Combinations and compositions comprising nicotinic acid or derivatives thereof and fatty acid or derivatives thereof

Abstract

The present invention relates to combinations and compositions comprising (i) nicotinic acid or a derivative thereof, and (ii) a fatty acid selected from tetradecyl thioacetic acid 5 (TTA) or a derivative thereof, or a derivative thereof. The invention also relates to the use of a pharmaceutical or nutraceutical combination or composition in a method for preventing or treating mitochondrial diseases, inflammatory diseases, metabolic disorders, neurodegenerative diseases and / or aging in an animal, and / or in a method for increasing brain metabolism in an animal, in which said pharmaceutical or nutraceutical combination or composition is administered to said animal, and wherein the pharmaceutical or nutritional combination or composition comprises (i) nicotinic acid or a derivative thereof, and (ii) a fatty acid selected from tetradecyl thioacetic acid (TTA) or a derivative thereof or a derivative thereof.

Description

Technical Field

[0001] The present invention relates to a combination and composition comprising nicotinic acid or its derivatives and fatty acids or their derivatives. More particularly, the present invention relates to such a combination and composition and its use, especially for improving mitochondrial function and / or reducing inflammation and / or reducing metabolic disorders in animals, and preventing or treating mitochondrial-related diseases, inflammatory diseases and / or metabolic disorders, as well as preventing or treating neurodegenerative diseases, neurodegeneration or aging in animals including humans and / or enhancing energy flow between the liver and the brain. Background Art

[0002] Fatty acids are essential for all living organisms. They are integral components of all types of cell membranes and are involved in various ways in energy generation and storage, in modifying membrane structure and function, and in regulating cell signaling pathways. Disturbances in lipid metabolism are closely associated with many common lifestyle-related diseases or the so-called metabolic syndrome, see Figure 1 The manifestations of many of these disorders can be influenced by diet.

[0003] Mitochondrial diseases are a group of metabolic disorders whose symptoms can vary, depending on how many mitochondria are defective and where they are located in the body. Sometimes only one organ, tissue, or cell type is affected. But often the problem affects many of them. Muscle and nerve cells have particularly high energy demands, so muscle and nerve problems are common. The disease can be mild or severe. Some types can be fatal.

[0004] Other metabolic disorders include obesity, type 2 diabetes, prediabetes, and metabolic syndrome. The global health crisis of such disorders is well recognized. The prevalence of each of them has reached pandemic proportions worldwide, and their prevalence is expected to continue to rise in the coming decades, further exacerbating the current worldwide health crisis surrounding these diseases.

[0005] The beneficial effects of marine oils are well established, although their health effects vary depending on the source of the oil, the metabolic disorder to be addressed, and the population being targeted (age, sex, lifestyle, etc.). Omega-3 fatty acids and other dietary compounds have been found to affect liver mitochondrial function in some animals, and their use can increase mitochondrial fatty acid oxidation, a process that burns long-chain fatty acids. Studies on the effects of dietary lipids and other dietary compounds have further demonstrated their effects on insulin and glucose homeostasis, plasma lipids, fat depots, and antioxidant and anti-inflammatory activities, including reducing plaque formation in the aorta of mice and improving the health of the inflammatory bowel. Studies have further shown that combinations of omega-3 fatty acids and other dietary compounds have positive effects on lipid metabolism and have shown that they enhance the lipid-lowering effects of marine oils (fish, krill) and improve mitochondrial function.

[0006] Although a variety of compounds and compositions are known to be useful for improving the function of various organs of the body, as well as for preventing or treating several of these disorders and diseases, there is still a need for new and improved compounds and compositions that can be used to prevent, reduce, alleviate or reverse mitochondrial dysfunction and / or improve mitochondrial function in animals, including humans. There is also a need for new and improved compounds and compositions that can be used to prevent, reduce, alleviate or reverse inflammation in animals, including humans. In addition, there is a need for new and improved compounds and compositions that can be used to prevent, reduce, alleviate or reverse metabolic disorders in animals, including humans. Finally, there is a need for new and improved compounds that can be used to prevent, reduce, alleviate or reverse the energy gap that is reduced during neurodegeneration and aging in animals, including humans, and to enhance energy flow between the liver and the brain, such as ketones from the liver and substances that can penetrate the blood-brain barrier. Summary of the invention

[0007] One object of the present invention is to provide a combination, composition and compound that effectively prevents, reduces, alleviates or reverses mitochondrial dysfunction and / or improves mitochondrial function in animals.

[0008] Another object of the present invention is to provide a combination, composition and compound that is effective in preventing, reducing, alleviating or reversing inflammation in animals.

[0009] Another object of the present invention is to provide a combination, composition and compound that is effective in preventing, reducing, alleviating or reversing metabolic disorders in animals.

[0010] Another object of the present invention is to provide a combination, composition and compound that can be used to prevent, reduce, alleviate or reverse the reduced energy gap during neurodegeneration and aging in animals including humans, and enhance energy flow between the liver and brain, such as ketones from the liver and substances that can penetrate the blood-brain barrier.

[0011] Another object of the present invention is to provide a pharmaceutical or nutritional combination, composition and compound that can be used to prevent or treat mitochondrial diseases, inflammatory diseases, metabolic disorders, neurodegenerative diseases and / or aging in animals.

[0012] The present invention provides a combination, composition and compound that can be used to prevent or treat severe conditions and / or diseases of animals, such as mitochondrial diseases, inflammatory diseases and / or metabolic disorders. The example of such mitochondrial diseases includes diseases caused by or associated with mitochondrial dysfunction in one or more organs of the animal body, that is, mitochondrial diseases or mitochondrial-related diseases, such as, for example, neurodegenerative diseases (ND), such as Parkinson's disease (PD), Huntington's disease (HD), dementia, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS); cancer, diabetes including type 1 diabetes, type 2 diabetes (T2D), gestational diabetes and maternal inherited diabetes with deafness (MIDD), nephropathy, lung disease and cardiovascular disease including atherosclerosis. The example of inflammatory diseases that can be prevented or treated according to the present invention includes chronic inflammatory diseases, also referred to as autoimmune diseases. The example of metabolic disorders that can be prevented or treated according to the present invention includes metabolic syndrome (MS), obesity such as abdominal obesity, type 2 diabetes (T2D) and prediabetes.

[0013] According to the present invention, the combinations, compositions and compounds of the present invention provide improved effects, often synergistic effects, i.e., the effects of the combinations, compositions and compounds are greater than, or provide benefits different from, the effects of each individual compound of the combinations and compositions when administered alone.

[0014] Thus, the present invention can achieve the prevention, inhibition, reduction, treatment, alleviation and / or reversal of organ dysfunction, organ pathology, (chronic) inflammation, disorders and / or diseases, milder symptoms of disorders and / or diseases, as well as improvement in health, overall health and / or enhanced quality of life.

[0015] Thus, in one aspect, the invention relates to a combination or composition comprising:

[0016] (i) nicotinic acid or a derivative thereof, and

[0017] (ii) Fatty acids or their derivatives.

[0018] In another aspect, the present invention relates to a pharmaceutical or nutritional combination or composition for use in a method for preventing or treating mitochondrial disease, inflammatory disease, metabolic disorder, neurodegenerative disease and / or aging in an animal, wherein the pharmaceutical or nutritional combination or composition is administered to the animal, and wherein the pharmaceutical or nutritional combination or composition comprises:

[0019] (i) nicotinic acid or a derivative thereof, and

[0020] (ii) Fatty acids or their derivatives.

[0021] In another aspect, the invention relates to a method of preparing a composition comprising mixing:

[0022] (i) nicotinic acid or a derivative thereof, and

[0023] (ii) fatty acids or their derivatives.

[0024] In another aspect, the present invention relates to a method for preventing or treating mitochondrial diseases, inflammatory diseases, metabolic disorders, neurodegenerative diseases and / or aging, the method comprising administering to a subject in need thereof a combination or composition comprising:

[0025] (i) nicotinic acid or a derivative thereof, and

[0026] (ii) fatty acids or their derivatives.

[0027] In another aspect, the invention relates to a method of preventing or treating a reduced energy gap during or caused by neurodegeneration or aging, enhancing energy flow between the liver and brain, and / or increasing brain metabolism, the method comprising administering to a subject in need thereof a combination or composition comprising:

[0028] (i) nicotinic acid or a derivative thereof, and

[0029] (ii) fatty acids or their derivatives.

[0030] In other aspects, the present invention relates to combinations, compositions, pharmaceutical combinations, drug combinations, nutritional combinations and nutritional compositions as defined herein, and methods and uses as defined herein, comprising:

[0031] (i) nicotinic acid or a derivative thereof, and

[0032] (ii) a fatty acid or a derivative thereof selected from tetradecylthioacetic acid (TTA) or a derivative thereof.

[0033] These and other objects and aspects of the present invention will be described in further detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Schematic representation of the cardiometabolic syndrome and lifestyle-related diseases.

[0035] Figure 2 is a schematic diagram of the choline oxidation pathway that occurs in mitochondria.

[0036] Figure 3 is a schematic diagram of the tryptophan-kynurenine and tryptophan-nicotinamide pathways.

[0037] Figure 4 is a schematic diagram of the tryptophan-nicotinamide pathway.

[0038] Figure 5 is a schematic diagram of oleic acid metabolism in rat brain cells when a compound of the present invention is used compared to when only the compound alone is used. DETAILED DESCRIPTION

[0039] The present invention generally relates to a combination or composition comprising:

[0040] (i) nicotinic acid or a derivative thereof, and

[0041] (ii) Fatty acids or their derivatives.

[0042] According to a preferred embodiment of the present invention, the fatty acid or its derivative is tetradecylthioacetic acid (TTA) or its derivative, preferably tetradecylthioacetic acid (TTA).

[0043] Additionally, the present invention generally relates to a pharmaceutical or nutritional combination or composition for use in a method for preventing or treating mitochondrial disease, inflammatory disease, metabolic disorder, neurodegenerative disease and / or aging in an animal, and / or for use in a method for increasing brain metabolism in an animal, wherein the pharmaceutical or nutritional combination or composition is administered to the animal, and wherein the pharmaceutical or nutritional combination or composition comprises:

[0044] (i) nicotinic acid or a derivative thereof, and

[0045] (ii) Fatty acids or their derivatives.

[0046] In a preferred embodiment of the present invention, the fatty acid or its derivative is tetradecylthioacetic acid (TTA) or its derivative, preferably tetradecylthioacetic acid (TTA).

[0047] As used herein, the terms "compound" and "compounds" refer to a compound and two or more compounds, respectively. As used herein, the term "compound of the present invention" refers to nicotinic acid or its derivatives and fatty acids or their derivatives, which are included or contained in the combination and composition of the present invention. As used herein, the term "combination" refers to two or more chemical compounds or agents, which can be separate, such as used alone, or together, such as in the form of a composition. As used herein, the term "composition" refers to a mixture of two or more chemical compounds or agents. As used herein, the term "agent" refers to a chemical compound or a mixture of two or more chemical compounds. Unless otherwise stated, as used herein, the term "combination of the present invention" is meant to include a combination of the present invention, a pharmaceutical combination of the present invention, and a nutritional combination of the present invention. Unless otherwise stated, as used herein, the term "composition of the present invention" is meant to include a composition of the present invention, a pharmaceutical composition of the present invention, and a nutritional composition of the present invention. Unless otherwise stated, as used herein, the term "combination of the present invention and composition" is meant to include both a combination of the present invention and a composition of the present invention.

[0048] As used herein, the term "pharmaceutical composition" refers to a composition comprising one or more compounds or agents that are pharmaceutically active in animals or humans, and / or a composition comprising an active pharmaceutical ingredient (API) that produces one or more desired effects in the animal or human body.

[0049] As used herein, the term "nutritional composition" refers to a composition comprising any ingestible substance for animal or human consumption (including but not limited to nutritional supplements, functional foods, herbal supplements, etc.). The term also includes foods for human consumption and animal feeds, in which the composition of the present invention is an additive rather than a major ingredient. This particularly relates to animal feeds, in which any feed can be supplemented with the nutritional composition of the present invention to obtain its biological effects.

[0050] As used herein, the terms "prevent", "preventing" and "prevention" include preventing a medical condition or one or more symptoms or complications associated with the condition, reducing the risk of its development and delaying its onset. As used herein, the terms "treat", "treating" and "treatment" include alleviating, improving, inhibiting its progress, reversing or eliminating a medical condition or one or more symptoms or complications associated with the condition, and alleviating, improving or eradicating one or more causes of the condition. Reference to "treatment" of a medical condition includes prevention of the condition. As used herein, the term "medical condition" (or simply "condition") includes one or more diseases and illnesses. The terms "disease" and "illness" are used interchangeably herein.

[0051] According to the present invention, examples of suitable nicotinic acid and its derivatives include nicotinic acid (also known as nicotinic acid and vitamin B3), its amides and esters, including nicotinamide (NAM) (also known as niacinamide) and its derivatives, including nicotinic acid riboside compounds, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), including derivatives of both oxidized and reduced forms of NR (NRH), nicotinic acid riboside (NAR), including derivatives of both oxidized and reduced forms of NAR, (NARH) and its derivatives, nicotinamide adenine dinucleotide (NAD) and its derivatives, including both oxidized and reduced forms of NAD, including NAD+ and NADH, nicotinic acid esters, including nicotinic acid methyl ester (nicotinic acid methyl ester), nicotinic acid pentaerythritol ester (niceritrol), 2-aminopyridine-3-carboxylic acid, 5-aminopyridine-3-carboxylic acid, 2-fluoro-6-(pyrrolidinone-1-yl)nicotinic acid methyl ester, 2-chloro-6-methylnicotinic acid, 5-hydroxy-2-(2-methyl-3-trifluoromethylanilino)nicotinic acid, and combinations thereof. According to the present invention, preferred examples of nicotinic acid and its derivatives include nicotinic acid, nicotinamide (NAM), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinic acid riboside (NAR), nicotinic acid esters and combinations thereof, such as nicotinamide riboside (NR), nicotinic acid riboside (NAR) and combinations thereof.

[0052] The fatty acid or its derivative according to the present invention can be represented by

[0053] a) General formula R"-COO-(CH2) 2n+1-X-R', wherein X is a sulfur atom, a selenium atom, an oxygen atom, a CH2 group, a SO group or a SO2 group; n is an integer from 0 to 11; and R' is a saturated or unsaturated, optionally substituted straight or branched alkyl group, wherein the main chain of said R' contains 13 to 23 carbon atoms and optionally one or more hetero groups selected from the group consisting of oxygen atoms, sulfur atoms, selenium atoms, oxygen atoms, CH2 groups, SO groups and SO2 groups; and R" is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms;

[0054] and / or

[0055] b) general formula (I),

[0056]

[0057] Where R1, R2 and R3 represent

[0058] i) a hydrogen atom; or

[0059] ii) a group of formula CO-R, wherein R is a saturated or unsaturated, optionally substituted, linear or branched alkyl group, and the main chain of said R contains 1 to 25 carbon atoms; or

[0060] iii) having the formula CO-(CH2) 2n+1 -X-R' group, wherein X is a sulfur atom, a selenium atom, an oxygen atom, a CH2 group, a SO group or a SO2 group; n is an integer from 0 to 11; and R' is a saturated or unsaturated, optionally substituted straight or branched alkyl group, wherein the main chain of R' contains 13 to 23 carbon atoms and optionally one or more hetero groups selected from the group consisting of oxygen atoms, sulfur atoms, selenium atoms, oxygen atoms, CH2 groups, SO groups and SO2 groups;

[0061] iv) an entity selected from the group consisting of: -PO3CH2CHNH3COOH (serine), PO3CH2CH2NH3 (ethanolamine), PO3CH2CH2N(CH3)3 (choline), PO3CH2CHOHCH2OH (glycerol) and PO3(CHOH)6 (inositol);

[0062] wherein R1, R2 and R3 are independently selected from i), ii), iii) or iv), but at least one of R1, R2 or R3 is defined by iii); and / or

[0063] c) general formula (II),

[0064]

[0065] wherein A1, A2 and A3 are independently selected and represent an oxygen atom, a sulfur atom or an N-R4 group, wherein R4 is a hydrogen atom or a saturated or unsaturated, optionally substituted, straight or branched chain alkyl group containing 1 to 5 carbon atoms;

[0066] Where R1, R2 and R3 represent

[0067] i) a hydrogen atom or a saturated or unsaturated, optionally substituted, straight-chain or branched alkyl group containing 1 to 23 carbon atoms; or

[0068] ii) a group of formula CO-R, wherein R is a saturated or unsaturated, optionally substituted, linear or branched alkyl group, and the main chain of said R contains 1 to 25 carbon atoms; or

[0069] iii) having the formula CO-(CH2) 2n+1 -X-R' group, wherein X is a sulfur atom, a selenium atom, an oxygen atom, a CH2 group, a SO group or a SO2 group; n is an integer from 0 to 11; and R' is a saturated or unsaturated, optionally substituted straight or branched alkyl group, wherein the main chain of R' contains 13 to 23 carbon atoms and optionally one or more hetero groups selected from the group consisting of oxygen atoms, sulfur atoms, selenium atoms, oxygen atoms, CH2 groups, SO groups and SO2 groups;

[0070] iv) an entity selected from the group consisting of: -PO3CH2CHNH3COOH (serine), PO3CH2CH2NH3 (ethanolamine), PO3CH2CH2N(CH3)3 (choline), PO3CH2CHOHCH2OH (glycerol) and PO3(CHOH)6 (inositol);

[0071] wherein R1, R2 and R3 are independently selected from i), ii), iii) or iv), but at least one of R1, R2 or R3 is defined by iii); and / or

[0072] A salt, prodrug or complex of a compound according to a) to c).

[0073] Examples of suitable fatty acids and their derivatives according to the present invention include those wherein:

[0074] - At least one of R1, R2 and R3 is an alkyl group;

[0075] - at least one of R1, R2 and R3 is an alkenyl group;

[0076] - at least one of R1, R2 and R3 is an alkynyl group;

[0077] - X is a sulfur atom or a selenium atom, preferably a sulfur atom;

[0078] - said n is 0 or 1;

[0079] - At least one of R1, R2 and R3 is tetradecylthioacetic acid;

[0080] - at least one of R1, R2 and R3 is tetradecylselenoacetic acid; and / or

[0081] - fatty acids or derivatives thereof having a saturated, unsaturated or polyunsaturated chain or backbone and comprising 13 to 23 carbon atoms and optionally one or more hetero groups selected from the group consisting of oxygen atoms, sulfur atoms, selenium atoms, oxygen atoms, SO groups and SO2 groups.

[0082] According to the present invention, examples of preferred fatty acids and derivatives thereof include those wherein at least one of R1, R2 and R3 is tetradecylthioacetic acid or a tetradecylthioacetic acid group.

[0083] Examples of suitable fatty acids and derivatives thereof include non-β-oxidizable fatty acids, tetradecylthioacetic acid (TTA), tetradecylselenoacetic acid, TTA containing one or more carbon-carbon triple bonds, such as 2-(tridec-12-yne-1-thio) acid, 3-thio-15-heptadecyne, and esters thereof, including monoesters, diesters and triesters thereof, monoacylglycerols, diacylglycerols and triacylglycerols thereof, amides thereof, including monoamides, diamides and triamides thereof, peptides thereof; compounds containing phospholipids, including phospholipids selected from the group consisting of phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol; phosphatidylcholine (PC) derivative 1,2-di-tetradecene Alkylthioacetyl-sn-glycero-3-phosphocholine, phosphatidylethanolamine (PE) derivative 1,2-di-tetradecylthioacetyl-sn-glycero-3-phosphoethanolamine; monoacylglycerols, diacylglycerols and triacylglycerols of fatty acids; polyunsaturated fatty acids in the form of monoglycerides, diglycerides or triglycerides, esters such as ethyl esters, free fatty acids or salts thereof; ω-3, ω-6 and / or ω-9 polyunsaturated fatty acids in the form of monoglycerides, diglycerides or triglycerides, esters such as ethyl esters, free fatty acids or salts thereof; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of monoglycerides, diglycerides or triglycerides, esters such as ethyl esters, free fatty acids or salts thereof, and combinations thereof;

[0084] Examples of preferred fatty acids and their derivatives include non-β-oxidizable fatty acids and their derivatives, tetradecylthioacetic acid (TTA) and its derivatives, including their derivatives as defined above; monoacylglycerols, diacylglycerols and triacylglycerols of fatty acids, including fatty acids as defined above; polyunsaturated fatty acids and their derivatives, including their derivatives as defined above, as well as EPA and DHA and their derivatives as defined above, such as tetradecylthioacetic acid (TTA) and its derivatives, and combinations thereof.

[0085] During beta-oxidation, the fatty acid is enzymatically oxidized, cleaving between carbon 2 and carbon 3 (when counted from the carboxyl end of the fatty acid), resulting in the removal of two carbon atoms on either side of the oxidation site in the form of acetic acid. This step is then repeated on the fatty acid, which is now two carbons short, and again until the fatty acid is fully oxidized. Beta-oxidation is the normal way that most fatty acids are broken down and metabolized in the body. Blocking of beta-oxidation in some of the compounds of the present invention is achieved by inserting a non-oxidizable group in the X position in the above formula, where X is defined as S, O, SO, SO2, CH2, or Se. Fatty acids containing S, O, SO, SO2, CH2, or Se at the X position in the above formula are referred to as non-beta-oxidizable fatty acids.

[0086] As used herein, the term "mitochondrial disease", also referred to as "mitochondrial-related disease", refers to a disorder caused by dysfunctional mitochondria, or mitochondrial dysfunction, and may occur when the mitochondria of a cell cannot produce enough energy for cell or organ function. Mitochondrial disease can be attributed to, for example, congenital genetic defects or acquired defects. Mitochondrial disease can be caused by, for example, oxidative damage during aging, elevated intracellular calcium levels, exposure of affected cells to nitric oxide, ischemia, hypoxia, microtubule-related defects in mitochondrial axonal transport, or expression of mitochondrial uncoupling proteins. Congenital mitochondrial disease is caused by genetic mutations, deletions or other defects in mitochondrial DNA, nuclear genes that regulate mitochondrial DNA integrity, or nuclear genes that encode proteins. Acquired mitochondrial defects can be caused by, for example, damage to mitochondrial DNA caused by oxidative processes or aging, mitochondrial dysfunction, inhibition of respiratory chain complexes, mitochondrial respiratory defects and deficiencies, oxygen deficiency, impaired nuclear-mitochondrial interactions, and expression of mitochondrial uncoupling proteins in response to, for example, lipids, oxidative damage, or inflammation.

[0087] Mitochondrial dysfunction plays a major role in several neurological disorders. The pathogenesis and clinical manifestations stem from the fundamental role of bioenergetics in cell biology. Ultimately, if ATP is depleted, the cell will die. Mitochondrial damage may lead to the release of pro-apoptotic factors such as cytochrome c. Many pathways implicated in mitochondrial dysfunction in one mitochondrial disease may also be prevalent in the pathogenesis of other mitochondrial diseases.

[0088] Examples of diseases that can be prevented or treated according to the present invention include diseases caused by or associated with mitochondrial dysfunction in one or more organs of an animal's body, i.e., mitochondrial diseases or mitochondrial-related diseases, such as, for example, neurodegenerative diseases (ND), such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), Huntington's disease (HD), dementia, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS); cancer, diabetes including type 1 diabetes, type 2 diabetes (T2D), gestational diabetes and maternal inherited diabetes with deafness (MIDD), nephropathy, lung disease and cardiovascular disease including atherosclerosis. Other examples of diseases that can be prevented or treated according to the present invention include inflammatory diseases, including chronic inflammatory diseases, also known as autoimmune diseases and metabolic disorders.

[0089] Cancer is a disease caused by the uncontrolled division of abnormal cells in one or more parts of an animal's body. Abnormal (cancer) cells have a metabolism that is different from normal cells, which allows them to survive longer and grow faster. Resistance to apoptosis is a key feature of cancer cells, and given the importance of mitochondria in apoptosis, the relationship between cancer development and mitochondrial dysfunction has been demonstrated on multiple occasions and in a variety of ways. Therefore, cancer is considered a mitochondrial-related disease.

[0090] Mitochondrial dysfunction can also lead to pancreatic beta cell dysfunction, such as impaired insulin dysfunction and beta cell failure, and insulin resistance in various parts of the body. Therefore, mitochondrial dysfunction may lead to diabetes, including type 1 diabetes, type 2 diabetes, gestational diabetes, and maternally inherited diabetes with deafness (MIDD), also known as mitochondrial diabetes, or adversely affect the condition of diabetic patients.

[0091] The kidney is an organ rich in mitochondria in the body. Abnormalities and dysfunction of renal mitochondria may affect several cellular pathways, which may lead to increased oxidative stress, apoptosis, microvascular loss, and fibrosis, all of which may impair renal function.

[0092] Mitochondrial dysfunction is a hallmark of early and persistent lung disease. In particular, mitochondria are central to pathological processes and clinical phenotypes associated with a variety of lung diseases. Abnormal mitochondrial function plays an important role in many lung diseases, such as asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPC), lung cancer, pneumonia, tuberculosis, pulmonary hypertension, and idiopathic pulmonary fibrosis (IPF).

[0093] Mitochondrial dysfunction is also related to the pathogenesis of several cardiovascular diseases, including myocardial infarction, cardiomyopathy of various causes, arrhythmia, atherosclerosis and hypertension. Because the heart is highly dependent on mitochondrial oxidative energy, it can be found that defects in mitochondrial structure and function are related to different heart diseases. As used herein, the term "cardiovascular disease" (CVD) refers to the disease of the heart and blood vessels. Other examples of cardiovascular disease include coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, deep vein thrombosis and pulmonary embolism (also referred to as venous thromboembolism) and arteriosclerosis (which is coronary artery disease (CAD)). Arteriosclerosis is characterized by inflammation, macrophage invasion, foam cell formation, intimal thickening, cholesterol accumulation and atherosclerotic plaque formation, which can become calcified over time. Atherosclerosis is always associated with inflammation and starts with endothelial destruction at the luminal side of the intima. Atherosclerosis always occurs in large arteries, such as, for example, in the aorta and coronary arteries. In more advanced stages, there may be plaque rupture leading to sudden vascular occlusion, myocardial infarction, and cerebrovascular accident (stroke).

[0094] As used herein, the term "inflammatory disease" refers to a condition caused by factors such as bacteria and viruses, in which the combination of specific antibodies with the factors leads to a cascade reaction and causes an inflammatory response. When the factors are removed, inflammation is downregulated and the tissue will return to normal. Inflammatory diseases also include chronic inflammatory diseases, which refer to conditions in which inflammation still exists even in the absence of such factors. "Chronic inflammatory disease" is an inflammatory disease caused by an immune response (i.e., an autoimmune response) to the subject's own proteins, and these conditions are also referred to as "autoimmune diseases." The term "chronic" means that the inflammatory disease is maintained or continues for a long period of time, for example, several years or a lifetime.

[0095] Examples of autoimmune diseases that can be prevented or treated according to the present invention include acquired hemophilia, acute motor axonal neuropathy, Addison's disease, adult-onset Still's disease, alopecia areata, ankylosing spondylitis, anti-glomerular basement membrane nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-N-methyl-D-aspartate receptor encephalitis, antisperm antibodies, antiphospholipid syndrome, antisynthetase syndrome, aplastic anemia, autoimmune angioedema, autoimmune encephalitis, autoimmune enteropathy, autoimmune gastritis, autoimmune hemophilia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune central nervous system disease, autoimmune hemorrhage ... granulocytopenia, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune polyendocrine syndrome type 1, autoimmune polyendocrine syndrome type II, autoimmune polyendocrine syndrome type 3, autoimmune progesterone dermatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroiditis, autoimmune urticaria, autoimmune uveitis, baloconcentric sclerosis, Behcet's disease disease), Bickerstaff encephalitis, brachial plexopathy (Parsonage-Turner syndrome), bullous pemphigoid, celiac disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, disease), complex regional pain syndrome, CREST syndrome, Crohn's disease, cryptogenic organizing pneumonia, cutaneous lupus erythematosus, dermatitis herpetiformis, dermatomyositis, type 1 diabetes mellitus, diffuse interstitial keratitis, discoid lupus erythematosus, endometriosis, enthesitis-related arthritis, eosinophilic esophagitis, eosinophilic fasciitis, epidermolysis bullosa acquisita, episcleritis, encephalopathy associated with autoimmune thyroid disease, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, Felty syndrome, fibromyalgia, pemphigoid gestationis, giant cell arteritis, Goodpasture's syndrome syndrome, Graves' disease, Graves' ophthalmopathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, hidradenitis suppurativa, idiopathic dilated cardiomyopathy, idiopathic pulmonary fibrosis, IgA nephropathy, IgG4-related systemic disease, inclusion body myositis, inflammatory bowel disease (IBD), intermediate uveitis, interstitial cystitis, juvenile arthritis, Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease, lupus nephritis, lupus vasculitis, Lyme disease (chronic), Ménière's disease, microscopic colitis, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer morphea), Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myelin oligodendrocyte glycoprotein disease (MOG), myocarditis, myositis, narcolepsy cataplexy, neuromyelitis optica, neuromyotonic opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, relapsing rheumatic disease, paraneoplastic cerebellar degeneration, Parry-Romberg syndromeRomberg syndrome), Parsonage-Turner syndrome, streptococcal autoimmune neuropsychiatric disorders in children, pemphigus vulgaris, pernicious anemia, acute lichen vulgaris, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis post-myocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis including guttate psoriasis, inverse psoriasis, erythrodermic psoriasis and pustular psoriasis, psoriatic arthritis (PsA), pure red cell aplasia, rheumatic purpura, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, relapsing polychondritis, restless legs syndrome, retinocochleocerebral vasculopathy, retroperitoneal fibrosis, rheumatic chorea, rheumatic fever, rheumatoid arthritis (RA), rheumatoid vasculitis, sarcoidosis, Schnitzler syndrome, scleritis, scleroderma, Sjogren's syndrome, stiff-man syndrome, subacute bacterial endocarditis, Susac syndrome, chorea, sympathetic ophthalmia, systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu arteritis, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (UC), undifferentiated connective tissue disease, urticaria, urticarial vasculitis, vasculitis, vitiligo, warm antibody autoimmune hemolytic anemia, autoimmune cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and combinations thereof, including multiple autoimmune syndromes, i.e., a combination of at least three autoimmune diseases (MAS).

[0096] As used herein, the term "metabolic disorder" refers to conditions associated with abnormal systemic glucose, lipid and / or protein metabolism in an animal and the pathological consequences resulting therefrom, including metabolic syndrome (MS), type 2 diabetes, obesity and prediabetes, which are also associated with the risk of developing cardiovascular disease.

[0097] Examples of metabolic disorders that can be prevented or treated according to the present invention include metabolic syndrome, obesity such as abdominal obesity and prediabetes. The key elements of metabolic disorders include impaired fasting glucose or impaired glucose tolerance, increased waist circumference, increased fasting plasma glucose, increased fasting plasma triglycerides, reduced fasting high-density lipoprotein levels, increased blood pressure, insulin resistance, hyperinsulinemia, cardiovascular disease (or its components such as atherosclerosis, coronary artery disease, peripheral vascular disease or cerebrovascular disease), congestive heart failure, increased plasma norepinephrine, increased cardiovascular-related inflammatory factors, increased plasma factors that enhance endothelial dysfunction, hyperlipoproteinemia, atherosclerosis or arteriosclerosis. Atherosclerosis, hyperthermia, overeating, hyperglycemia, hyperlipidemia and hypertension or high blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or its plasma markers, increased circulating hypercoagulable state, hepatic steatosis, renal disease including renal failure and renal insufficiency, liver disease including fatty liver disease, metabolic dysfunction associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).

[0098] Examples of preferred metabolic disorders that may be prevented or treated according to the present invention include obesity, obesity-related complications, hypertension, cardiovascular disease, kidney disease, elevated plasma glucose concentrations, type 2 diabetes (T2D), type 1 diabetes, hyperglycemia, insulin resistance, hyperthermia and fatty liver disease.

[0099] Prevention and / or treatment according to the present invention are suitable for a period of time during which the condition and / or disease or its symptoms, manifestations and complications persist. Since symptoms, manifestations and complications may last for weeks, months or years, the time period for prevention, treatment and / or administration can be at least 1 week, or at least 2 weeks, or at least 4 weeks, or at least 3 months, or at least 12 months, or at least 18 months, or at least 36 months, or the rest of the experimenter's life.

[0100] The combinations, compositions and compounds of the invention may include one or more additional pharmaceutically acceptable components, including one or more pharmaceutically acceptable inactive components, such as carriers, excipients and diluents, and / or one or more pharmaceutically acceptable active components.

[0101] As used herein, the term "pharmaceutically acceptable" refers to a substance (e.g., an inactive or active component, ingredient, or excipient) that is suitable for contact with tissues and organs of a subject without excessive stimulation, allergic response, immunogenicity, and toxicity, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. A "pharmaceutically acceptable" excipient or carrier of a pharmaceutical composition is also compatible with the other ingredients of the composition.

[0102] Examples of suitable pharmaceutically acceptable inactive ingredients include inert diluents such as carbonates, for example calcium carbonate and sodium carbonate; buffers such as phosphates, for example calcium phosphate and sodium phosphate, citrate, succinate, acetic acid and other organic acids and their salts; antioxidants such as ascorbic acid; hydrophilic polymers, for example polyvinyl pyrrolidone and polyethylene glycol; granulating and disintegrants, for example corn starch or alginic acid; binders, for example starch, gelatin or gum arabic; lubricants, for example magnesium stearate, stearic acid and talc; solvents, for example organic solvents, water and aqueous electrolyte solutions; preservatives; chelating agents , such as EDTA; effervescent agents; natural or artificial sweeteners, such as glucose, mannose, dextrin, mannitol and sorbitol; carbohydrates, such as monosaccharides, disaccharides and other cellulose derivatives; flavorings; coloring agents; masking agents; acidulants; lactose, surfactants and emulsifiers, such as polysorbates, poloxamers and polyethylene glycol (PEG); thickeners; suspending, dispersing and wetting agents; oils; waxes; fibers; fats; proteins; carbohydrates; minerals; agents for improving taste, texture, color, odor, stability and / or shelf life; the like; and combinations thereof.

[0103] Examples of suitable pharmaceutically acceptable active ingredients include vitamins, such as vitamin A, vitamin C, vitamin D, including vitamin D1, vitamin D2 (ergocalciferol, or calciferol), vitamin D3 (cholecalciferol) and vitamin D analogs, such as alfacalcidol (or 1-hydroxycholecalciferol), dihydrotachysterol (DHT) and calcitriol (also known as 1,25-dihydroxycholecalciferol); vitamin E and vitamin K; antibiotics; anticoagulants, such as acetylsalicylic acid and COX-2 inhibitors; oils; fermented soy protein materials; peptides; carnitine; astaxanthin; etc.; and combinations thereof.

[0104] The combinations, compositions and compounds of the present invention can be administered to an animal or subject in need thereof by various routes, such as one or more of the following: nasal, ocular, oral, enteral, intragastric, sublingual, buccal, rectal, topical, transdermal, inhalation, pulmonary, parenteral, intradermal, intraarterial, intramuscular, intravascular, intravenous, intracardiac, intraperitoneal, intraocular, subcutaneous, intraarticular, intracapsular, subcapsular, intraorbital, transtracheal, intrasternal, intrathecal, intraspinal and subarachnoid administration. If administered separately in combination but simultaneously or sequentially, the compounds of the present invention can be administered by the same or different routes of administration as defined above.

[0105] If administered continuously, the compounds of the invention are generally administered by injection 1 to 4 times per day each or by continuous or semi-continuous subcutaneous infusion, for example using a mini-pump. Intravenous bag solutions may also be used.

[0106] For several routes of administration, such as parenteral administration, the compounds of the present invention can be prepared by mixing each compound at the desired purity in a unit dosage injectable form (solution, suspension or emulsion) with a pharmaceutically acceptable carrier to provide a composition of the present invention.

[0107] The composition of the present invention can be prepared by contacting the compound of the present invention uniformly and closely with one or more liquid carriers or one or more subdivided solid carriers or both. Preferably, the carrier is a parenteral carrier, more preferably a solution isotonic with the subject's blood. Examples of suitable carriers include aqueous carriers, such as water, aqueous solutions, saline, Ringer's solution, dextrose solution, and non-aqueous carriers, such as oils, ethyl oleate and liposomes.

[0108] The pharmaceutical and nutraceutical combinations, compositions and compounds of the present invention may be provided in any form suitable for the intended use or administration.The nutraceutical combinations, compositions and compounds of the present invention are preferably provided for oral administration.

[0109] The pharmaceutical combinations, compositions and compounds of the present invention can be provided in the form of pills, tablets (coated or uncoated), hard or soft capsules, dragees, lozenges, oral solutions, suspensions and dispersions, syrups or sterile preparations, for example, for parenteral, intradermal, intraarterial, intramuscular, intravascular, intravenous, intracardiac, intraperitoneal, intraocular, subcutaneous, intraarticular, intracapsular, subcapsular, intraorbital, transtracheal, intrasternal, intrathecal, intraspinal and subarachnoid administration.

[0110] The nutrient combination of the present invention, composition and compound can be provided in the form of food and beverage products and pills, tablets (coated or uncoated), hard capsules or soft capsules, dragees, lozenges, oral solutions, suspensions and dispersants, syrups or sterile preparations. The example of suitable food and beverage products includes fruit juice drinks, dairy beverages, powdered beverages, sports drinks, mineral water, soy beverages, hot chocolate, malt beverages, biscuits, bread, crackers, candies, chocolate, chewing-gum, butter, margarine, spreads, yogurt, breakfast cereals, snack bars, meal replacements, protein powders, desserts, medical nutrition feeds, nutritional supplements and tablets. The nutrient combination of the present invention, composition and compound can be used as animal feed or a part thereof, for example, for the feed of the above-mentioned animal.

[0111] The compositions and medicaments or nutritional compositions of the present invention may contain (i) nicotinic acid or a derivative thereof, and (ii) a fatty acid such as tetradecylthioacetic acid (TTA) or a derivative thereof, in amounts and ratios that may vary within wide limits. The compositions and medicaments or nutritional compositions may contain a therapeutically effective amount of (i) nicotinic acid or a derivative thereof and (ii) a fatty acid such as tetradecylthioacetic acid (TTA) or a derivative thereof when intended to be administered as a single administration per day, or half of the therapeutically effective amount when intended to be provided by twice daily administration, or 1 / x of the therapeutically effective amount when intended to be provided by x administrations per day. The molar ratio between (i) nicotinic acid or a derivative thereof and (ii) a fatty acid such as tetradecylthioacetic acid (TTA) or a derivative thereof may be from 99:1 to 1:99, typically from 80:20 to 20:80, suitably from 60:40 to 40:60, and preferably about 50:50.

[0112] As used herein, the term "therapeutically effective amount" refers to an amount of an agent or therapeutic agent or a combination of agents or therapeutic agents that, when administered to a subject, is sufficient to prevent the medical condition being treated, reduce the risk of its development, delay its onset, slow its development, or cause its regression, or to alleviate to some extent one or more symptoms or complications of the medical condition or the condition, at least in a portion of the subjects taking the agent. The term "therapeutically effective amount" also refers to an amount of an agent or therapeutic agent or a combination of agents or therapeutic agents that is sufficient to elicit the biological or medical response of a cell, tissue, organ, system, animal or human being sought by a researcher, veterinarian, physician or clinician.

[0113] As used herein, the term "therapeutic agent" refers to any biologically, physiologically or pharmacologically active substance that acts locally or systemically in a subject and is administered to a subject for the purpose of diagnosing, treating, alleviating, curing or preventing disease or enhancing a desired physical or mental development or condition.

[0114] (i) The therapeutically effective amount of niacin or its derivatives may correspond to a dosage of 10 to 2,000 μg / day, or 50 to 1,500 μg / day, or 100 to 1,000 μg / day. (i) The therapeutically effective amount of niacin or its derivatives may correspond to a dosage of 70 to 14,000 μg / week, or 350 to 10,500 μg / week, or 700 to 7,000 μg / week.

[0115] (ii) A therapeutically effective amount of a fatty acid such as tetradecylthioacetic acid (TTA) or a derivative thereof may correspond to a dosage of 10 to 2,000 μg / day, or 50 to 1,500 μg / day, or 100 to 1,000 μg / day. (ii) A therapeutically effective amount of a fatty acid such as tetradecylthioacetic acid (TTA) or a derivative thereof may correspond to a dosage of 70 to 14,000 μg / week, or 350 to 10,500 μg / week, or 700 to 7,000 μg / week.

[0116] When vitamin D is present in the combinations, compositions and compounds of the invention, the dosage of vitamin D may be 1 to 500 μg / day, or 2 to 250 μg / day, or 5 to 100 μg / day.

[0117] The method for medicine and nutrition combination and prevention or treatment of mitochondrial disease and / or inflammatory disease according to the present invention can include the combined use of the nicotinic acid or its derivatives of the first amount and the fatty acid of the second amount such as tetradecylthioacetic acid (TTA) or its derivatives.It should be understood that, as used herein, "combination" or "combined" can refer to simultaneous use and / or sequential use.For example, the present invention can include the use of the nicotinic acid or its derivatives of the first amount, and then before or during the activity of the nicotinic acid or its derivatives of the first amount in vivo (or become), the fatty acid of the second amount such as tetradecylthioacetic acid (TTA) or its derivatives, or vice versa.The method can include the simultaneous or approximately simultaneous use of the nicotinic acid or its derivatives of the first amount and the fatty acid of the second amount such as tetradecylthioacetic acid (TTA) or its derivatives.

[0118] The first amount and the second amount can be applied in one or more daily doses. It should be understood that "dose" refers to the number of agents applied at a specific time point. The nicotinic acid or its derivatives of the first amount can be applied or delivered in a single daily dose, or can be applied or delivered in the process of multiple doses per day. For example, the nicotinic acid or its derivatives of the first amount can be applied in one, two, three, four, five or more daily doses, wherein each dose comprises the nicotinic acid or its derivatives of the same or different amounts relative to one or more other doses. Similarly, the fatty acid of the second amount such as tetradecylthioacetic acid (TTA) or its derivatives can be applied in one, two, three, four, five or more daily doses, wherein each dose comprises the fatty acid such as tetradecylthioacetic acid (TTA) or its derivatives of the same or different amounts relative to one or more other doses. Each dose of nicotinic acid and its derivatives can be independently applied or delivered simultaneously or sequentially relative to the dose of fatty acid such as tetradecylthioacetic acid (TTA) or its derivatives. In addition, the fatty acid of each dose such as tetradecylthioacetic acid (TTA) or its derivatives can be applied simultaneously or almost simultaneously with the nicotinic acid or its derivatives of a dose.

[0119] The amount or first amount of nicotinic acid or a derivative thereof can be a therapeutically effective amount, optionally when administered in combination with a fatty acid such as tetradecylthioacetic acid (TTA) or a derivative thereof. The therapeutically effective amount of nicotinic acid or a derivative thereof can be an amount thereof that reduces the therapeutically effective amount of a fatty acid such as tetradecylthioacetic acid (TTA) or a derivative thereof.

[0120] The amount or second amount of a fatty acid, such as tetradecylthioacetic acid (TTA) or a derivative thereof, can be a therapeutically effective amount, optionally when administered in combination with nicotinic acid or a derivative thereof. A therapeutically effective amount of a fatty acid, such as tetradecylthioacetic acid (TTA) or a derivative thereof, can be an amount thereof that reduces the therapeutically effective amount of nicotinic acid or a derivative thereof.

[0121] Animals according to the present invention can be any animal and / or mammal, including fish and shellfish, such as salmon, cod, tilapia, clams, oysters, lobsters and crabs; amphibians, such as frogs; reptiles, such as turtles; birds, such as chickens such as hens, cockerels and roosters, and turkeys; Anatidae, such as ducks, geese and swans; Felidae, such as cats; Canidae, such as dogs and wolves; Rodents, such as mice, rats, hamsters, gerbils and guinea pigs; Lagomorpha, such as rabbits and hares; Camelidae, such as camels, llamas and alpacas; Farm animals, such as pigs, sheep, goats, horses, cattle, deer and minks; Other mammals, such as species in zoos and conservation centers not mentioned above, such as hippopotamuses, rhinos, etc.; Primates, such as apes, chimpanzees, monkeys and humans. Preferably, the animal is a mammal, and preferably, the mammal is a human. The term "subject" used herein refers to any animal, including mammalian subjects, such as human subjects.

[0122] Example

[0123] The present invention is further illustrated in the following examples, which are, however, not intended to limit the present invention. Unless otherwise indicated, parts and % refer to parts by weight and % by weight, respectively, and all suspensions are aqueous.

[0124] Example 1

[0125] This example illustrates an animal study conducted using male Wistar rats fed NR, NAR, TTA, and combinations thereof.

[0126] Animal studies were conducted in accordance with the Guidelines for the Care and Use of Experimental Animals and in accordance with the Norwegian legislation and regulations governing experiments using live animals. All efforts were made to optimize the animal environment and reduce suffering. Eight-week-old male Wistar rats, Rattus Norvegicus, weighing 400-450 g, were purchased from Taconic (Ejby, Denmark). Upon arrival, rats were randomized using a study randomizer

[12] , marked and placed in open cages, two per cage, where they were allowed to acclimate to their surroundings for one week. During the acclimatization and experimental period, rats had unrestricted access to tap water, but food was restricted to obtain a constant dose throughout the experiment.

[0127] The rats were placed in a 12-hour light / dark cycle at a constant temperature (22±2°C) and a relative humidity of 55% (±5%). At the beginning of the experiment, the rats were randomized to the respective interventions. All rats were divided into seven groups. The first group of animals (control group) was fed a high-fat diet (HF) with 25% fat by weight, consisting of 23% lard by weight and 2% soybean oil by weight, referred to as "HF". The second group was fed a high-fat diet (HF) supplemented with tetradecylthioacetic acid (TTA) (250 mg / day / kg body weight), referred to as "HF+TTA". The third group was fed a high-fat diet (HF) supplemented with nicotinamide riboside (NR) (100 mg / day / kg body weight), referred to as "HF+NR". The fourth group was fed a high-fat diet (HF) supplemented with nicotinic acid riboside (NAR) (40 mg / day / kg body weight), referred to as "HF+NAR". The fifth group was fed a high-fat diet (HF) supplemented with tetradecylthioacetic acid (TTA) (250 mg / day / kg body weight) and nicotinamide riboside (NR) (100 mg / day / kg body weight), referred to as "HF+TTA+NR". The sixth group was fed a high-fat diet (HF) supplemented with tetradecylthioacetic acid (TTA) (250 mg / day / kg body weight) and nicotinic acid riboside (NAR) (40 mg / day / kg body weight), referred to as "HF+TTA+NAR". The seventh group was fed a low-fat diet, referred to as "LF".

[0128] All animals were weighed daily and food intake was measured weekly. Animal experiments were performed for 12 weeks. At the time of sacrifice, rats were anesthetized by inhalation of 2-5% isoflurane (Schering-Plough, Kent, UK), the abdomen was opened along the midline, and cardiac puncture was used for bleeding. EDTA-blood was collected and immediately cooled and frozen on ice. Samples were centrifuged and plasma was stored at -80 ° C before analysis. Different tissues were collected, weighed, and immediately flash-frozen in liquid nitrogen, and stored at -80 ° C until further analysis.

[0129] Example 2

[0130] Analysis of the samples obtained in Example 1 involving HF, TTA, NR, combinations thereof and LF, with respect to compounds related to mitochondrial function, the immune system, inflammatory response, metabolic function and / or cellular processes, shows the results listed in Table 1, where the values ​​are given in μM.

[0131] Table 1

[0132]

[0133] Example 3

[0134] Analysis of samples obtained in Example 1 involving HF, TTA, NAR, combinations thereof and LF, with respect to compounds related to mitochondrial function, immune system, metabolic function and / or cellular processes, shows the results listed in Table 2, where the values ​​are given in μM.

[0135] Table 2

[0136]

[0137]

[0138] Example 4

[0139] As is apparent from Tables 1 and 2 of Examples 2 and 3, respectively, the amounts of compounds analyzed related to mitochondrial, immune system and metabolic functions and / or cellular processes were higher or significantly higher in plasma samples of rats fed a high fat diet (HF) supplemented with compounds according to the invention (referred to as "HF+TTA+NR" or "HF+TTA+NAR") compared to plasma samples of rats fed a high fat diet (HF) supplemented with TTA ("HF+TTA"), NR ("HF+NR") or NAR ("TTA+NAR"). In tests, the combination or composition comprising niacin or a derivative thereof and a fatty acid or a derivative thereof according to the invention showed an unexpected and synergistic effect or increase in the amounts of the analyzed compounds.

[0140] Glycine and Serine

[0141] Mitochondrial dysfunction is a key feature of Alzheimer's disease (AD) and is associated with amyloid accumulation, synaptic failure, and neuronal death, processes that are associated with disease progression. Compounds that stimulate mitochondrial biogenesis and mild mitochondrial uncoupling are promising therapeutic targets in AD. Glycine and serine are metabolites of the choline oxidation pathway that occurs in mitochondria, see Figure 2 .

[0142] According to the present invention, when rats were fed a high-fat diet supplemented with tetradecylthioacetic acid (TTA) and nicotinamide riboside (NR) or nicotinic acid riboside (NAR), higher amounts of glycine and serine were formed in the mitochondria. Compounds that cause increased production of glycine and serine can therefore be used to prevent, reduce, alleviate or reverse mitochondrial dysfunction, reduce the risk of cognitive dysfunction and the development of ischemic stroke. Therefore, the combination or composition comprising nicotinic acid or its derivatives and fatty acids or their derivatives according to the present invention can be used to prevent or treat mitochondrial and neurodegenerative diseases.

[0143] 3-Hydroxybutyrate and acetoacetate

[0144] According to the present invention, when rats are fed a high-fat diet supplemented with tetradecylthioacetic acid (TTA) and nicotinamide riboside (NR), higher amounts of 3-hydroxybutyric acid and acetoacetic acid are formed in mitochondria. 3-Hydroxybutyric acid and acetoacetic acid are ketones and are referred to as mitochondrial-derived metabolites produced by mitochondria. It is noteworthy that, since subjects with Alzheimer's disease (AD) and Parkinson's disease (PD) cannot absorb glucose as a substrate for ATP formation, they are able to absorb ketones and possible bioactive amino acids to reduce the energy cap (energycap) formed when glucose cannot be absorbed. Ketones can penetrate the blood-brain barrier and are therefore valuable energy for the brain of subjects with mitochondria and neurodegenerative diseases such as, for example, Alzheimer's disease (AD). Therefore, these results indicate that the combination or composition including nicotinic acid or its derivatives and fatty acids or their derivatives according to the present invention can be used to prevent or treat mitochondria and neurodegenerative diseases.

[0145] 3-Hydroxyanthranilic acid and quinolinic acid

[0146] According to the present invention, when rats were fed a high-fat diet supplemented with both tetradecylthioacetic acid (TTA) and nicotinamide riboside (NR), higher amounts of 3-hydroxyanthranilic acid and quinolinic acid were formed. 3-Hydroxyanthranilic acid and quinolinic acid are metabolites of the tryptophan-kynurenine pathway, see Figure 3, which is associated with inflammation, immune system and neurological disorders. It is the main pathway for tryptophan catabolism in the liver and the starting point for the synthesis of nicotinamide adenine dinucleotide (NAD) in animals.

[0147] It is reported that the change of 3-hydroxyanthranilic acid plasma level is related to chronic and acute inflammation, and the enzyme responsible for its formation is present in mitochondria and / or cytosol. Test results show that the increased output of 3-hydroxyanthranilic acid obtained by the combination or composition of the present invention can be used to treat inflammation and neurological diseases, especially for cancer patients receiving chemotherapy. Therefore, the combination or composition comprising nicotinic acid or its derivatives and fatty acid or its derivatives according to the present invention can be used to prevent or treat mitochondrial diseases, neurodegenerative diseases, cancer and inflammatory diseases.

[0148] Vitamin B3 analogs: niacin, niacinamide, N1-methylniacinamide and trigonelline

[0149] The B3 isovitamin is a cofactor for many enzymatic redox reactions, such as β-oxidation of fatty acids and substrate oxidation in the Krebs cycle, as well as the synthesis of carnitine. In one-carbon metabolism, vitamin B3 is used as a reducing agent for both MTHFR and MSR, and also for the conversion of choline to betaine.

[0150] Dysregulation of the tryptophan-nicotinamide pathway has been implicated in several pathological conditions, and metabolites in this pathway are known to affect mitochondrial respiration and redox status. B3 is a metabolite of the tryptophan-nicotinamide pathway, see Figure 3 and Figure 4 , and each B3 equivalent vitamin is NAD + Precursor, NAD + It is a substance necessary for cellular energy production. NAD is an essential molecule in all organisms, which has two main biological functions. First, it acts as a biochemical catalyst to extract and convert energy from food sources to start biological processes. Second, NAD is involved in a variety of regulatory events that coordinate cellular functions according to metabolic needs and possibilities. In the regulatory process that depends on NAD, NAD is consumed, which requires permanent resynthesis of the molecule. In the past few years, many scientific studies have shown that a decrease in NAD concentration is generally associated with aging, and is particularly associated with age-related diseases (including cancer, diabetes and neurodegeneration). Correction of NAD status can be achieved by nutritional supplementation with intermediates of NAD biosynthesis (NAD supplements). In animal models of obesity and diabetes and neurodegeneration, the restoration or improvement of NAD levels has produced impressive results, which is important in mitochondrial and neurodegenerative diseases such as Alzheimer's disease.

[0151] Tables 1 and 2 show that when rats were fed a high-fat diet supplemented with tetradecylthioacetic acid (TTA) and nicotinamide riboside (NR) or nicotinic acid riboside (NAR) according to the present invention, higher amounts of B3 equivalent vitamins nicotinic acid, nicotinamide, N1-methylnicotinamide and trigonelline were formed. The observed higher amounts of B3 equivalent vitamins were accompanied by a reduction in rat body weight, a reduction in white adipose tissue, plasma lipids and liver lipids, and an increase in ketone amounts. Therefore, the increased production of these compounds means an increase in the amount of intermediates of NAD biosynthesis (NAD supplements), and the combination or composition comprising nicotinic acid or its derivatives and fatty acids or their derivatives according to the present invention can be used to prevent or treat mitochondrial diseases, neurodegenerative diseases, cancer, diabetes, inflammatory diseases, obesity and metabolic disorders.

[0152] Pyridoxal 5′-phosphate (P5P) and pyridoxal

[0153] Pyridoxal 5'-phosphate and pyridoxal are B6 equivalent vitamins, which are cofactors for approximately 150 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. Previous reports have shown that vitamin B6 deficiency is associated with both increased oxidative stress and inflammation. Previous reports have also shown a significant negative correlation between vitamin B6 levels and diabetes, as well as a significant protective effect of vitamin B6 against diabetic complications, and a protective effect of vitamin B6 against diabetes and cancer (e.g., breast cancer in menopausal women). Therefore, the increased production of these B6 equivalent vitamins obtained by the combinations and compositions according to the present invention including niacin or its derivatives and fatty acids or their derivatives indicates that they can be used to prevent or treat mitochondrial diseases, inflammatory diseases, and metabolic disorders.

[0154] 2-Aminoadipic acid

[0155] Previous reports have shown that 2-aminoadipic acid, an intermediate metabolite of lysine metabolism, can regulate insulin secretion and predict type 2 diabetes (T2D). Previous reports have also shown that treatment of diet-induced obese animals with 2-aminoadipic acid significantly reduced body weight, reduced fat accumulation, and reduced fasting blood sugar. The increased output of 2-aminoadipic acid obtained in the test shows that the combination or composition including nicotinic acid or its derivatives and fatty acid or its derivatives according to the present invention can be used for preventing or treating obesity, type 2 diabetes (T2D), mitochondria, metabolism and endocrine disorders, thereby preventing or treating mitochondrial diseases and metabolic disorders.

[0156] Example 5

[0157] Analysis of the samples obtained in Example 1 involving HF, TTA, NR, a combination thereof and LF showed the results listed in Table 3 with respect to parameters and / or substances related to mitochondrial function, immune system, inflammatory response, metabolic function and / or cellular process.

[0158] Table 3

[0159]

[0160]

[0161] As is evident from Table 3 of Example 5, the amounts of compounds analyzed related to mitochondrial, immune system and metabolic functions and / or cellular processes were better or significantly better in samples of rats fed a high fat diet (HF) supplemented with compounds according to the invention (referred to as "HF+TTA+NR") compared to samples of rats fed a high fat diet (HF) supplemented with TTA ("HF+TTA") or NR ("HF+NR"). In the tests, the combination or composition according to the invention comprising niacin or a derivative thereof and a fatty acid or a derivative thereof showed unexpected and synergistic effects in the parameters and / or substances analyzed, including lower body weight (less weight gain) and lower amounts of plasma triglycerides, plasma and liver cholesterol and total fatty acids in plasma at the end of the test.

[0162] Example 6

[0163] This example illustrates the effects of the compounds of the invention (TTA+NR) on brain cell metabolism in rats compared to the individual compounds when used alone. The same type of rats as used in Example 1 were used in this example.

[0164] Cell culture and treatment

[0165] Brain (SH-SY5Y) cells were maintained in Dulbecco's modified Eagle's medium / nutrient mixture F-12 Ham (DMEM / F12) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 2 mM L-glutamine, 2 mM L-glutamine, 1% non-essential amino acids, penicillin (50 IU) and streptomycin (50 g / ml).

[0166] For this experiment, brain cells were cultured individually in 96-well CellBIND microplates and maintained at 37°C in a humidified 5% CO2 atmosphere. The culture medium was changed regularly every 2-3 days. When the cells reached 80% confluence, the treatment incubation began 24 or 48 hours before the experiment. Before each experiment, a 100mM stock solution of nicotinamide riboside (NR) was prepared in cell culture medium. A 6mM stock solution of tetradecylthioacetic acid (TTA) was prepared in 0.1M NaOH and mixed with 2.49mM bovine serum albumin (BSA) to be used as a carrier for TTA. The treatments and final solution concentrations are detailed in Table 4.

[0167] Table 4

[0168] Basic conditions TTA treatment Base Control (cell culture medium) 100 μM TTA NR 0.5mM NR 100μM TTA+0.5mM NR

[0169] Substrate oxidation assay

[0170] Radioactive substrate oxidation assays were performed to evaluate the effects of TTA and NR on cellular metabolism. After incubation with these compounds and their combinations, the cells were treated with [1- 14 C] oleic acid (OA) (0.5 μCi / ml, 100 μM) substrate was added to replace the culture medium and the capture was performed as previously described by Weensaas et al. 2007

[33] . Briefly, 96 wells were mounted on the top of a 96-well plate. The microplate was activated by adding 1M NaOH to capture CO2. After 4 hours, the captured 14 CO2 and radioactive substrate uptake rates were measured by adding scintillation fluid (Ultima Gold XR) and counting in a 2450 MicroBeta2 scintillation counter. All results were adjusted for protein content, which was determined using the VICTOR TM Measurements were performed using the Bio-Rad Protein Assay X4 Multilabel Plate Reader.

[0171] Statistical analysis

[0172] Unless otherwise stated, data are presented as mean ± standard error mean (SEM) from at least two to three independent experiments with at least four observations per condition. Statistical analysis was performed using GraphPad Prism 8.0.1 for Windows. Unpaired t-test was used to assess differences between control and TTA (*); basal and NR conditions ( b ); TTA and TTA+NR combination ( # ). Differences with p-value ≤ 0.05 were considered statistically significant.

[0173] The results are as follows Figure 5, which shows oleic acid (OA) metabolism in brain cells (SH-SY5Y). (AD) Complete OA oxidation (CO2) and uptake rate (absolute data) after 24 hours (AB) and 48 hours (CD) of treatment with 0.5 μM NR and 100 μM TTA alone and in combination. (EH) Effect of TTA treatment on complete OA oxidation (CO2) and uptake rate (normalized to control (ctr) values) after 24 hours (EF) and 48 hours (GH) of treatment with 0.5 μM NR and 100 μM TTA alone and in combination. * Statistically significant difference between Ctr and TTA treatment under basal and NR conditions (*p≤0.05 unpaired t-test). # Statistically significant difference between TTA (basal) and TTA+NR treatment (#p≤0.05 unpaired t-test).

[0174] in conclusion

[0175] As shown in this example, the compounds of the present invention (TTA+NR) have a significant effect on the metabolism of rat brain cells compared to when the individual compounds TTA and NR are used alone. When used in combination, the compounds of the present invention increase the metabolism of oleic acid and increase the production of CO2 in brain cells. Therefore, the combination or composition comprising nicotinic acid or its derivatives and fatty acids or their derivatives according to the present invention can be used to prevent or treat mitochondrial diseases that have adverse effects on the brain, such as, for example, neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and for preventing or treating neurodegeneration or aging in animals, for example, by reducing the energy gap caused by neurodegeneration or aging, and / or increasing the metabolism of the brain of the animal, for example, enhancing the energy flow between the liver and the brain.

Claims

1. A combination or composition comprising: (i) nicotinic acid or a derivative thereof, and (ii) a fatty acid or a derivative thereof selected from tetradecylthioacetic acid (TTA) or a derivative thereof.

2. A pharmaceutical or nutritional combination or composition for use in a method for preventing or treating mitochondrial disease, inflammatory disease, metabolic disorder, neurodegenerative disease and / or aging in an animal, and / or in a method for increasing brain metabolism in an animal, wherein the pharmaceutical or nutritional combination or composition is administered to the animal, and wherein the pharmaceutical or nutritional combination or composition comprises: (i) nicotinic acid or a derivative thereof, and (ii) a fatty acid or a derivative thereof selected from tetradecylthioacetic acid (TTA) or a derivative thereof.

3. A pharmaceutical or nutritional combination or composition for use in a method according to any one of the preceding claims, wherein: The mitochondrial disease is selected from the group consisting of neurodegenerative diseases (ND), Parkinson's disease (PD), Huntington's disease (HD), dementia, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), cancer, type 1 diabetes, type 2 diabetes, gestational diabetes, maternally inherited diabetes with deafness (MIDD), kidney disease, lung disease and cardiovascular disease, atherosclerosis and combinations thereof.

4. A pharmaceutical or nutritional combination or composition for use in a method according to any one of the preceding claims, wherein: The inflammatory disease is selected from the group consisting of chronic inflammatory diseases, autoimmune diseases, and combinations thereof.

5. A pharmaceutical or nutritional combination or composition for use in a method according to any one of the preceding claims, wherein: The metabolic disorder is selected from the group consisting of metabolic syndrome, obesity, abdominal obesity, prediabetes and a combination thereof, preferably the metabolic disorder comprises a condition selected from the group consisting of impaired fasting glucose, impaired glucose tolerance, increased waist circumference, increased fasting plasma glucose, increased fasting plasma triglycerides, decreased fasting high-density lipoprotein (HDL) levels, increased blood pressure, insulin resistance, hyperinsulinemia, cardiovascular disease, arteriosclerosis or atherosclerosis, coronary artery disease, peripheral vascular disease, cerebrovascular disease, congestive heart failure, increased plasma norepinephrine, increased cardiovascular-related inflammatory factors, increased plasma factors that enhance endothelial dysfunction, hyperlipoproteinemia, overeating, hyperglycemia, hyperlipidemia, hypertension or high blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or its plasma indicators, increased circulating hypercoagulable state, hepatic steatosis, kidney disease, renal failure, renal insufficiency and a combination thereof.

6. A pharmaceutical or nutritional combination for use in a method according to any one of the preceding claims, wherein: Said (i) nicotinic acid or a derivative thereof, and (ii) a fatty acid or a derivative thereof selected from tetradecylthioacetic acid (TTA) or a derivative thereof, Administer separately simultaneously or sequentially.

7. A pharmaceutical or nutritional combination for use in a method according to any one of the preceding claims, wherein: The animal is selected from the group consisting of: fish and shellfish including salmon, cod, tilapia, clams, oysters, lobsters and crabs; amphibians including frogs; reptiles including turtles; birds including chickens, hens, cockerels, roosters and turkeys; anatidae including ducks, geese and swans; felines including cats; canines including dogs and wolves; rodents including mice, rats, hamsters, gerbils and guinea pigs; lagomorphs including rabbits and hares; camelids including camels, llamas and alpacas; farm animals including pigs, sheep, goats, horses, cattle, deer and minks; other mammals including species in zoos and conservation centres including hippopotamus, rhinoceros; primates including apes, chimpanzees, monkeys and humans, preferably the animal is a mammal, and more preferably the animal or mammal is a human.

8. A combination or composition according to any one of the preceding claims, or a pharmaceutical or nutritional combination or composition for use in a method according to any one of the preceding claims, wherein: The (i) nicotinic acid or its derivative is selected from the group consisting of nicotinic acid, nicotinamide (NAM) and its derivatives, nicotinic acid riboside compounds, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), derivatives of both oxidized and reduced forms of NR (NRH), nicotinic acid riboside (NAR), derivatives of both oxidized and reduced forms of NAR (NARH), derivatives thereof, NAD+, nicotinic acid esters, nicotinic acid methyl ester (nicotinic acid methyl ester), nicotinic acid pentaerythritol ester, 2-aminopyridine-3-carboxylic acid, 5-aminopyridine-3-carboxylic acid and combinations thereof, preferably, the (i) nicotinic acid or its derivative is selected from the group consisting of nicotinic acid, nicotinamide (NAM), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinic acid riboside (NAR), nicotinic acid esters and combinations thereof, more preferably, the (i) nicotinic acid or its derivative is selected from the group consisting of nicotinamide riboside (NR), nicotinic acid riboside (NAR) and combinations thereof.

9. A combination or composition according to any one of the preceding claims, or a pharmaceutical or nutritional combination or composition for use in a method according to any one of the preceding claims, wherein: The (ii) tetradecylthioacetic acid (TTA) or its derivatives are represented by the following a) General formula R"-COO-(CH2) 2n+1 -X-R', wherein X is a sulfur atom, a selenium atom, an oxygen atom, a CH2 group, a SO group or a SO2 group; n is an integer from 0 to 11; and R' is a saturated or unsaturated, optionally substituted straight or branched chain alkyl group, wherein the main chain of R' contains 13 to 23 carbon atoms and optionally one or more hetero groups, The hetero group is selected from the group consisting of an oxygen atom, a sulfur atom, a selenium atom, an oxygen atom, a CH2 group, a SO group and a SO2 group; and R" is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms; and / or b) general formula (I), Where R1, R2 and R3 represent i) a hydrogen atom; or ii) a group of formula CO-R, wherein R is a saturated or unsaturated, optionally substituted, linear or branched alkyl group, and the main chain of said R contains 1 to 25 carbon atoms; or iii) having the formula CO-(CH2) 2n+1 -X-R' group, wherein X is a sulfur atom, a selenium atom, an oxygen atom, a CH2 group, a SO group or a SO2 group; n is an integer from 0 to 11; and R' is a saturated or unsaturated, optionally substituted straight or branched alkyl group, wherein the main chain of R' contains 13 to 23 carbon atoms and optionally one or more hetero groups selected from the group consisting of oxygen atoms, sulfur atoms, selenium atoms, oxygen atoms, CH2 groups, SO groups and SO2 groups; iv) an entity selected from the group consisting of: -PO3CH2CHNH3COOH (serine), PO3CH2CH2NH3 (ethanolamine), PO3CH2CH2N(CH3)3 (choline), PO3CH2CHOHCH2OH (glycerol) and PO3(CHOH)6 (inositol); wherein R1, R2 and R3 are independently selected from i), ii), iii) or iv), but at least one of R1, R2 or R3 is defined by iii); and / or c) general formula (II), wherein A1, A2 and A3 are independently selected and represent an oxygen atom, a sulfur atom or an N-R4 group, wherein R4 is a hydrogen atom or a saturated or unsaturated, optionally substituted, straight or branched chain alkyl group containing 1 to 5 carbon atoms; Where R1, R2 and R3 represent i) a hydrogen atom or a saturated or unsaturated, optionally substituted, straight-chain or branched alkyl group containing 1 to 23 carbon atoms; or ii) a group of formula CO-R, wherein R is a saturated or unsaturated, optionally substituted, linear or branched alkyl group, and the main chain of said R contains 1 to 25 carbon atoms; or iii) having the formula CO-(CH2) 2n+1 -X-R' group, wherein X is a sulfur atom, a selenium atom, an oxygen atom, a CH2 group, a SO group or a SO2 group; n is an integer from 0 to 11; and R' is a saturated or unsaturated, optionally substituted straight or branched alkyl group, wherein the main chain of R' contains 13 to 23 carbon atoms and optionally one or more hetero groups selected from the group consisting of oxygen atoms, sulfur atoms, selenium atoms, oxygen atoms, CH2 groups, SO groups and SO2 groups; iv) an entity selected from the group consisting of: -PO3CH2CHNH3COOH (serine), PO3CH2CH2NH3 (ethanolamine), PO3CH2CH2N(CH3)3 (choline), PO3CH2CHOHCH2OH (glycerol) and PO3(CHOH)6 (inositol); wherein R1, R2 and R3 are independently selected from i), ii), iii) or iv), but at least one of R1, R2 or R3 is defined by iii); and / or A salt, prodrug or complex of a compound according to a) to c).

10. The combination or composition according to claim 9, or the pharmaceutical or nutritional combination or composition for use in the method according to claim 9, wherein: In the (ii) tetradecylthioacetic acid (TTA) or its derivatives, the X is a sulfur atom, and / or the n is 0 or 1, and / or at least one of the R1, R2 and R3 is tetradecylthioacetic acid (TTA) or a tetradecylthioacetic acid group.

11. A combination or composition according to any one of the preceding claims, or a pharmaceutical or nutritional combination or composition for use in a method according to any one of the preceding claims, wherein: The (ii) tetradecylthioacetic acid (TTA) or its derivatives are selected from tetradecylthioacetic acid (TTA), TTA containing one or more carbon-carbon triple bonds, including 2-(tridec-12-yne-1-thio) acid, 3-thio-15-heptadecyne, and their monoacylglycerols, diacylglycerols and triacylglycerols, their esters, their monoesters, diesters and triesters, their amides, their monoamides, diamides and triamides, their peptides, compounds containing phospholipids; phosphatidylcholine (PC) derivatives 1,2-ditetradecylthioacetyl-sn-glycero-3-phosphocholine, phosphatidylethanolamine (PE) derivatives 1,2-dimethoxy-1-phosphocholine, ... Tetradecylthioacetyl-sn-glycero-3-phosphoethanolamine; polyunsaturated fatty acids in the form of diglycerides or triglycerides, esters or salts thereof; ω-3, ω-6 and / or ω-9 polyunsaturated fatty acids in the form of diglycerides or triglycerides, esters or salts thereof; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of diglycerides or triglycerides or salts thereof; preferably, the (ii) tetradecylthioacetic acid (TTA) and its derivatives are selected from monoacylglycerols, diacylglycerols and triacylglycerols of fatty acids, polyunsaturated fatty acids and their derivatives, EPA and DHA and their derivatives, and combinations thereof.

12. A combination or composition according to any one of the preceding claims, or a pharmaceutical or nutritional combination or composition for use according to any one of the preceding claims, wherein: The (ii) tetradecylthioacetic acid (TTA) or its derivatives include phospholipids, preferably the phospholipids are selected from the group consisting of phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol and diphosphatidylglycerol and mixtures thereof.

13. A combination or composition according to any one of the preceding claims, or a pharmaceutical or nutritional combination or composition for use according to any one of the preceding claims, wherein: It further comprises one or more pharmaceutically acceptable inactive ingredients, preferably the one or more pharmaceutically acceptable inactive ingredients are selected from the group consisting of: inert diluents, including carbonates, including calcium carbonate and sodium carbonate; buffers, including phosphates, including calcium and sodium phosphates, citrates, succinates; Organic acids, including acetic acid and its salts; antioxidants, including ascorbic acid; hydrophilic polymers, including polyvinyl pyrrolidone and polyethylene glycol; granulating and disintegrants, including corn starch or alginic acid; binders, including starch, gelatin and gum arabic; lubricants, including magnesium stearate, stearic acid and talc; solvents, including organic solvents, water and aqueous electrolyte solutions; preservatives; chelating agents, including EDTA; effervescent agents; natural or artificial sweeteners, including glucose, mannose, dextrin, mannitol and sorbitol; carbohydrates, including monosaccharides, disaccharides and cellulose derivatives; flavoring agents; coloring agents; taste masking agents; acidulants; lactose, surfactants and emulsifiers, including polysorbates, poloxamers and polyethylene glycol (PEG); thickeners; suspending, dispersing and wetting agents; oils; fibers; fats; proteins; carbohydrates; minerals; agents for improving taste, texture, color, odor, stability and / or shelf life; and combinations thereof.

14. A combination or composition according to any one of the preceding claims, or a pharmaceutical or nutritional combination or composition for use according to any one of the preceding claims, wherein: It further comprises one or more pharmaceutically acceptable active ingredients, preferably the one or more pharmaceutically acceptable active ingredients are selected from the group consisting of: vitamins, including vitamin A, vitamin C, vitamin D, including vitamin D1, vitamin D2, vitamin D3 and vitamin D analogs, including alfacalcidol, dihydrotachysterol and calcitriol; vitamin E, vitamin K; antibiotics; anticoagulants, including acetylsalicylic acid and COX-2 inhibitors; oils; Fermented soy protein material; peptide; carnitine; astaxanthin; and combinations thereof.

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