Mixtures and compositions containing sulforaphane and glycine

Abstract

The present disclosure generally relates to mixtures and compositions comprising sulforaphane or an analog thereof and at least one amino acid or an analog thereof. In particular, the present disclosure relates to the use of said mixtures and compositions for treating or preventing oxidative stress.

Description

[Technical field]

[0001]

[0001] The present disclosure relates generally to mixtures and compositions comprising sulforaphane or an analog thereof and glycine or an analog thereof. In particular, the present disclosure relates to the use of said mixtures and compositions for treating or preventing oxidative stress. [Background technology]

[0002]

[0002] Oxidative stress is a phenomenon in which there is an imbalance between the production and accumulation of reactive oxygen species (ROS) in cells and tissues and the ability of biological systems to detoxify these reactive products. When the normal redox state of cells is disturbed, toxic effects can occur due to the production of peroxides and free radicals that damage cellular components such as proteins, cell membranes, lipids, and DNA, ultimately resulting in cell death.

[0003]

[0003] Free radicals and oxidants are known to play a key role in the pathogenesis of cancer (e.g., via DNA damage). 1~3 ), cardiovascular disease 4~6 , neurological disorders 7~9 , respiratory diseases 10~12 , rheumatoid arthritis 2,13,14 , liver disease 15 and kidney disease 16 ,inflammation 17~19 , diabetes 20,21 , metabolic disorders (lipids and glucose) 22~24 , and aging 25,26 It has been implicated as a contributing factor to many diseases and conditions, including rheumatoid arthritis.

[0004] From the perspective of human health, free radical exposure and oxidative stress cannot be completely avoided. However, oxidative stress can be reduced by dietary antioxidant supplementation. Vitamins C and E, flavonoids (a class of polyphenolic compounds), and carotenoids are examples of antioxidant compounds that have been comprehensively studied for their benefits to human health. Typically, health care professionals recommend multiple daily intakes of fruits and vegetables, which are natural sources of such antioxidants. Thus, identifying other natural antioxidant compounds has been the focus of intensive research to further improve human health by combating the causes of oxidative stress.

[0005] Sulforaphane is a naturally occurring organosulfur compound (isothiocyanate) found in vegetables from the Brassicaceae family, which includes cauliflower, cabbage, kale, garden cress, bok choy, and Brussels sprouts, but most notably broccoli, which has high levels of sulforaphane. 27,28 Sulforaphane has the chemical structure 4-methylsulfinylbutylisothiocyanate or 1-isothiocyanato-4-methylsulfinylbutane and is a phytochemical that exists in plants in the form of its biologically inactive precursor glucoraphanin. Glucoraphanin belongs to a group of phytochemicals called glucosinolates. Glucosinolates have a sugar moiety (most often d-glucose) incorporated into their structure and are rapidly converted to the isothiocyanate form by an enzyme called myrosinase. 29 The process of conversion occurs when the enzyme myrosinase is released after the breakdown of plant tissue (e.g., by biting, chewing, slicing, etc.). Destruction of myrosinase during food preparation by cooking or microwave processing can greatly reduce the bioavailability of isothiocyanates, but an alternative source of isothiocyanates from the ingestion of cooked vegetables can be provided by the degradation of glucosinolates by the gut microbiota, which is in any case not efficient and can be variable.30,31 .

[0006]

[0006] Studies with extracted or purified forms of sulforaphane have demonstrated that this compound may be beneficial in humans in combating oxidative stress (antioxidant 32 and chemoprotectants 33 Furthermore, some studies suggest that sulforaphane is a potent activator of the transcription factor Nrf2, which in turn is a potent activator of the cellular defense against oxidative stress. 34 .

[0007]

[0007] It would therefore be desirable to provide compositions in which the beneficial activity of sulforaphane in combating oxidative stress is enhanced.

[0008]

[0008] The discussion or reference of any prior art in this specification should not be construed as an admission that that prior art is part of the common general knowledge of those skilled in the art hereof. Summary of the Invention

[0009]

[0009] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0010]

[0010] The present disclosure is based on the discovery that a combination of sulforaphane or an analog thereof and glycine or an analog thereof can enhance the treatment or prevention of oxidative stress compared to the individual components applied separately.

[0011]

[0011] According to one aspect of the present disclosure, there is provided a mixture comprising sulforaphane or an analog thereof and glycine or an analog thereof.

[0012] In an embodiment, the sulforaphane analog is 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, cis- or trans-3-(methylsulfonyl)cyclohexylmethyl isothiocyanate, and The combination is selected from the group consisting of these.

[0013] In an embodiment, the mixture is for treating a disease or condition associated with oxidative stress, preferably cancer, cardiovascular disease, Neurological disorders, respiratory diseases, Rheumatoid arthritis, Liver disease, kidney disease, inflammation, diabetes, Metabolic disorders, and Aging The present invention is for use in the treatment or prevention of at least one disease or condition selected from the group consisting of:

[0014]

[0014] In an embodiment of the mixture of the present disclosure, the sulforaphane or analog thereof and the glycine or analog thereof are formulated for simultaneous or sequential administration to a subject in need thereof.

[0015]

[0015] In an embodiment of the mixture of the present disclosure, the molar ratio of sulforaphane or an analog thereof to glycine or an analog thereof is about 1:1000 to about 1000:1, preferably about 1:800 to about 800:1, and most preferably about 1:500.

[0016] In another aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: Sulforaphane or an analog thereof; glycine or an analog thereof; and optionally at least one additional ingredient.

[0017] In an embodiment, the at least one raw material is Lipids, protein, carbohydrates, Prebiotics, Probiotics, essential fatty acids, nucleotide, Nucleosides, Vitamins, and Minerals is selected from the group consisting of:

[0018] In yet another aspect, there is provided a method of making the compositions of the present disclosure, in an embodiment, the method comprises combining sulforaphane or an analog thereof with glycine or an analog thereof and optionally at least one additional ingredient.

[0019] In yet another aspect, the present disclosure provides a method of treating or preventing a disease or condition associated with oxidative stress.

[0020]

[0020] Other embodiments of the nutritional compositions according to the present disclosure will become apparent from the detailed description that follows. [Brief description of the drawings]

[0021] [Figure 1]1 shows the survival of zebrafish larvae in vitro in the absence and presence of hydrogen peroxide and other additives. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Interpretation definitions and statements

[0022] As used in the context of describing the embodiments (particularly in the claims), the terms "a," "an," and "the" and similar references are to be construed as including both the singular and the plural, unless otherwise indicated in the specification or clearly contradicted by context.

[0023]

[0023] The methods and processes described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context.

[0024]

[0024] Any and all example or exemplary language provided herein (e.g., "etc.") is intended to be merely clarifying and is not intended to limit the scope of the claims. No language in the specification should be construed as indicating any non-claimed essential element.

[0025]

[0025] Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range. Unless otherwise indicated herein, each value is incorporated herein as if it were individually recited herein. For example, if a range is from about 1 to about 50, the range is deemed to include, for example, 1, 7, 34, 46.1, 23.7, or any other value or range within the range.

[0026]

[0026] Unless otherwise stated, all percentages herein refer to weight percentages, where applicable.

[0027]

[0027] In this specification and the claims, the words "comprise," "comprises," "comprised," "comprising," "including," "having," and the like are used in an inclusive sense, i.e., to specify the presence of stated features but do not exclude the presence of additional or further features.

[0028]

[0028] The specific embodiments disclosed herein may be further limited in the claims based on the composition or essential composition of the words. When used in the claims, whether as filed or as added by amendment, the transitional phrase "consisting of" excludes any component, step, or ingredient not recited in the claim. The transitional phrase "consisting essentially of" limits the claim to the recited materials or steps and those that do not materially affect the basic and novel property(ies). Thus, the claimed embodiments are essentially or explicitly recited and enabled herein.

[0029]

[0029] Unless otherwise defined, all technical and scientific terms have the same meaning and should be given the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0030]

[0030] "Pharmaceutical composition", "nutraceutical composition" or "composition" refers to a product manufactured to contain one or more active ingredients, and may include one or more inactive ingredients, and any product resulting directly or indirectly from the combination of any two or more of the ingredients, from complexation or aggregation, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, a composition of the present disclosure encompasses any composition made by mixing a compound, substance or ingredient of the present disclosure with, optionally, a pharma- ceutical or nutraceutically acceptable excipient (a pharma- ceutical acceptable carrier).

[0031] It should be understood that pharma ceutically or nutraceutical acceptable derivatives of bioactive substances are included within the scope of this disclosure.

[0032]

[0032] The term "pharmaceutical or nutraceutical acceptable derivative" includes, but is not limited to, pharmaceutical or nutraceutical acceptable salts, esters, salts of such esters, ethers, or any other derivatives, including prodrugs and metabolites, which, upon administration to a subject in need thereof (e.g., a patient, human or animal), are capable of directly or indirectly providing a biologically active substance as otherwise described herein.

[0033]

[0033] As used herein, the term "pharmaceutical or nutraceutical acceptable salt" refers to a salt which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, or the like, and which is commensurate with a reasonable benefit / risk ratio.

[0034]

[0034] The term "sulforaphane analog" is used herein to refer to analogs of naturally occurring sulforaphane, such as sulforaphene, erucin (sulforaphane in which the sulfur is not oxidized, i.e., has a methylsulfide group), and erytholin (sulforaphane in which the sulfur is peroxidized, i.e., has a methylsulfone group).

[0035]

[0035] "Amino acid analog" (or "nonstandard amino acid") is meant to include all amino acid-like compounds that are similar in structure and / or overall shape to one or more of the 20 L-amino acids commonly found in naturally occurring proteins (Ala or A, Cys or C, Asp or D, Glu or E, Phe or F, Gly or G, His or H, Ile or I, Lys or K, Leu or L, Met or M, Asn or N, Pro or P, Gln or Q, Arg or R, Ser or S, Thr or T, Val or V, Trp or W, Tyr or Y, as defined and listed in WIPO Standard ST.25 (2009), Annex C, Appendix 2, Table 3). Amino acid analogs can include naturally occurring amino acids that contain modified side chains or backbones. Modifications may include, but are not limited to, substitution of an atom (e.g., N) for an associated atom (e.g., S), addition of a group (e.g., a methyl group, or a hydroxyl group) or atom (e.g., Cl or Br), deletion of a group, replacement of a covalent bond (e.g., a double bond for a single bond), or combinations thereof (see, e.g., WIPO Standard ST.25(2009), Annex C, Appendix 2, Table 4). As used herein, reference to an "amino acid" in relation to compositions and methods for combating oxidative stress includes amino acid analogs.

[0036]

[0036] An "analog" of a substance in other contexts includes a functionally equivalent substance, which may be achieved by modifying the structure of the original substance using chemical or recombinant techniques, or by identifying a substance with a different structure that has the same or a similar function as the original substance.

[0037]

[0037] The term "mixture" refers to a combination of components (such as compounds, substances or ingredients) where the components of the mixture are prepared separately and the mixture is achieved by mixing the components before or during use. In this regard, the mixture may be achieved by mixing the components before administering the mixture to a subject in need thereof. In embodiments, the mixture may be achieved by simultaneous or sequential administration of the components. Thus, the mixture includes the mixture achieved within a subject in need thereof.

[0038]

[0038] The compounds, substances or raw materials used in making the mixtures or compositions of the present disclosure may be derived from any conceivable source, including animal, vegetable, mineral, or synthetic ("man-made") sources.

[0039]

[0039] The terms "isolated" or "purified" refer to a material that has been removed from its original environment (e.g., the natural environment if it occurs in nature). For example, a material is said to be "purified" when it is present in a particular composition or mixture at a concentration higher than that present in the native or wild-type organism, or when it is present in combination with components that are not normally present upon expression from the native or wild-type organism. For example, a naturally occurring protein / polypeptide present in an organism is not isolated, but the same protein / polypeptide separated from some or all of the coexisting materials in the natural system is isolated. Such a protein / polypeptide can be, for example, part of a composition and can also be isolated in that such a composition is not part of the protein / polypeptide's natural environment.

[0040]

[0040] Terms such as "co-administration" or "co-administering" refer to the administration of a single composition containing two or more active agents, or the administration of each active agent as a separate composition, and / or the administration of each active agent delivered by a separate route, either contemporaneously or simultaneously, or sequentially within a sufficiently short time period that the effective results are equivalent to those obtained when all such active agents are administered as a single composition. "Co-administration" means that the active agents are administered together at substantially the same time, preferably in the same formulation.

[0041]

[0041] As used herein, "treat", "treating" or "treatment" of a disease or disorder means achieving one or more of the following: (a) reducing the severity and / or duration of the disorder, (b) limiting or preventing the onset of symptoms characteristic of the disorder(s) being treated, (c) inhibiting the worsening of symptoms characteristic of the disorder(s) being treated, (d) limiting or preventing the recurrence of the disorder(s) in patients who have previously had the disorder(s), and (e) limiting or preventing the recurrence of symptoms in patients who have previously exhibited symptoms of the disorder(s). As used herein, "prevent", "preventing", "prevention", or "prophylaxis" of a disease or disorder means preventing the development of a disease or disorder in a subject.

[0042] The term "effective amount" or "therapeutic amount" is intended to mean an amount of a substance that will elicit a biological or medical response in a tissue, system, animal or human that is sought by a researcher, veterinarian, physician or other clinician. The term "prophylactically effective amount" is intended to mean an amount of a substance that will prevent or reduce the risk of the occurrence of a biological or medical event that is sought to be prevented in a tissue, system, animal or human by a researcher, veterinarian, physician or other clinician.

[0043]

[0043] As used herein, the expressions "for administration" and "administered" have the same meaning as "prepared for administration." In other words, a description that an active compound is "for administration" should be understood to mean that the active compound is formulated and configured in a dosage amount so that it is in a state where it can exert its therapeutic activity.

[0044] Mixtures according to the present disclosure

[0044] The present disclosure relates to a mixture for treating or preventing oxidative stress.

[0045] In one aspect, the present disclosure provides a mixture comprising sulforaphane or an analog thereof and glycine or an analog thereof.

[0046] In an embodiment, the sulforaphane is 4-methylsulfinylbutylisothiocyanate or 1-isothiocyanato-4-(methylsulfinyl)butane.

[0047] In other embodiments, sulforaphane analogs useful in preparing the mixtures of the invention include one or more of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate, or mixtures thereof.

[0048]

[0048] Preferably, the sulforaphane and / or sulforaphane analogs of the present disclosure may be derived from any suitable natural source. For example, sulforaphane and / or its analogs may be extracted from broccoli, Brussels sprouts, cabbage, cauliflower, bok choy, kale, collards, broccoli raab, kohlrabi, mustard, turnip, radish, arugula, watercress, or other natural sources. Thus, in embodiments, the natural source is selected from one or more of these natural vegetable sources. Sulforaphane or its analogs may be extracted directly from the source material or from an extract prepared from the natural source material. In other embodiments, sulforaphane and / or sulforaphane analogs may be synthetic (i.e., man-made).

[0049] In an embodiment, the mixture of the present disclosure is for use in the treatment or prevention of a disease or condition associated with oxidative stress. In this context, "associated with" means that oxidative stress may be directly or indirectly linked to the disease or condition. Preferably, the disease or condition is selected from at least one of cancer, cardiovascular disease, neurological disease, respiratory disease, rheumatoid arthritis, liver disease, kidney disease, inflammation, diabetes, metabolic disorders, or aging.

[0050] In embodiments, the mixtures of the present disclosure are formulated for administration to a subject in need thereof. The subject may be a human or a non-human animal. The mixtures may be formulated for simultaneous administration, i.e., the components of the mixture are administered simultaneously to a subject in need thereof. Simultaneous administration includes premixing the components of the mixture or administering the separate components simultaneously. Alternatively, the components of the mixture may be administered sequentially. In this regard, the present disclosure also encompasses a method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject the mixtures or compositions disclosed herein.

[0051]

[0051] The mixtures, components combined to achieve a mixture, or compositions of the present disclosure may include liquid preparations for administration by any orifice or surface, including oral, nasal, anal, vaginal, peroral, intragastric, and mucosal (e.g., perlinqual, alveolar, gingival, olfactory, or respiratory tract) administration. Liquids may include suspensions, syrups or elixirs, and preparations for parenteral, subcutaneous, intradermal, intramuscular, intraperitoneal, or intravenous administration (e.g., by injection), such as sterile suspensions or emulsions. In embodiments, the liquid mixture (or components thereof) or composition may include a carrier, diluent, or excipient, such as sterile water, saline, or glucose. In embodiments, the mixtures (or components thereof) or compositions of the present disclosure may contain auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, gelling or thickening additives, preservatives, flavoring agents, and coloring agents, depending on the route of administration and the preparation desired. Suitable preparations can be prepared without undue experimentation with the aid of standard textbooks, such as "REMINGTON'S PHARMACEUTICAL SCIENCE", 17th Edition, 1985, which is incorporated herein by reference.

[0052] In embodiments, the mixtures (or components combined to achieve a mixture) or compositions of the present disclosure may be provided in "solid" forms such as pills, tablets, capsules, and caplets, including sustained release "solid" preparations, or "solid" preparations having a liquid tilling, such as a gelatin coating liquid, so that the gelatin dissolves in the stomach and is delivered to the intestine. If nasal or respiratory (mucosal) administration is desired, the compositions may be shaped and delivered by a squeeze spray dispenser, pump dispenser, or aerosol dispenser. Aerosols are usually pressurized by hydrocarbons. Pump dispensers can preferably deliver a metered dose or a dose having a particular particle size.

[0053]

[0053] Liquid preparations may be the preferred form of administration by injection or oral administration to animals, children, especially infants, and other subjects who may have difficulty swallowing pills, tablets, capsules, etc., or in multiple dose situations, whereas viscous preparations may be formulated within an appropriate viscosity range to prolong the period of contact with mucous membranes (e.g., the lining of the stomach or nasal mucosa).

[0054]

[0054] The selection of appropriate carriers and other additives will depend on the exact route of administration and the nature of the particular dosage form, for example, a liquid dosage form (i.e., a solution, suspension, gel or another liquid form), or a solid dosage form (i.e., a pill, tablet, capsule, caplet, sustained release form or liquid filled form).

[0055]

[0055] Solutions, suspensions and gels usually contain a major amount of water (preferably purified water) in addition to the active ingredients. Minor amounts of other ingredients may also be present, such as pH adjusters (e.g., bases such as NaOH), emulsifiers or dispersants, buffers, preservatives, wetting agents, gelling agents (e.g., methylcellulose), colorants, and / or flavoring agents. The compositions can be isotonic, i.e., have the same osmotic pressure as blood and tears.

[0056] The desired isotonicity of the compositions of the present disclosure may be achieved using sodium tartrate, propylene glycol, or other inorganic or organic solutes. Sodium chloride is particularly preferred for buffers containing sodium ions.

[0057] The viscosity of the composition can be maintained at a selected level using a pharma- ceutically acceptable thickening agent. Methylcellulose is preferred because it is readily and economically available and easy to handle. Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, and carbomer. The preferred concentration of the thickening agent will vary with the agent selected. The important point is to use an amount that achieves the selected viscosity. Viscous compositions are usually prepared from solutions by the addition of such thickening agents.

[0058]

[0058] Pharmaceutically acceptable preservatives can be used to extend the shelf life of the composition. Benzyl alcohol may be preferred, but various preservatives such as parabens, thimerosal, chlorobutanol, or benzalkonium chloride can also be used. Suitable concentrations of preservatives are about 0.02% to about 2% by total weight, but may vary considerably depending on the agent selected.

[0059]

[0059] In other embodiments, the mixture of the present disclosure may contain sulforaphane or an analog thereof and glycine or an analog thereof in a molar ratio of about 1:1000 to about 1000:1, preferably about 1:800 to about 800:1, and most preferably about 1:500.

[0060]

[0060] In an embodiment, the ingredients for preparing the mixture or composition of the present disclosure may include a compound, substance or raw material in an amount of about 1 μmol / kg body weight to about 100 mmol / kg body weight, preferably about 10 μmol / kg body weight to about 1 mmol / kg body weight, and more preferably about 100 μmol / kg body weight to about 500 μmol / kg body weight.

[0061] In an embodiment, sulforaphane or an analog thereof can be formulated for administration at a dose of about 50 nmol / kg body weight to about 500 μmol / kg body weight, preferably about 500 nmol / kg body weight to about 100 μmol / kg body weight, more preferably about 100 nmol / kg body weight to about 50 μmol / kg body weight, more preferably about 50 nmol / kg body weight to about 5 μmol / kg body weight. Preferably, administration is by the oral route.

[0062]

[0062] In an embodiment, glycine or an analog thereof may be formulated for administration at a dose of about 10 μmol / kg body weight to about 500 mmol / kg body weight, preferably 10 μmol / kg body weight to 100 mmol / kg body weight, more preferably 10 μmol / kg body weight to 10 mmol / kg body weight, more preferably 50 μmol / kg body weight to 2 mmol / kg body weight.

[0063] In another aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: Sulforaphane or an analog thereof; glycine or an analog thereof; and optionally at least one ingredient.

[0064] In an embodiment, the at least one ingredient is selected from the group consisting of lipids, proteins, carbohydrates, prebiotics, probiotics, essential fatty acids, nucleotides, nucleosides, vitamins, and minerals.

[0065]

[0065] In embodiments, the proteins include casein, alpha-lactalbumin, lactoferrin, serum albumin, whey, soy protein, rice protein, corn protein, oat protein, barley protein, wheat protein, rye protein, pea protein, egg protein, sunflower seed protein, potato protein, fish protein, meat protein, immunoglobulins, and combinations thereof.

[0066]

[0066] In embodiments, carbohydrates include lactose, sucrose, maltodextrin, starch, and mixtures thereof.

[0067]

[0067] In embodiments, the lipids include palm olein, high oleic sunflower oil, high oleic safflower oil, canola oil, fish oil, coconut oil, milk fat, or mixtures thereof.

[0068] In an embodiment, the essential fatty acids may include linoleic acid (LA), alpha-linolenic acid (ALA), and polyunsaturated fatty acids (PUFAs). The nutritional composition of the present invention may further include gangliosides monosialoganglioside-3 (GM3) and disialoganglioside-3 (GD3), phospholipids such as sphingomyelin, phospholipids phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and the like, and combinations thereof.

[0069]

[0069] In an embodiment, the prebiotics include oligosaccharides, optionally containing fructose, galactose, mannose; dietary fiber, especially soluble fiber, soy fiber; inulin; or mixtures thereof. Preferred prebiotics are fructooligosaccharides (FOS), galactooligosaccharides (GOS), isomaltooligosaccharides (IMO), xylooligosaccharides (XOS), arabinoxylooligosaccharides (AXOS), mannanoligosaccharides (MOS), soy oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose oligosaccharides (PAO), maltooligosaccharides, gums and / or hydrolysates thereof, pectin and / or hydrolysates thereof, and combinations thereof.

[0070]

[0070] In an embodiment, the probiotics include those of the genus Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, Kluyveromyces, Saccharomyces, and Candida, and in particular, those of the genus Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium animalis, Bifidobacterium breve, and Bifidobacterium infantis. infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus salivarius, Lactococcus lactis, Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus salivarius, Lactococcus lactis, Enterococcus faecium faecium, Saccharomyces cerevisiae, Saccharomyces boulardiiboulardii) or mixtures thereof, preferably selected from the group consisting of Bifidobacterium longum NCC3001 (ATCC BAA-999), Bifidobacterium longum NCC2705 (CNCM I-2618), Bifidobacterium longum NCC490 (CNCM I-2170), Bifidobacterium lactis NCC2818 (CNCM I-3446), Bifidobacterium breve strain A, Lactobacillus paracasei NCC2461 (CNCM I-2116), Lactobacillus johnsonii NCC533 (CNCM I-1225), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus NCC4007 (CNCM I-2226), Lactobacillus ...2226), Lactobacillus lactis NCC2818 (CNCM I-2226), Lactobacillus lactis NCC2818 (CNCM I-2226), Lactobacillus lactis NCC2818 (CNCM I-2226), Lactobacillus lactis NCC2818 (CNCM I-2226), Lactobacillus lactis NCC2818 (CNCM I-22 1.3724), Enterococcus faecium SF68 (NCC2768; NCIMB10415), and mixtures thereof.

[0071]

[0071] In embodiments, the nucleotides include cytidine monophosphate (CMP), uridine monophosphate (UMP), adenosine monophosphate (AMP), guanosine monophosphate (GMP), or any mixture or derivative thereof.

[0072] In an embodiment, the vitamins and minerals include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine, and mixtures thereof. Minerals are usually added in the form of a salt.

[0073]

[0073] In another aspect, the disclosure provides methods of making mixtures (or components thereof) and compositions. In embodiments, methods of preparing components for use in preparing mixtures and compositions may include synthetic production or extracting, isolating or purifying substances, compounds or raw materials from natural sources, and optionally formulating such substances, compounds or raw materials for administration. The substances, compounds or raw materials may be in liquid or solid form and may include auxiliary substances, etc.

[0074] In an embodiment, a method of making a composition of the present disclosure includes a step of mixing substances, compounds, or raw materials. In an embodiment, the method includes a step of mixing sulforaphane or an analog thereof with at least one substance and optionally at least one additional raw material. The method may optionally further include a step of mixing a pharma- ceutically acceptable carrier or excipient.

[0075]

[0075] Those skilled in the art will understand that all features of the present disclosure disclosed herein can be freely combined. Furthermore, features described for different embodiments of the present disclosure may be combined.

[0076] Furthermore, where known equivalents exist to specific features, such equivalents are incorporated as if specifically referred to herein.

[0077] Further examples of the present disclosure are described below. However, the present disclosure should not be limited to these examples, and it should be understood that the aspects and embodiments disclosed herein are capable of variations, modifications, and / or additions other than those specifically described, and the present disclosure includes all such variations, modifications, and / or additions that fall within the scope of the claims. EXAMPLES

[0078] Example 1 - Reduction of oxidative stress in zebrafish Larval zebrafish provide a suitable vertebrate model for studying oxidative stress in vitro 35 Figure 1 shows data generated by an in vitro study of zebrafish larval viability. The viability assay was performed according to a previously described protocol. 36 The method was performed as described previously with some modifications. Briefly, wild-type zebrafish larvae (AB strain, ZFIN ID: ZDB-GENO-960809-7) were used. At 3.5 days post-fertilization (dpf), 24 larvae per condition were placed in 60 mm Petri dishes containing 5 mL egg water (0.6 g / L sea salt, Tecniplast). Compounds of interest were added directly to the egg water for 12 h. Compounds were subsequently removed at 4 days post-fertilization (dpf4) and larvae were cultured in 2.5 mM hydrogen peroxide (H2O2) in 96-well plates. 2 O 2 The mice were then transferred to a volume of 200 μL of fresh water containing 100 mM NaCl (Sigma Merck). Survival was monitored 24 hours after treatment.

[0079]

[0079] The juvenile fish in the breeding water (vehicle) containing no additives were cultured under H 2 O 2 Various groups in the rearing water incubated with vehicle + 2.5 mM H 2 O 2 , vehicle + 2.5 mM H 2 O 2 + 1 μM sulforaphane (Sfn; Molport MolPort-003-850-350, stock prepared in DMSO, Sigma Merck), vehicle + 2.5 mM H 2 O 2 + 500 μM L-glycine (Gly; Sigma Merck, stock prepared in water), or vehicle + 2.5 mM H 2 O 2 Compared with +1 μM sulforaphane + 500 μM L-glycine.

[0080] FIG. 1 shows that only in the vehicle did 100% of the larvae survive after 24 hours. In comparison, in the vehicle + 2.5 mM H2 O 2 Only about 10% of the juveniles survived in the presence of vehicle + 2.5 mM H 2 O 2 + 1 μM Sfn or vehicle + 2.5 mM H 2 O 2 +500 μM L-glycine. 2 O 2 Larvae incubated in +1 μM sulforaphane + 500 μM L-glycine showed no other H 2 O 2 The survival rate of the control group was statistically significantly increased compared to the control group. Statistical significance was calculated by two-way analysis of variance, Tukey's multiple comparison test, as summarized in Table 1.

[0081] [Table 1]

[0082]

[0081] Although exemplary aspects and embodiments have been illustrated and described, including the best mode known to the inventors, those skilled in the art will recognize that variations of the aspects and embodiments are considered to be within the scope of the disclosure.

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Claims

1. A mixture comprising sulforaphane or an analog thereof and glycine or an analog thereof.

2. The analog of sulforaphane is 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, cis- or trans-3-(methylsulfonyl)cyclohexylmethyl isothiocyanate, and combinations thereof, The mixture according to claim 1, selected from the group consisting of.

3. The mixture according to claim 1 or 2, wherein the mixture comprises sulforaphane and glycine.

4. The mixture according to claim 1 or 2, which is for use in the treatment or prevention of a disease or condition associated with oxidative stress.

5. The mixture is cancer, cardiovascular disease, neural disease, respiratory disease, rheumatoid arthritis, liver disease, kidney disease, inflammation, diabetes, metabolic disorders, and aging The mixture according to claim 1 or 2, which is for use in the treatment or prevention of at least one disease or condition selected from the group consisting of.

6. The mixture according to claim 1 or 2, wherein sulforaphane or an analog thereof and glycine or an analog thereof are formulated for simultaneous or sequential administration to a subject in need thereof.

7. The mixture according to claim 1 or 2, wherein the molar ratio of sulforaphane or an analog thereof to glycine or an analog thereof is from 1:1000 to 1000:

1.

8. Sulforaphane or an analog thereof, glycine or an analog thereof, Optionally, a pharmaceutically acceptable carrier, The mixture according to claim 1 or 2, consisting of.

9. The mixture according to claim 1 or 2, wherein the mixture further comprises at least one raw material.

10. The at least one raw material is lipids, proteins, carbohydrates, prebiotics, probiotics, essential fatty acids, nucleotides, nucleosides, vitamins, and minerals The mixture according to claim 9, selected from the group consisting of.

11. The mixture according to claim 1 or 2, wherein the mixture is formulated for intravenous administration, subcutaneous administration, or oral administration.

12. The mixture according to claim 1 or 2, wherein the mixture of sulforaphane or an analog thereof and glycine or an analog thereof can act synergistically to treat or prevent a disease or condition as compared to sulforaphane or an analog thereof or glycine or an analog thereof when administered separately.

13. Sulforaphane or an analog thereof, glycine or an analog thereof, optionally, at least one raw material and / or a pharmaceutically acceptable carrier, A composition comprising.

14. The at least one raw material is lipids, proteins, carbohydrates, prebiotics, probiotics, essential fatty acids, nucleotides, nucleosides, vitamins, and minerals The composition according to claim 13, which is selected from the group consisting of.

15. A method for producing the composition according to claim 13 or 14, comprising: mixing the sulforaphane or an analog thereof with the at least one amino acid or an analog thereof, and optionally the at least one additional raw material and / or the pharmaceutically acceptable carrier.

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