengono contate le cellule presenti nei 5 quadrati di ognuna di due camere dell'emocitometro, separando le vive (translucide) dalle morte (blu) e facendo una media dei conteggi. II numero medio di cellule per millilitro di soluzione à ̈ calcolato per mezzo della formula: The study of cell proliferation was done using the Trypan Blue exclusion method. The cells are sown and left to grow for 3 days, then the mixture to be analyzed is added and after 24 hours the live cells are counted. For cell counting, 20 Î1⁄4l of 0.1% Trypan blue and 20 Î1⁄4l of cell suspension are used. The cells present in the 5 squares of each of two chambers of the hemocytometer are counted under the optical microscope, separating the living (translucent) from the dead (blue) and making an average of the counts. The average number of cells per milliliter of solution is calculated using the formula:
Cellule per mi = conteggio medio per quadrato x fattore di diluizione x 10<4>Cells per mi = mean count per square x dilution factor x 10 <4>
La vitalità delle cellule viene calcolata come: Cell viability is calculated as:
% di vitalità = (numero dì cellule vive / numero totale di cellule) x 100 % viability = (number of living cells / total number of cells) x 100
Questi esperimenti mostrano come tutti gli ingredienti usati nella miscela siano essenziali per la proliferazione degli osteoblasti. inoltre giustificano la somministrazione di più boli ad intervalli distanti 1-2 ore che abbassano la tossicità e supportano l'anabolismo delle cellule. These experiments show that all the ingredients used in the mixture are essential for the proliferation of osteoblasts. they also justify the administration of more boluses at 1-2 hour intervals which lower toxicity and support the anabolism of the cells.
Esemplo 2. Effetto della composizione sulla trascrizione genica. Example 2. Effect of composition on gene transcription.
Carboidrati, lipidi e proteine sono i maggiori componenti del cibo e vengono ingeriti attraverso l'alimentazione. In tutte le diete à ̈ fondamentale l'introduzione di aminoacidi essenziali, vitamine e sostanze prodotte dall'uomo in quantità subottimale. In una dieta il bilancio tra carboidrati e proteine à ̈ fondamentale per il bilancio tra catabolismo e anabolismo. Lo squilibrio della dieta può determinare un cambiamento metabolico il cui effetto può essere dimagrante oppure opposto (2). In alcuni stati fisiologici come quelli di uno sportivo durante un'intensa attività oppure quelli di un anziano si possono manifestare sbilanciamenti metabolici che si manifestano con un consumo di grassi ma anche con un consumo anomalo della massa magra corporea. Molti sportivi o anche anziani possono avere una riduzione della massa muscolare con un'effetto negativo sull'intero stato fisiologico per cui à ̈ necessario integrare opportunamente la dieta al fine di regolare il catabolismo cellulare. Una diminuzione di massa muscolare ha effetti negativi anche sul sistema cardiovascolare che può risultare affaticato e si può trovare in uno stato anaerobico con lo sviluppo di radicali liberi (13). Un altro effetto negativo particolarmente evidente negli anziani à ̈ associato al peggioramento dell'osteopenia e sarcopenia (14). L'esercizio e il movimento dei muscoli scheletrici sollecitano l'attività degli osteoblasti ma la diminuzione della massa muscolare incide negativamente sull'omeostasi della matrice extracellulare degli osteoblasti (cioà ̈ l'osso). Per questo non solo à ̈ importante lo sviluppo anabolico della massa muscolare ma à ̈ utile l'attivazione degli osteoblasti già ottenuta con una composizione come quella dell'esempio 1. Stabilito un dosaggio stimolante per gli osteoblasti abbiamo ottenuto una composizione in cui tra i vari elementi studiati si à ̈ valutato l'effetto nutrigenomico della miscela alla concentrazione fissata. Per gli studi sono state utilizzate tecniche di analisi in amplificazione a catena in tempo reale (PCR-real time) utilizzando lo strumento 7300 Applied Biosystems. Per gli scopi sono strate trattate cellule umane di osteoblasti SAOS-2; le cellule sono state cresciute nelle condizioni generali come descritto fino all'80% di confluenza, dopo di che sono state trattate per 24 ore con la miscela scelta ma usata alle concentrazioni di 6.5mg, 13mg e 19.5mg. E' stato scelto di valutare l'effetto sulla modulazione della trascrizione di tre differenti geni coinvolti in importanti meccanismi cellulari: IL1β che ha un ruolo di primaria importanza nei processi infiammatori, iNOS che à ̈ l'enzima metabolicamente inducibife e coinvolto nella produzione dell'Ossido Nitrico (NO) e IGF-I che à ̈ un fattore coinvolto nel metabolismo glucidico associato a forme di diabete e obesità . I livelli di espressione dei geni codificanti per IL1β, iNOS e IGF-I sono stati analizzati mediante Real Time PCR per valutare una possibile modulazione. Da ciascuna campione coltivato à ̈ stato estratto lRN A messaggero totale in accordo al metodo descritto altrove (15). Ciascun RNA messaggero, per i geni scelti, à ̈ stato analizzato utilizzando la RT-PCR e i risultati sono stati analizzati nel seguente modo: le cellule non trattate (CTL) sono usate per calibrare i risultati, la variazione del trascritto nelle CTL à ̈ assunto come valore 1.0. I valori del gene target Ct sono stati normalizzati rispetto al valore del gene codificante per la GAPDH. I dati nelle cellule trattate sono stati usando il metodo 2<-ΔCt>ed espressi come la variazione rispetto al CTL secondo le seguenti espressioni: Carbohydrates, lipids and proteins are the major components of food and are ingested through food. In all diets the introduction of essential amino acids, vitamins and substances produced by man in suboptimal quantities is essential. In a diet, the balance between carbohydrates and proteins is fundamental for the balance between catabolism and anabolism. The imbalance of the diet can lead to a metabolic change whose effect can be slimming or opposite (2). In some physiological states such as those of a sportsman during intense activity or those of an elderly person, metabolic imbalances can occur which manifest themselves with a consumption of fat but also with an abnormal consumption of lean body mass. Many sportsmen or even the elderly may have a reduction in muscle mass with a negative effect on the entire physiological state so it is necessary to properly integrate the diet in order to regulate cellular catabolism. A decrease in muscle mass also has negative effects on the cardiovascular system which can be fatigued and can be found in an anaerobic state with the development of free radicals (13). Another negative effect particularly evident in the elderly is associated with the worsening of osteopenia and sarcopenia (14). Exercise and movement of the skeletal muscles stimulate the activity of the osteoblasts but the decrease in muscle mass negatively affects the homeostasis of the extracellular matrix of the osteoblasts (ie the bone). For this reason, not only is the anabolic development of muscle mass important but it is also useful to activate the osteoblasts already obtained with a composition like that of example 1. Having established a stimulating dosage for the osteoblasts, we have obtained a composition in which, among the various elements studied the nutrigenomic effect of the mixture was evaluated at the fixed concentration. Real-time PCR analysis techniques were used for the studies using the Applied Biosystems 7300 instrument. For the purposes, human SAOS-2 osteoblast cells were treated; the cells were grown under the general conditions as described up to 80% confluence, after which they were treated for 24 hours with the chosen but used mixture at concentrations of 6.5mg, 13mg and 19.5mg. It was chosen to evaluate the effect on the modulation of the transcription of three different genes involved in important cellular mechanisms: IL1β which has a role of primary importance in inflammatory processes, iNOS which is the metabolically inducible enzyme and involved in the production of Nitric Oxide (NO) and IGF-I which is a factor involved in glucose metabolism associated with forms of diabetes and obesity. The expression levels of the genes encoding IL1β, iNOS and IGF-I were analyzed by Real Time PCR to evaluate a possible modulation. Total messenger RN A was extracted from each cultured sample according to the method described elsewhere (15). Each messenger RNA, for the chosen genes, was analyzed using RT-PCR and the results were analyzed as follows: untreated cells (CTL) are used to calibrate the results, the variation of the transcript in the CTL is assumed as a value 1.0. The values of the target gene Ct were normalized with respect to the value of the gene coding for GAPDH. The data in the treated cells were using the 2 <-Î ”Ct> method and expressed as the change with respect to the CTL according to the following expressions:
ΔΔC = ΔC2-Δ C1 Î ”Δ C = Î ”C2-Δ C1
dove where is it
ΔCt 1= Ctgene controllo - Ct(GAPDH) controllo; Î ”Ct 1 = Ctgene control - Ct (GAPDH) control;
ACt 2 = Ctgene trattato - Ct (GAPDH ) trattato ACt 2 = treated Ctgene - treated Ct (GAPDH)
I risultati sono mostrati nella figura 2. (FIGURA 2) The results are shown in Figure 2. (FIGURE 2)
Per quanto riguarda IL1β e IGF-I la miscela non ha indotto modulazione nell'espressione genica a nessuna delle concentrazioni utilizzate. In altre parole l'espressione genica dei campioni trattati era confrontabile con quella dei campioni di controllo (cellule non trattate). Per quanto riguarda iNOS, la miscela alia concentrazione più alta ha indotto un aumento leggermente significativo dei livelli di espressione di questo gene, in quanto la sua espressione era raddoppiata rispetto a quella del campione non trattato. Ciò conferma che aumentando le dosi di prodotto si possono ottenere azioni fisiologiche differenti. As regards IL1β and IGF-I, the mixture did not induce modulation in gene expression at any of the concentrations used. In other words, the gene expression of the treated samples was comparable with that of the control samples (untreated cells). As for iNOS, the mixture at the highest concentration induced a slightly significant increase in the expression levels of this gene, as its expression was doubled compared to that of the untreated sample. This confirms that by increasing the doses of the product, different physiological actions can be obtained.
Esempio 3: MyoD_Ossa à ̈ la composizione preferita. Example 3: MyoD_Ossa is the preferred composition.
Le WP sono molto utilizzate in vari tipi di dieta, come quella per gli atleti, al fine di favorire la formazione di massa magra muscolare o come dimagrante in associazione ad altre sostanze ma non à ̈ descritto un uso per le ossa che supportano i muscoli scheletrici. La miscela nella forma preferita, indicata come MyoD_Ossa, à ̈ prodotta in capsule di gelatina predosate anche analizzando l'effetto con aggiunta di vitamine e micronutrienti. I risultati in figura 3A mostrano che la composizione preferita MyoD_Dssa induce un aumento della proliferazione degli osteoblasti. (FIGURA 3A) WPs are widely used in various types of diets, such as that for athletes, in order to promote the formation of lean muscle mass or as a slimming in association with other substances but a use for bones that support skeletal muscles is not described. . The mixture in the preferred form, indicated as MyoD_Ossa, is produced in pre-dosed gelatin capsules also analyzing the effect with the addition of vitamins and micronutrients. The results in figure 3A show that the preferred composition MyoD_Dssa induces an increase in the proliferation of osteoblasts. (FIGURE 3A)
In particolare il fattore miogenico 1 Ã ̈ stato analizzato mediante due oligonucleotidi disegnati al 5' e al 3'del DNA che codifica per il fattore miogenico 1 (M Accession Number NM_002478 miogenic differentation 1), rispettivamente identificati come: In particular, the myogenic factor 1 was analyzed by means of two oligonucleotides drawn at 5 'and 3' of the DNA that encodes the myogenic factor 1 (M Accession Number NM_002478 myogenic differentation 1), respectively identified as:
MyoD1 FORWARD : 5' CCGCCTGAGCAAAGTAAATGAG 3' MyoD1 FORWARD: 5 'CCGCCTGAGCAAAGTAAATGAG 3'
MyoD1 REVERSE : 5' GCAACCGCTGGTTTGGATT 3' MyoD1 REVERSE: 5 'GCAACCGCTGGTTTGGATT 3'
Questi oligo nel tipo di esperimento, noto ad un esperto in arte della materia, non discriminano tra gli alleli MyoD. I risultati in figura 3B mostrano l'effetto sui principali geni analizzati e come si vede solo l'RNA messaggero corrispondente ai gene MyoD viene significativamente aumentato. These oligos in the type of experiment, known to an expert in the art of the subject, do not discriminate between the MyoD alleles. The results in figure 3B show the effect on the main genes analyzed and as we can see only the messenger RNA corresponding to the MyoD gene is significantly increased.
CONCLUSIONI DEGLI STUDI CONCLUSIONS OF THE STUDIES
Si può dunque concludere che la composizione scelta nella sua realizzazione preferita corrisponde a quella che nella presente invenzione à ̈ il MyoD_Ossa. Questa composizione comprende una miscela a 6,5 mg per dose ed à ̈ possibile assumere fino a 10 dosi al giorno. Questa composizione ha un effetto proliferativo sugli osteoblasti e sulla trascrizione del regolatore dei mioblasti MyoD per cui può essere utile strumento per una dieta in cui ci sia sintesi di proteine e può essere utile anche nei casi di sarcopenia (16). Allora li soggetto può assumere più boii ad un dosaggio di aminoacidi con una percezione psicologica della quantità assunta che ne migliora il controllo quantitativo riducendo eventuali effetti collaterali. It can therefore be concluded that the composition chosen in its preferred embodiment corresponds to that which in the present invention is the MyoD_Ossa. This composition comprises a blend at 6.5 mg per serving and it is possible to take up to 10 servings per day. This composition has a proliferative effect on osteoblasts and on the transcription of the myoblast regulator MyoD so it can be a useful tool for a diet in which there is protein synthesis and can also be useful in cases of sarcopenia (16). Then the subject can take more boii at a dosage of amino acids with a psychological perception of the quantity taken which improves the quantitative control by reducing any side effects.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5654019A (en) * | 1991-12-26 | 1997-08-05 | Snow Brand Milk Products Co., Ltd. | Bone enhancing factors from whey and compositions containing the same |
| WO2009105164A2 (en) * | 2008-02-15 | 2009-08-27 | President And Fellows Of Harvard College | Blood substitute solution |
| US20100119499A1 (en) * | 2009-09-17 | 2010-05-13 | Kneller Bruce W | Stilbene-based compositions and methods of use therefor |
-
2012
- 2012-07-30 IT IT000368A patent/ITRM20120368A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5654019A (en) * | 1991-12-26 | 1997-08-05 | Snow Brand Milk Products Co., Ltd. | Bone enhancing factors from whey and compositions containing the same |
| WO2009105164A2 (en) * | 2008-02-15 | 2009-08-27 | President And Fellows Of Harvard College | Blood substitute solution |
| US20100119499A1 (en) * | 2009-09-17 | 2010-05-13 | Kneller Bruce W | Stilbene-based compositions and methods of use therefor |
Non-Patent Citations (1)
| Title |
|---|
| JUHA J HULMI ET AL: "The effects of whey protein on myostatin and cell cycle-related gene expression responses to a single heavy resistance exercise bout in trained older men", EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY, SPRINGER, BERLIN, DE, vol. 102, no. 2, 9 October 2007 (2007-10-09), pages 205 - 213, XP019563459, ISSN: 1439-6327, DOI: 10.1007/S00421-007-0579-4 * |
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