USE OF A QUINIC ACID CONJUGATE WITH AT LEAST ONE CAFEIC ACID MOLECULE IN THE PREPARATION OF A COMPOS

专利摘要:
the present invention relates to the use of the composition for the prevention, improvement and / or treatment of disorders and diseases involving senescence of the cell, tissue or organ, or for the prevention, improvement and / or treatment of disorders and diseases involving tension of the organ, tissue, cell caused by an inflammatory process, the composition comprising a conjugate of quinic acid with at least one molecule of caffeic acid, or a derivative, isomer or its salt.
公开号:BR112016006926B1
申请号:R112016006926-9
申请日:2014-09-19
公开日:2020-09-24
发明作者:Iain William George Forbes；William Forbes
申请人:Calscience International Ltd.；
IPC主号:

专利说明:

[0001] [001] The present invention relates to the use of a composition for the prevention, amelioration and / or treatment of conditions associated with the process of senescence and / or inflammation.
[0002] [002] The term senescence, including cell senescence, involves noticeable changes in cells, such as a decrease in telomeres, ruptures of double-stranded DNA, an increase in the levels of p16 INK4a and p21, and an increase in the concentration of MMP -9. The senescence process can be natural, premature, induced or accelerated. Accelerated or induced senescence has been found to be involved in some diseases, and in transplanted cells, tissues and organs. Accelerated senescence has been observed in diseased organs, such as the kidney. The natural senescence processes of the skin, as evidenced externally by wrinkles and / or pigmented or non-pigmented skin lesions, can be accelerated through injury produced by ultraviolet radiation from the sun, or through other radiation sources. In addition, the natural senescence process can be accelerated by heat damage to the skin, such as burns and scalds.
[0003] [003] Sirtuins (SIRTs) are mammalian homologues of the Silent Information Regulatory Protein (Sir2) found in yeast and are enzymes of class III histone deacetylases (HDACs). Class III HDACs cause transcriptional repression and gene silencing by removing acetyl groups from histones and regulating gene expression depending on changes in redox and cell metabolism. The Sirtuin 2 (Sir2) family depends on the nicotinamide adenine dinucleotide (NAD +) for subsequent reactions, conversion of acetyl lysine in the presence of NAD + to Oacetyl-ADP-ribose and nicotinamide. Regulated by the ratio of NAD + to NADH, the activity of sirtuins varies not only with metabolic changes in the cell, but also with an inhibition of regeneration due to the level of nicotinamide generated.
[0004] [004] Seven members of the sirtuin family have been found in mammals and are typically numbered SIRT1 through SIRT7. SIRT1 is located mainly in the nucleus and has complex functions in cell senescence and tumor suppression by limiting DNA damage by reactive oxygen species and genomic instability. The latter is the subject of current research in cancer cells. SIRT2 is a deacetylase present in the cytosol and is mainly found colocalized with tubulin, which is deacetylated (North, BJ, et al., Mol Cell, 2003, 11 (2), 437-44; Inoue, T., And others, Oncogene 2007, 26 (7), 945-57). SIRT2 functions as a regulator of mitotic progression and, as a result, overexpression of SIRT2 has been discovered to delay a cell cycle progression. SIRT2 is typically ubiquitated and degraded through the 26s proteasome mechanism. SIRT3 is found in the nucleus and in mitochondria and performs its function as a deacetylase only after cleavage of its signal peptide. It has been found that SIRT3 expression can be improved due to a polymorphism and that the allele needing this activity is also absent in men over 90 years of age (Bellizzi, D. et al., Genomics, 2005, 85 (2) , 258-63). This can link the insufficiency of SIRT3 to the senescence process. SIRT3 is mainly a nuclear enzyme, but is located for mitochondria when the cell is under tension or when the enzyme overexpression occurs (Scher, M.B., et al., Genes Dev (2007) 21 (8), 920-28). Of the remaining sirtuins, SIRT4 may require deacetylase activity and is found with SIRT5 in mitochondria. The latter cannot yet be shown to have a precise biological function and is a deacetylase. SIRT6 is located in the nucleus and can be involved in promoting resistance to DNA damage and repair by excision of the base pair. SIRT7 is found in the nucleolus. Depletion of SIRT7 stops cell proliferation and causes apoptosis.
[0005] [005] Matrix metalloproteinases (MMPs) are part of the family of endopeptidases (proteolytic enzymes) and are distinguished by having a zinc atom associated with three cysteine residues, together with a methionine residue. More than thirty MMPs are present in mammals and are therefore numbered, for example, MMP-1 (collagenase 1), MMP-2 (gelatinase A) and MMP-9 (gelatinase B). MMPs are known to hydrolyze large proteins in connective tissue, degrade large proteins in the extracellular matrix and basal leaves (eg collagen, gelatin, elastin, proteoglycan and fibronectin) and are expressed at very low levels under normal growth conditions. organ, tissue regeneration and renewal. Under certain conditions in mammals, overexpression of MMPs, and in particular MMP-9, can result in disorganization and / or destruction of the extracellular matrix and / or the growth of cancer. MMPs are induced by proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta).
[0006] [006] Matrix metalloproteinases are also involved in the activation of other MMPs and are necessary in the biosynthesis of the main proinflammatory cytokine, TNF-alpha. This cytokine may influence the activation of other pro-inflammatory cytokines, such as interleukin-1 beta (IL-1 beta) and is of significance in the regulation above the nuclear factor B cap (NF-cap B). The latter in turn is capable of activating MMP-9, for this reason creating a self-perpetuating stimulating pro-inflammatory curve. TNF-alpha is relevant in a wide range of clinical conditions and diseases and its overexpression may be a major contributory factor in several disorders. In addition, TNF-alpha can contribute significantly to downstream effects or events in the cell. Conditions or diseases in which this cytokine has been shown to be overexpressed include: autoimmune conditions, such as, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, Multiple Sclerosis, graft rejection, cancer, cachexia (including that of cancer) , infectious diseases including tuberculosis and leprosy, radiation damage (including ultraviolet), anorexia and septic shock.
[0007] [007] An excess of activity of a matrix metalloproteinase (MMP), or an imbalance between an MMP and the corresponding natural tissue inhibitor of the matrix metalloproteinase (TIMP) is associated with the destruction or decomposition of the extracellular matrix in cells and can therefore this reason, result in tissue damage, disease or the extent of the disease.
[0008] [008] Although certain MMPs are necessary for normal embryonic development, these enzymes are known to appear and disappear in an exact period of time, but in a concentration range. MMPs, and in particular MMP-9, are overexpressed in a range of diseases that are linked equally by the direct and downstream effects of these enzymes, for example: diseases of the central nervous system, such as, Parkinson's disease, Alzheimer's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis and Fragile X Syndrome; Muscular dystrophy, including Duchenne muscular dystrophy and low-belt muscular dystrophies; primary human neoplasms and metastasis, for example, prostate and breast cancer; alopecia, including areata and totalis; and diseases and conditions associated with inflammatory processes, such as acute infections and wound healing. MMP-9 is also found to be present in dermal papillary fibroblasts.
[0009] [009] Certain genetic disorders have been shown to involve an increase in cellular levels of MMP-9. In addition, MMP-9 has been shown to be associated with controlling blood-brain barrier permeability. MMP-9 also activates alpha-synuclein (a cell protein involved in programmed cell death) by removing a short terminal sequence, resulting in the soluble and insoluble aggregate forms of the latter. These insoluble aggregates have been found to be present in Lewy bodies in Parkinson's disease and can lead to apoptosis. Alpha-synuclein is also found in beta-amyloid, a protein of significance in the pathology of Alzheimer's disease. The formation of dopamine from dopa is catalyzed by the enzyme tyrosine hydroxylase and the latter enzyme is inhibited by alpha-synuclein. An increase in MMP-9 levels may therefore indirectly affect the levels of dopamine in dopaminergic neurons. Since an important feature of Parkinson's disease is dopamine depletion, overexpression of MMP-9 may be of greater importance in this disease.
[0010] [0010] MMP-9 has also been found to be an important factor in the growth of cancer, in which it is involved in altering the cancer cells surrounding the medium, so that the cancer cells can be more easily involved in the surrounding tissues . This process typically occurs during the extension of the primary tumor, spread to the lymph nodes and in metastatic spread to other parts of the body, in which cancer cells can flourish and extend their influence.
[0011] [0011] A number of small non-peptide molecules have been shown to inhibit MMP-9, but so far, this has been of relatively low potency. These molecules include antibiotics, such as minocycline, doxycycline and erythromycin. Other low to medium inhibitors of MMP-9 are: arginine, nicotinamide, vitamin D3 and curcumin (of the turmeric spice). In any case, none of these compounds have been shown to have anti-aging properties. Efforts have been made to identify highly selective MMP inhibitors with little or no side effects. These highly selective inhibitors of MMPs, particularly MMP-9, have not previously been shown to have an inhibitory effect on cell senescence. In US 2004/0034098, Varani et al., Suggest that human skin senescence can be delayed with the topical application of an MMP inhibitor, preferably a retinoid (which indirectly inhibits MMP). In US 2004/0127420 and US 2003/0166567, Quirk et al., Describe peptide inhibitors of MMPs for the treatment of wounds. These inhibitors have sequences related to the cleavage regions of the MMP proenzyme forms.
[0012] [0012] Some publications that refer to the inhibition of matrix metalloproteinases (MMPs) are: Wadda et al., J Med. Chem, 45, 219-232; US 2002/0037827; US 2004/0029945; US 2004/0175349; US 2004/0176393; US 2004/0167120; US 2004/0142950; US 2004/0044000; US 2004/0116491 and US 2004/0105897. The following publications refer to conditions and disorders that may benefit from MMP inhibition: US 2006/0074108; US 2004/0034098; US 2004/0127420; US 2003/0166567; Agren, M. S., Arch. Dermatol. Res., 1999, 291583-291590; Browner, M. F. et al., Biochemistry, 1995, 34, 6602-6610; Moses, M. A. et al., J Cell Biochem., 60, 379; Saarialho and Kere, UK Arch. Dermatol. Res., 1998, 290 (Suppl), 47-54; Vaalamo, Mr6 et al., 1996, Brit. J. Dermatol., 135, 52-59. Although these publications suggest a biological function for these compounds, accurate cell pathways have been demonstrated.
[0013] [0013] The present invention seeks to provide a composition for use in preventing, ameliorating and / or treating conditions involving senescence and / or inflammation processes.
[0014] [0014] According to the invention, at this point the use of a cosmetic composition for preventing and / or improving senescence of the tissue or cell is provided, the composition comprising a conjugate of quinic acid with at least one molecule of caffeic acid , or a derivative, l or its salt.
[0015] [0015] In a preferred embodiment, the conjugate is represented by the following formula (I):
[0016] [0016] where at least one of R1, R2, R3 or R4 is a hydrogen atom: and
[0017] [0017] in which at least one of R1, R2, R3 or R4 that is not hydrogen is a caffeine group, represented by the following formula (II):
[0018] [0018] or a derivative, isomer or its salt.
[0019] [0019] Within the context of the present invention, the conjugate means a compound formed by joining together at least two individual portions.
[0020] [0020] In particular, the conjugate is preferably an ester of caffeic acid and quinic acid.
[0021] [0021] Preferably, in the formation of the conjugate, the hydrogen of OR1, OR2, OR3 and / or OR4 reacts with the caffeic acid carboxylic acid functional group to form an ester.
[0022] [0022] As an example, a typical reaction that can occur to form a conjugate within the context of the invention is shown below:
[0023] [0023] The example above shows the formation of 3-caffeoylquinic acid. The invention is not limited to the use of a composition comprising this conjugate and other conjugates can be employed in accordance with the present invention.
[0024] [0024] Preferably, the cosmetic composition comprises a Dicafeoilquinic acid and / or a tricafeoilquinic acid, or a derivative, isomer or its salt.
[0025] [0025] Preferably, the conjugate is selected from 1,3-Dicafeoylquinic acid, 1,4-Dicafeoylquinic acid, 1,5-Dicafeoylquinic acid, 3,4-Dicafeoylquinic acid, 3,5-Dicafeoylquinic acid, 4,5 -dicafeoilquinic, or 3,4,5-tricafeoylquinic acid, or a derivative, isomer or its salt.
[0026] [0026] The nomenclature of Dicafeoiloquinoic or tricafeoiloquinoic acids can be represented as, for example, 1,3-O-Dicafeoiloquinoic acid or 3,4,5-O-Tricafeoiloquinoic acid, etc.
[0027] [0027] In one modality, the conjugate is extracted from a natural source. Preferably, the conjugate is a plant extract, preferably an artichoke extract. In another modality, the conjugate is synthesized or genetically designed from plants, bacteria, fungi, mold, algae or other suitable sources. Preferably, the composition comprises a plant extract.
[0028] [0028] In one embodiment, the conjugate also comprises a lipid, fatty acid, alcohol or sugar fixing to another tipfeoylquinic acid or tricafeoylquinic acid, or a derivative, isomer or its salt.
[0029] [0029] Preferably, the conjugate comprises at least one acceptable vehicle and can be transported in a vesicle, mycelium, liposome, nanoparticle or other suitable vehicle.
[0030] [0030] Typically, the cosmetic composition is applied to the skin. In another modality, the cosmetic composition is applied to the hair and / or scalp. Typically, the cosmetic composition can be provided in the form of a serum, lotion, cream, gel, powder, ointment or other means suitable for topical administration of the composition to the skin, or for administration to the hair and / or scalp. Typically, the cosmetic composition can be administered through a delivery system that can comprise skin cleansers, surfactants, skin conditioning agents, hair conditioning agents, vitamins, hormones, minerals, plant extracts, plant extract concentrates , anti-inflammatory agents, antioxidants, emollients, humectants, skin protectors, skin penetration enhancers, solubilizers, and / or pH adjusters.
[0031] [0031] The term senescence can refer to accelerated, natural, premature or induced senescence.
[0032] [0032] In a preferred embodiment, the use of the cosmetic composition inhibits the activity of MMP-9. MMP-9 is a collagenase and is associated with the breakdown of various skin components, such as, elastin, gelatin types I and V, collagen types IV and V and fibrillin, which can decrease skin elasticity and firmness. The inhibition of MMP-9, for this reason, prevents the decomposition of these components and improves the properties of the skin, such as elasticity and firmness.
[0033] [0033] Advantageously, the use of the cosmetic composition is to increase the cohesion of the extracellular matrix, preferably of the skin. Advantageously, the use of the cosmetic composition is to stimulate the biosynthesis of fibrillar collagens, elastin and / or fibrillins. Advantageously, the use of the cosmetic composition is to inhibit the decomposition of elastin and / or collagenase type IV. Advantageously, the use of the cosmetic composition is to provide skin elasticity and / or skin firmness. Preferably, use of the cosmetic composition is to prevent, ameliorate and / or treat a condition associated with a loss of skin elasticity (i.e., to reduce the loss of skin elasticity), for example, as evident from stretch marks that can be associated with weight loss or pregnancy.
[0034] [0034] Advantageously, the use of the cosmetic composition is to protect the skin against circumstantial injury and / or injury caused by ultraviolet radiation, including injury from the sun. Advantageously, the cosmetic composition improves the skin's natural protective functions. Advantageously, the cosmetic composition can provide protection against injury caused by factors such as pollution, smoke and stress.
[0035] [0035] Preferably, the use of the cosmetic composition is to reduce the formation of wrinkles, reduce the redness of the skin, reduce the appearance of telangiectasias, delay the appearance of fine lines, and / or reduce the appearance of dark circles around the eyes. eyes.
[0036] [0036] Thus, the use of a cosmetic composition, according to the present invention can help in the prevention and / or improvement of the conditions associated with skin senescence, for example, as exemplified by the blemishes, skin thinning, and / or skin wrinkling.
[0037] [0037] Advantageously, the use of the cosmetic composition is to improve and / or enhance the appearance of the skin.
[0038] [0038] Preferably, the cosmetic composition is used to prevent and / or improve the conditions associated with an excess of subcutaneous fat. Such conditions can be mediated by MMP-9 and can be exemplified by the appearance of dimples in the skin.
[0039] [0039] In another embodiment, the use of the cosmetic composition helps in preventing, and / or ameliorating a condition associated with senescence of hair and / or hair follicles, for example, including a loss or reduction of natural hair coloring, such as can be exemplified by the graying of the hair. Advantageously, the composition can be used to improve the condition and / or appearance of the hair.
[0040] [0040] According to a second aspect, at this point the use of a composition is provided for the prevention, improvement and / or treatment of disorders and diseases involving senescence of the organ, tissue or cell, the composition comprising a conjugate of quinic acid with at least one molecule of caffeic acid, or a derivative, isomer or its salt.
[0041] [0041] In a preferred embodiment, the composition as used in the second aspect is as defined with respect to the first aspect.
[0042] [0042] Preferably, the conjugate is represented by the structures shown in formula (I) and formula (II).
[0043] [0043] In one embodiment, the conjugate comprises an amino acid, peptide, protein, lipid, sugar, polysaccharide, organic or inorganic acid attached to one of the hydroxyl groups. In another embodiment, the conjugate comprises an alkyl or aryl or alkali metal group joined at the R1, R2, R3 or R4 position. More preferably, the alkyl or aryl or alkali metal group is joined at the R1 position.
[0044] [0044] In one embodiment, the composition is pyrogen-free.
[0045] [0045] In one embodiment, the conjugate is provided in the form of a free base or a pharmaceutically acceptable salt.
[0046] [0046] In one embodiment, the conjugate comprises a pharmaceutically acceptable carrier or delivery system which may be in the form of water and oil emulsions, suspensions, colloids, microemulsions, suspensions or emulsions of vesicles, mycelia, liposomes, microparticles, nanoparticles , powders or anhydrous conditions. The conjugate can also be coated or combined with a material, such as a lipid or sugar, or a combination thereof. The conjugate can be linked to an amino acid, peptide, antibody or other suitable molecule to allow the targeting of the conjugate to cells, tissues or organs. In one embodiment, the conjugate is attached to a protein, amino acid, aryl group, alkyl group, fatty acid, sugar, lipid, flavonoid, sugar, salt or ester or other functional group, or an isoform thereof. In one embodiment, the conjugate is attached to a glycine or taurine residue. Preferably, the target guide material or coating dissolves to allow sufficient and efficient release of the conjugate to cells, tissues or organs.
[0047] [0047] The composition may comprise at least one anti-inflammatory agent selected from Boswellia serrata, corosolic acid, ursolic acid, oleanolic acid, salicinol (salacia), rosmarinic acid, ruscogenins, darutoside, asiaticoside, sericoside, harpagoside, horse chestnut ( escin, esculin), ginger (gingerol), turmeric extract (tetrahydrocurcuminoids), coridalis, myricetin, artichoke, alfalfa, tea, coffee and / or combinations of these, or an antioxidant. The composition may comprise a divalent metal ion and / or a polyvalent, for example, copper, zinc, iron, selenium, vanadium or manganese.
[0048] [0048] In one embodiment, the composition is administered parenterally or orally. Typically, the composition can be administered via a dermal, intradermal, transdermal, topical, intramuscular, subcutaneous, intravenous, nasal, oral, sublingual, lingual or rectal route, or through inhalation or instillation. In another embodiment, the composition is administered by incorporation into an implant, or by the use of a pumping device. In one embodiment, the composition is administered in an infusion that is transmitted through the organs, or added to isolated cells, tissues or organs. In another embodiment, the conjugate is administered in the form of a tablet.
[0049] [0049] In one embodiment, the composition is administered in combination with an adjuvant, such as an anti-inflammatory drug, an extract or a natural agent. In another embodiment, the composition also comprises an antioxidant, and / or Nuclear Factor inhibitor layer B (NF-layer B), or an inhibitor of a matrix metalloproteinase (MMP), or an antibiotic or vitamin, for example, vitamin D, vitamin D3, vitamin C dehydroascorbate, vitamin B, vitamin E, or another suitable vitamin and / or cofactor.
[0050] [0050] In one embodiment, the composition is incorporated into a food or drink.
[0051] [0051] Advantageously, the composition can be employed for the prevention, amelioration and / or treatment of a disorder or disease associated with an increase in the expression of the sirtuin 2 protein or gene, and / or a decrease in the expression of the protein or gene of the sirtuin 2 sirtuin 3.
[0052] [0052] Advantageously, the composition is capable of activating the expression of the sirtuin 3 gene to increase the production of the sirtuin 3 protein. Advantageously, the composition is capable of inhibiting the expression of the sirtuin 2 gene to inhibit the production of the sirtuin 2 protein. reduced level of SIRT3 in cells and tissues is believed to be a marker of senescence.
[0053] [0053] Advantageously, the composition is capable of inhibiting the expression of the p16INK4a gene in cells, tissues or organs, for example, after oxidative stimulation.
[0054] [0054] Advantageously, the use of the composition can inhibit the over-regulation of SIRT2 that occurs in neurodegenerative and other diseases of the nervous system. Preferably, the composition can be employed to prevent, ameliorate and / or treat the neurotoxic effects caused by over-regulation of alpha-synuclein in neurodegenerative and other diseases of the nervous system.
[0055] [0055] Preferably, the use of the composition inhibits the main pro-inflammatory cytokines, for example, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha ), chemokine interleukin-8 (CXCL-8; IL-8) and gamma interferon (IFN-gamma) in cells, tissues or organs.
[0056] [0056] In one embodiment, the use of the composition modulates the expression of the Telomere Human Protection 1 gene product (hPOT1). Such modulation indicates a significant protective effect on telomeres which under normal circumstances shortens with the oxidizing stimulus.
[0057] [0057] Advantageously, the composition can be used to inhibit MMPs, NF-cover B and genes associated with senescence.
[0058] [0058] In one embodiment, the composition is used for the prevention, improvement and / or treatment of senescence associated with degeneration in stem cells, or in cells of the nervous system, skin, tissues or organs, in which senescence can be induced by natural factors, or where senescence can be accelerated. Typically, accelerated senescence can be caused by exposure to radiation or chemotherapy; a genetic anomaly, such as in progeria or associated disorders; disease; or the transplantation of cells, tissues or organs. In one embodiment, the composition is used for the prevention, treatment and / or improvement of senescence (for example, accelerated senescence) that can occur in transplanted cells, tissues or organs, such as the kidney. The cells, tissues or organs for transplantation purposes can be autologous, or they can be obtained through cloning, laboratory production, industrial production, or from a mammalian source.
[0059] [0059] In one embodiment, the composition is used to reverse degeneration associated with cell senescence, including stem cells and cells of the nervous system, tissues and / or organs.
[0060] [0060] Preferably, the composition is also used for the prevention, improvement and / or treatment of a condition associated with accelerated senescence in transplanted or diseased organs or tissues, or in transplanted or infused cells including bone marrow, stem cells, cells white or red blood, cell lines, and / or organs stored for transplant.
[0061] [0061] In another modality, the composition is used to maintain or prolong the viability of organs or cells, including stem cells, before and / or after the transplantation process, and / or in cell lines.
[0062] [0062] In one embodiment, the composition is used for the prevention, improvement and / or treatment of a disorder or disease associated with the immune system.
[0063] [0063] In one embodiment, the composition is used for the prevention, improvement and / or treatment of a disease or disorder in the skin.
[0064] [0064] In another embodiment, the composition is used for the prevention, improvement and / or treatment of a disorder or disease associated with senescence of the hair or hair follicles. Typically, the composition can be used to prevent, ameliorate or treat a disorder or disease associated with hair loss or damage to hair follicles, hair thinning, or alopecia. Preferably, the composition is applied to the hair in the form of a spray, cream, lotion or serum.
[0065] [0065] In another modality, the composition is used for the prevention, improvement and / or treatment of a pathological disorder associated with the senescence of cells or tissues.
[0066] [0066] In yet another modality, the composition is used for the prevention, improvement and / or treatment of a disorder or disease associated with the kidney, lung, liver, heart and / or pancreas. In one embodiment, the composition can be administered in combination with an adjuvant.
[0067] [0067] Preferably, the composition is employed for the prevention, amelioration and / or treatment of a condition associated with neurodegeneration.
[0068] [0068] In one embodiment, the composition is used for the prevention, improvement and / or treatment of senescence occurring in the cells of the nervous system, including neurons, astrocytes, oligodendrites, glial cells, Schwann cells and blood-brain barrier cells. In another embodiment, the composition is used for the prevention, improvement and / or treatment of disorders or diseases of the peripheral and / or central nervous system. Preferably, the composition is employed for the prevention, amelioration and / or treatment of Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Fragile X Syndrome and / or Charcot-Marie-T ooth Syndrome.
[0069] [0069] In another modality, the composition is used for the prevention, improvement and / or treatment of a condition associated with senescence of the ear, such as, deafness, loss of hair cells in the inner ear or tinnitus; a condition associated with senescence of the eye, such as macular degeneration, cataracts or glaucoma; osteoporosis; osteoarthritis; degeneration of the intervertebral disc; type 2 diabetes; prostate hypertrophy and / or emphysema.
[0070] [0070] In another modality, the composition is used for the prevention, improvement and / or treatment of diseases of the cardiovascular system.
[0071] [0071] In another embodiment, the composition is used for the prevention, improvement and / or treatment of a condition associated with senescence in the endothelial cells, or in the prevention, improvement and / or treatment of a condition associated with senescence in liver cirrhosis.
[0072] [0072] In another embodiment, the composition is used for the prevention, improvement and / or treatment of mitochondriopathies, including neuromitochondriopathies. Advantageously, the composition can contribute to the repair of mitochondrial DNA by over-regulation of sirtuin 3 and, thus, favoring the interaction of sirtuin 3 with glycosylase 8-oxoguanine-DNA (OGG1), a DNA repair enzyme.
[0073] [0073] Typically, the composition may be able to maintain structural integrity against possible enzymatic attack in the alimentary tract, plasma, the liver and / or other organs.
[0074] [0074] In one embodiment, the composition is produced in a laboratory or on an industrial scale by means of solid phase synthesis or other means, and can be purified to provide a therapeutically effective dose of the composition.
[0075] [0075] Advantageously, the composition can be used in human therapy and / or veterinary practice, and is typically administered to a mammalian patient.
[0076] [0076] Advantageously, the composition can be administered with a high degree of safety.
[0077] [0077] According to a third aspect, the invention relates to the use of a composition for the prevention, improvement and / or treatment of disorders and / or diseases involving the tension of the organ, tissue, cell caused by an inflammatory process, the composition comprising a conjugate of quinic acid with at least one molecule of caffeic acid, or a derivative, isomer or its salt.
[0078] [0078] Preferably, the composition as used in the third aspect is as defined with respect to the first and second aspects.
[0079] [0079] Preferably, the conjugate is represented by the structures shown in formula (I) and formula (II).
[0080] [0080] Preferably, the composition is employed for the prevention, improvement and / or treatment of disorders or diseases associated with an increase in the expression of one or more proteins and / or matrix metalloproteinase (MMP) genes. In a preferred embodiment, the composition inhibits MMPs, NF-cover B, cytokines and / or tissue inhibitors of matrix metalloproteinase activators (TIMP). These factors are known to be involved in the inflammation process. In one embodiment, the disorder or disease is associated with an increase in the expression of MMP-9 and / or MMP-2. Typically, the composition inhibits MMP-9 and / or MMP-2.
[0081] [0081] In one embodiment, the composition is used for the prevention, improvement and / or treatment of a malignant or benign neoplasm. Preferably, the malignant neoplasm may be associated with breast, lung, colon, rectum, prostate, blood cells, oral cancer, skin cancer or melanoma or leukemia.
[0082] [0082] Preferably, the composition is employed for the prevention, improvement and / or treatment of cancer cell growth (e.g., metastasis), including invasion of the surrounding tissue site, and its spread to other tissues and / or organs. Typically, the composition can be used to prevent, ameliorate and / or treat lymphatic, capillary, venous or arterial invasion by cancer cells, including spread to lymph nodes.
[0083] [0083] In one embodiment, the composition is used in combination with other anti-cancer therapy including chemotherapy, synergistic compounds, antibodies, genes, gene products, cell therapy and / or radiation.
[0084] [0084] In another embodiment, the composition is used for the prevention, improvement and / or treatment of hypertrophy or hyperplasia of the prostate gland. In one embodiment, the composition is administered in combination with another agent, for example, an adjuvant.
[0085] [0085] In one embodiment, the composition is employed for the improvement and / or treatment of chronic inflammatory disease of the breast, or polycystic disease including polycystic disease of the ovary or kidney.
[0086] [0086] In another modality, the composition is used for the prevention, improvement and / or treatment of endometriosis, including invasion of the site, infiltration and / or propagation of endometrial cells in the walls of the uterus, surrounding tissues and organs.
[0087] [0087] In yet another modality, the composition is used for the prevention, improvement and / or treatment of adhesions after a medical or surgical procedure.
[0088] [0088] In one embodiment, the composition is used for the prevention, treatment and / or improvement of obstruction of the fallopian tubes or channels of the male reproductive organs after an inflammatory reaction.
[0089] [0089] In one embodiment, the composition is used for the prevention, improvement and / or treatment of periodontitis and / or retraction of the gums. In this embodiment, the composition is preferably administered orally, which may involve the use of a gel, spray, toothpaste and / or mouthwash.
[0090] [0090] In another embodiment, the composition is used for the prevention, improvement and / or treatment of disease of the hematopoietic system, such as primary and secondary hemophagocytic lymphohistiocytosis (HLH) or Langerhan cell histiocytosis (LCH).
[0091] [0091] Preferably, the composition is used for the prevention, improvement and / or treatment of disorders and diseases of the muscle, including muscular dystrophy or muscle injuries. In one embodiment, the composition is used for the prevention, improvement and / or treatment of Duchenne muscular dystrophy, low-belt muscular dystrophy and / or dystroglycanopathies. Advantageously, the composition can be used to promote or regenerate skeletal muscle fibers and / or to increase the numbers and biological activation of satellite cells or stem cells.
[0092] [0092] In another embodiment, the composition is used for the prevention, improvement and / or treatment of muscular dystrophies or other genetic or epigenetic disorders associated with the deacetylation of the genes by means of a mammalian histone deacetylase (that is, a member of the Family sirtuin).
[0093] [0093] Preferably, the composition is employed for the prevention, amelioration and / or treatment of Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Charcot-Marie-Tooth Syndrome, Huntington's disease, motor neuron disease, or a disease the peripheral or central nervous system in which an inflammatory reaction of the cellular tissue is involved.
[0094] [0094] In another embodiment, the composition is used for the prevention, improvement and / or treatment of injuries of the nervous system tissue including those of the brain, spinal cord and / or peripheral nerves. Preferably, the composition is employed for the prevention, amelioration and / or treatment of conditions associated with stroke, including multiple infarction syndrome.
[0095] [0095] In another embodiment, the composition is used for the prevention, improvement and / or treatment of conditions associated with increased blood-brain barrier permeability.
[0096] [0096] In one embodiment, the composition is used for the prevention, improvement and / or treatment of fatigue, including chronic fatigue syndrome, post-viral fatigue or fatigue associated with cancer.
[0097] [0097] In another embodiment, the composition is used for the prevention, improvement, and / or treatment of diseases of the eye, including uveitis, conjunctivitis, corneal opacities and / or dry eye. In one embodiment, the composition can be administered in combination with an adjuvant treatment.
[0098] [0098] In another embodiment, the composition is used for the prevention, improvement and / or treatment of diseases of the cardiovascular system, including atherosclerosis, arteriosclerosis, aneurysms, coronary heart disease and the stabilization of the carotid plaques.
[0099] [0099] In another embodiment, the composition is used to prevent, ameliorate and / or treat a condition associated with an increase in low-density lipoprotein levels. In another embodiment, the composition is used to reduce the level of low-density lipoproteins in the blood, body fluids, cells, tissues and organs.
[0100] [00100] In another modality, the composition is used for the prevention, improvement and / or treatment of a condition associated with the use of venous or arterial tubes.
[0101] [00101] In another embodiment, the composition is used for the prevention, improvement and / or treatment of inflammatory disorders of the respiratory system including chronic obstructive pulmonary disease (COPD), bronchiectasis and / or chronic bronchitis.
[0102] [00102] In one embodiment, the composition is employed for the prevention, amelioration and / or treatment of inflammatory bowel diseases, including irritable bowel disease, Crohn's disease or ulcerative colitis. Advantageously, the invention can be employed for the prevention, amelioration and / or treatment of pseudomembranous colitis that can be caused by infection with Clostridium difficile.
[0103] [00103] In another modality, the composition is used for the prevention, improvement and / or treatment of a condition associated with injury to the joints, tendons, synovial membrane and / or cartilage. Preferably, the composition is employed for the prevention, amelioration and / or treatment of arthritis, including rheumatoid arthritis and / or osteoarthritis.
[0104] [00104] In one embodiment, the composition is used for the prevention, improvement and / or treatment of immune or autoimmune diseases, including systemic lupus erythematosus (SLE), discoid (cutaneous) and / or neonatal lupus.
[0105] [00105] Advantageously, the composition can be used for the prevention, improvement and / or treatment of chronic or acute inflammatory conditions that can be induced by the disease or injury.
[0106] [00106] Advantageously, the composition can be used to inhibit analogs, orthologs, homologues, derivatives and variants of MMPs, preferably MMP-9. MMP-9 which is preferably inhibited comprises a functional metal cation in the local catalytic active and has the ability to hydrolyze the polypeptides. Advantageously, the composition can inhibit natural-sized mammalian matrix metalloproteinases (MMPs), or truncated forms of MMPs, or a catalytic domain of these enzymes that comprises a metal cation.
[0107] [00107] Variations and modifications of the invention are included within the scope of the invention and should be understood by those skilled in the art.
[0108] [00108] The invention should also be described by way of example and with reference to the figures that follow, in which:
[0109] [00109] Figure 1 shows the results of a WST-1 Cell Proliferation Assay of 1,5-Dicafeoylquinic Acid (1,5-DCQA);
[0110] [00110] Figure 2 shows the results of p16 expression in cells after incubation with 1,5-DCQA;
[0111] [00111] Figure 3 shows the results of p21 expression in cells incubated with 1,5-DCQA;
[0112] [00112] Figure 4 shows the results of XRCC5 expression in cells after incubation with 1,5-DCQA;
[0113] [00113] Figure 5 shows the results of hPOT1 expression in cells after incubation with 1,5-DCQA;
[0114] [00114] Figure 6 shows the relative levels of sirtuin 2 expression in cells after incubation with 1,5-DCQA;
[0115] [00115] Figure 7 shows the relative levels of sirtuin 3 expression in cells after incubation with 1,5-DCQA;
[0116] [00116] Figure 8 shows the results of the effect of 1,4-Dicafeoylquinic acid on p65 inhibition; and
[0117] [00117] Figure 9 shows the results of the effect of 1,5-Dicafeoylquinic acid on p65 inhibition.
[0118] [00118] With reference to the Figures, at this point the use of a cosmetic composition for the prevention of tissue or cell senescence is provided, the composition comprising a conjugate of quinic acid with at least one molecule of caffeic acid, or a derivative, isomer or its salt.
[0119] [00119] The cosmetic composition comprises a Dicafeoilquinic acid and / or a tricafeoilquinic acid, or a derivative, isomer or its salt. The cosmetic composition comprises a conjugate selected from 1,3-Dicafeoylquinic acid, 1,4-Dicafeoylquinic acid, 1,5-Dicafeoylquinic acid, 3,4-Dicafeoylquinic acid, 3,5-Dicafeoylquinic acid, 4,5- dicasfeoilquínico, 3,4,5-tricafeoilquinico acid, or a derivative, isomer, extract or its salt.
[0120] [00120] Preferably, the conjugate comprises an amino acid, peptide, protein, lipid, sugar, polysaccharide, organic or inorganic acid attached to one of the hydroxyl groups. The conjugate typically comprises an alkyl or alkali metal group joined at the R1, R2, R3 or R4 position. Preferably, the alkyl or aryl or alkali metal group can be joined at the R1 position.
[0121] [00121] The composition typically comprises one or more anti-inflammatory agents that can be selected from swellia serrata, corosolic acid, ursolic acid, oleanolic acid, salicinol (salacia), rosmarinic acid, ruscogenins, darutoside, asiaticoside, sericoside, harpagoside, horse chestnut (escin, esculin), ginger (gingerol), turmeric extract (tetrahydrocurcuminoids), coridalis, myricetin, artichoke, alfalfa, tea, coffee and / or combinations thereof. The composition can also comprise an anti-inflammatory compound, an antioxidant, an NF-kappa B inhibitor, a matrix metalloproteinase inhibitor, an antibiotic and / or can be administered in combination with an adjuvant treatment. The composition can comprise one or more of the vitamins, for example, vitamin D, vitamin D3, vitamin C and / or dehydroascorbate, vitamin B, vitamin E, or vitamins or cofactors. The composition may comprise a divalent or polyvalent metal ion or combinations thereof selected from copper, zinc, iron, selenium, vanadium and manganese.
[0122] [00122] The conjugate is preferably a plant extract, and typically an artichoke extract.
[0123] [00123] The cosmetic composition is typically transported in a vesicle, mycelium, liposome, nanoparticle or other suitable vehicle. Typically, the cosmetic composition is applied to the skin. The cosmetic composition can also be applied to hair and / or scalp. Typically, the cosmetic composition is provided in the form of a serum, lotion, cream, gel, powder, ointment or other means suitable for topical administration of the composition to the skin, hair and / or scalp.
[0124] [00124] Preferably, the cosmetic composition comprises a delivery system comprising skin cleansers, surfactants, skin conditioning agents, hair conditioning agents, vitamins, hormones, minerals, plant extracts, anti-inflammatory agents, antioxidants, concentrates of plant extracts, emollients, humectants, skin protectors, skin penetration enhancers, solubilizers, and / or pH adjusters.
[0125] [00125] The cosmetic composition is used in the prevention, improvement and / or treatment of a range of conditions, disorders or diseases that involve the senescence process. In the context of the present invention, the senescence process can be natural, premature, induced or accelerated. Accelerated senescence is typically due to genetics or external factors, including but not limited to, chemicals or radiation, including therapeutic radiation. Natural, premature and accelerated senescence is the characteristic affecting the skin and its components, including hair follicles, and the cycle associated with hair growth and natural hair pigmentation. Altered skin texture, firmness and changes in skin appearance due to lines and wrinkles are all manifestations of senescence and accelerated senescence, the latter often due to exposure to ultraviolet radiation, and / or smoke.
[0126] [00126] Advantageously, the cosmetic composition inhibits MMP-9. It is known that MMP-9 is a collagenase and increases the degradation of elastin, gelatine types I and V, collagen types IV and V and fibrillin. Type IV collagen is a major component of the dermal-epidermal junction and type V collagen is also known to be present in the skin. The decomposition of these components would have a significant function in reducing the firmness of the skin. Fibrillin is essential for the formation of elastic fibers in the skin and degradation would reduce the elasticity of the skin. In this way, inhibition of MMP-9 would reduce or prevent the decomposition of these components and thus help to maintain or improve the firmness or elasticity of the skin (Bolognia, Clin Geniatr Med 1993 (9): 209-229; Skj0t-Arkil and others , BMC Pulmonary Medicine 2012 (12): 34; Ashworth et al., Biochem Journal 1999 (340, Part 1): 171-181).
[0127] [00127] An increase in MMP-9 activity is known to cause decomposition or disturbance of the skin's extracellular matrix architecture and / or may result in injury such as UV irradiation, which can be exemplified by wrinkling, loss of elasticity and / or dilation of microcapillary vessels.
[0128] [00128] Advantageously, the cosmetic composition enhances the cohesion of the skin's extracellular matrix. Advantageously, the cosmetic composition stimulates the biosynthesis of fibrillary collagens, elastin and / or fibrillins. Advantageously, the cosmetic composition reduces the degradation of elastin. Advantageously, use of the cosmetic composition is to improve skin elasticity and / or skin firmness.
[0129] [00129] The use of the cosmetic composition advantageously protects the skin against circumstantial injury and / or injury caused by ultraviolet radiation. The cosmetic composition advantageously improves the skin's natural protective functions, and provides protection against injury that can be caused by pollution, smoke or stress. Advantageously, use of the cosmetic composition improves and / or enhances the appearance of the skin.
[0130] [00130] The use of the cosmetic composition prevents or improves the conditions associated with the senescence of the skin, for example, reducing the formation of wrinkles, reducing the redness of the skin, reducing the appearance of telangiectasias, delaying the appearance of fine lines, reducing the appearance of dark circles around the eyes, reducing the appearance of blemishes and / or reducing the thinning of the skin.
[0131] [00131] In another modality, the use of the cosmetic composition prevents or improves the conditions associated with senescence of the hair, for example, reducing loss of hair color and improving the condition of the hair. The graying of the hair can be a sign of senescence of the hair follicles. Although there are many products on the market to use dyes to hide gray hair, many people prefer to reverse or slow down the natural process of color change.
[0132] [00132] With reference to the Figures, this point also provides the use of a composition for the prevention, improvement and / or treatment of disorders and diseases involving senescence of the organ, tissue or cell, the composition comprising a conjugate of quinic acid with at least one molecule of caffeic acid, or a derivative, isomer, extract or its salt.
[0133] [00133] The conjugate can be supplied in the form of a free base, or in the form of a pharmaceutically acceptable salt.
[0134] [00134] The conjugate can be administered via a pharmaceutically acceptable delivery system which can be in the form of water and oil emulsions, suspensions, colloids, microemulsions, suspensions or emulsions of vesicles, mycelia, liposomes or nanoparticles, powders or anhydrous conditions . The conjugate can also be coated or combined with a material, such as a lipid, sugar, or combination thereof. The conjugate can be joined to the amino acid, peptide, antibody or other molecule to allow the targeting of the active material to specific cells, tissues or organs. The target guide material or coating preferably dissolves to allow sufficient and efficient release of the conjugate to cells, tissues or organs.
[0135] [00135] The composition can be administered parenterally or orally. The composition can also be administered via a dermal, intradermal, transdermal, topical, intramuscular, subcutaneous, intravenous, nasal, oral, sublingual, lingual, or rectal route, or through inhalation or instillation. The composition can also be administered by incorporating it into an implant or using any pumping device. In one embodiment, the composition can be administered in an infusion that is transmitted through the organs, or added to isolated cells, tissues or organs. The composition can be administered in the form of a tablet.
[0136] [00136] Advantageously, the composition inhibits p16 INK 4a, and / or modulates MMP-9, NF-cover B and / or major pro-inflammatory cytokines.
[0137] [00137] The composition can be used in the prevention, improvement and / or treatment of a disease or disorder in the skin.
[0138] [00138] The composition can be used to prevent, improve and / or treat conditions involving senescence of hair follicles, as evidenced by hair loss, hair thinning and alopecia (which can also be a product of radiation damage). The composition can be used for the prevention, improvement and / or treatment of diseases of the hair follicles that are due to a deficiency of the immune system, such as, for example, alopecia areata and totalis. The composition can be applied to hair or scalp in the form of a spray, cream, lotion or serum.
[0139] [00139] The use of the compositions of the invention can also improve the viability and delay the senescence process of the stem cells, if they are obtained from a laboratory process for the purposes of experimentation, planned for a production purpose, or a medical purpose. Stem cells can also be artificially produced cloned or harvested from a mammal's body, for example, from the tissue of the nose, hair follicle, blood or placenta.
[0140] [00140] Accelerated senescence has been found to be a characteristic of certain types of disease in kidney cells, tissues and organs; and it can be seen in the organs to be used for transplant purposes, or in cells, tissues or organs that have already been transplanted.
[0141] [00141] The most important cause of kidney transplant failure is rejection (Paul LC: Kidney Int 1995, 47; 1491-, SA Joosten et al .; Amer J Pathol, 2003, 162 (4): 1305-1312), which can occur over a variable period of time. Inspection of the histology of rejected organs demonstrates that there are changes in these organs that are similar to the kidneys of older individuals (Melk A and others Am Soc Nephrol 2000, 11: 444-453). Therefore, it is reasonable to postulate that an increase in the senescence rate may be involved in kidney transplantation, in fact, it may contribute to the deterioration of function and eventual graft rejection (Melk A, Halloran PF: J Am Soc Nephrol 2001,12 : 385-393). The cells involved in these processes, known as "senescent cells", have also been shown to contribute to a persistent inflammatory process (Serrano M, Blasco MA: Curr Opin Cell Biol 2001, 13: 748-753). Senescent cells exhibit various modifications, including those of shape, telomere shortening, collagen and matrix metalloproteinase expression (Dai CY, Enders GH: Oncogene 2000, 19: 1613-1622 and Linskens MH and others, Nucleic Acids Res 1995, 23: 3244-3251). It is also evident that older kidneys have shortened telomeres (Melk A and others Am Soc Nephrol 2000, 11: 444453) and that these organs have poorer graft survival rates (De Fijter JW J Am Soc Nephrol 2001, 12: 1538 - 1546).
[0142] [00142] Furthermore, there is evidence that p16 INK4a accumulates in these cells and is caused by maintaining senescence (Sherr CJ, Roberts JM: Genes Dev 1999, 13: 1501-1512 and Stein GH and others Mol Cell Biol 1999, 19 : 2109- 2117). An increase in the expression of senescence associated with the INK4a inhibitory p16 cell cycle was found both in kidney transplants and deterioration in the kidneys of patients (Melk et al., American Journal of Transplantation, 2005, 5 (6): 1375-1382). It has also been shown that expression lasts during the chronic rejection phase.
[0143] [00143] The control of p16INK4a expression during the entire process of chronic graft rejection could, therefore, be of primary importance for increasing the graft survival prospects. Therapeutic control of p16INK4a expression and oxidative damage can also be very important in older organs and tissues that could be made available for transplantation, thus increasing the number of organs and tissues that can be used. There is also evidence that in autologous hair transplantation, a variable percentage of transplanted plugs is rejected. Although the mechanism of this process is not known, a similar one to the one described above can be involved.
[0144] [00144] Diseased organs show signs of cellular senescence and therefore should benefit from therapeutic control of p16INK4a and oxidative damage. Since the compositions preferably have potent antisenescent and antioxidant properties, they can be candidates not only for use as a therapeutic agent to counteract the senescence process in older cells, tissues and organs in health and disease, but also for use in transplanted cells, tissues and organs, where the senescence process is a fundamental characteristic of rejection. It is also to be noted that since the compositions can be used to improve accelerated senescence in the skin, it can also be used for the purpose of counteracting this process.
[0145] [00145] The composition can be used in the prevention, improvement and / or treatment of conditions associated with neurodegeneration.
[0146] [00146] The blood barrier of the brain exists to keep unwanted substances from brain tissue from entering the blood, but allows essential materials to gain access via specialized transporters. These are essentially the properties of brain endothelial cells that control both the permeability of the junctions between them and the entry, through complex ports, of substances such as glucose, amino acids, vitamins, certain hormones, etc. These cells also express a series of specialized enzymes on their surfaces, which indicates that the brain's blood barrier is highly complicated and strictly controlled in normal health. The blood-brain barrier permeability is also supported by factors that emanate from cells on the abluminal side of endothelial cells. Cells like astrocytes can be considered very important for the blood-brain barrier, since they make physical contact with more than 90% of the single layered endothelium. Other cells in brain tissue, including glial cells and pericytes, are also very important for the normal functioning of the blood-brain barrier. An increase in the blood-brain barrier permeability may occur due to the loss of integrity of the normally highly restrictive tight and adherent joints. In certain diseases and conditions that affect the central nervous system, there is no evidence of greater permeability of the blood-brain barrier. This occurs in neurodegenerative diseases such as multiple sclerosis, Parkinson's disease and Alzheimer's disease, stroke, but also where there may be considerable disturbances in those parts of the brain's blood barrier near the injury site. Abnormal permeability is also seen in sepsis and the concomitant inflammatory processes.
[0147] [00147] Since there is evidence that IL-6 and MMP-9, play significant roles in the increasing permeability of the blood-brain barrier, the composition, which can inhibit both IL-6 and MMP-9, can provide a therapeutic approach in regaining control of the permeability and healing of the blood-brain barrier. In this way, the composition can help to improve the relapse phase of multiple sclerosis, and can be used to decrease or stop the entry of undesirable substances and therefore harmful in the disease, Alzheimer's stroke and inflammatory conditions of the central nervous systems and peripheral.
[0148] [00148] Alzheimer's disease is the most common cause of dementia, which affects about 26 to 30 million people worldwide. There is no known cure and treatment is based on symptom relief. The cause of this disease is not known, but mainly, it is understood to be related to increasing age. However, genetic components play an important role in diseases like Down syndrome, whose patients are likely to develop Alzheimer's disease as they live longer in old age. Classical pathological studies reveal widespread loss of cortical neurons, mainly the presence of senile plaques and neurofibrillary tangles (Donev et al, J. Cell Mol Med 2009; 13: 4329-4348). Several hypotheses have been proposed to explain the cause of Alzheimer's disease. The two main hypotheses are: (a) that beta-amyloid deposits (plaques) are the causative agents; or (b) that changes in the tau protein occur with hyperphosphorylation resulting in tangles and disintegration of the cell transport system (microtubules). Recently, it has been demonstrated that peptide fragment 1-42 of beta-amyloid is capable of causing neurotoxicity. So far, no mechanism has been put in place to explain the main features of Alzheimer's disease, which would allow for a rational approach to the treatment of this disease.
[0149] [00149] It has been shown that SIRT2 is capable of activating gamma-secretase that cleaves the transmembrane domain of amyloid precursor protein (APP), thereby releasing beta-amyloid and stimulating plaque formation. SIRT2 suppresses alpha-tubulin, a key protein in the structure of microtubules, the main cell transport system (North et al, Mol Cell, 2003: 11 (2) 437-444). This leads to dysfunction of the microtubules, disintegration and formation of tangles. Thus, it can activate gamma-secretase SIRT2 and, in turn, presenilin-dependent gamma-secretase activity affects neurite outgrowth (Figueroa et al., Neurobiology of Disease, 2002; vol 9, 49-60). This can contribute to neuritis, which is characteristic of the pathology of Alzheimer's disease. It has been shown in Parkinson's disease models that SIRT2 inhibition can rescue alpha-synuclein-mediated toxicity (Outieri, Science, 2007: vol 317 516-519). SIRT2 may also have this property in Alzheimer's disease. The suppression of expression throughout SIRT2 may therefore play an important role in the treatment of Alzheimer's disease.
[0150] [00150] Advantageously, suppression of SIRT2 by using the composition can stimulate the growth of neurites from cortical neurons, inhibit beta-amyloid cleavage from APP and, therefore, decrease the formation of amyloid plaques. By relieving the repression of alpha-tubulin, the composition can help maintain the integrity of the microtubules. The integrity of the mitochondria is very important for the functioning of the cell since the loss of one of these bodies will accelerate cellular senescence and apoptosis. Therefore, upward regulation of sirtuin 3 (SIRT3) can help maintain the integrity of mitochondria in Alzheimer's disease by suppressing reactive mitochondrial species (Kong et al., PloS One, 2010: 5 (7): e11707). In addition, SIRT3 also cleaves APP at a location, which provides a fragment of APP. However, in contrast to SIRT2 cleavage, SIRT3 cleavage produces a fragment that is not amyloidogenic. This is important in the treatment of Alzheimer's disease. The use of the SIRT3 up-regulating and down-regulating SIRT2 composition decreases the amyloidogenic fragment and increases the non-amyloidogenic APP fragment, therefore offering a rational approach to the treatment of Alzheimer's disease.
[0151] [00151] Advantageously, the composition can be used to prevent, ameliorate and / or treat Parkinson's disease. MMP-9, which can be inhibited by composition, has been shown to be neurotoxic to dopaminergic neurons of the substantia nigra (Lorenzl et al., Neuromolecular Med, 2004; 5 (2): 119-132) and to be able to cleave sequences alpha-synuclein terminals, thus creating toxic aggregates of the latter that are present in Lewy bodies (an important pathological sign of this disease), and neuronal destruction. In addition, MMP-9 is involved in processes that lead to an increased permeability of the blood-brain barrier, allowing undesirable molecules to penetrate brain tissue. IL-6 is also known to regulate MMP-9, thereby amplifying the effect on the blood-brain barrier. Thus, inhibition of MMP-9 and IL-6 is very important in the treatment of this condition. MMP-9 is upward regulated by CXCL8 (IL-8) and NF-kappa B. The latter also regulates interleukin-1, which in turn can stimulate microglia to produce key cytokines. Analysis of the known major molecular pathways associated with the pathology of Parkinson's disease suggests that the MMP-9 enzyme may play an important role in the development of the now well-recognized histological, biomolecular, and clinical features of the disease. There is growing evidence that the pathology of Parkinson's disease involves an inflammatory process and higher levels of pro-inflammatory cytokines have been found in the brains of patients who have suffered from this condition. In addition, in this disease, a relationship has been found between NF-kappa B plasma, p65 levels and certain cytokines.
[0152] [00152] Sirtuin 2 has been shown to improve the nigrostriatal damage toxin induced by deacetylation of forkhead box 03a (FOXO3a) (Lin et al., J. Biol Chem, 2012; 287: .. 32307-32311). In addition, SIRT2, a cellular senescence-based deacetylase, may be closely associated with the alpha-synuclein protein since inhibition of SIRT2 by pharmacological means protects neurons and can rescue alpha-synuclein-produced toxicity in cell systems ( Outieri, Science, 2007: vol 317 516-519). In the CNS, SIRT2 is an oligodendroglial protein also involved in the control of differentiation. This sirtuin has an inhibitory action on alpha-tubulin, a key component of the microtubular architecture and, if present in excess, can be harmful to the integrity of the cell. Therefore, SIRT2 itself can be considered as a possible therapeutic target for neurodegenerative diseases, including Parkinson's disease.
[0153] [00153] Multiple sclerosis is a chronic disease of the central nervous system, which involves the progressive destruction of myelin. In many patients, the associated axons are also damaged or destroyed. In addition, the blood-brain barrier can also be made more permeable to unwanted molecules and blood cells. The etiology of multiple sclerosis is currently unknown, but it is likely that there are many factors that contribute to this complex disease. Cytotoxic proinflammatory cytokines, including proteases, MMPs, and reactive oxygen species, all may, in part, contribute to the destruction of myelin. The breakdown of the tight junctions has been observed in active multiple sclerosis and may involve down regulation of the expression of the genes of the junction proteins in endothelial cells. It is thought that pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) may be involved. Studies also indicate that the chemokine CXCL8 (IL-8) may also be increased. MMP-9 must also be found to be regulated in patients with multiple sclerosis, although they are usually absent in cerebrospinal fluid (CSF). Over expression of MMP-9 is therefore considered to be of considerable importance in the pathology of multiple sclerosis, in addition to increasing the permeability of the blood-brain barrier.
[0154] [00154] Thus, the cytotoxic TNF-alpha, IFN-gamma and IL-6 (which are all over-regulated by NF-cover B), the chemokine CXCL-8 (IL-8) and MMP- 9 are all potential targets in rational processes for Multiple Sclerosis therapy.
[0155] [00155] In the CNS, SIRT2 is also an oligodendroglial protein involved in the control of differentiation. It has an inhibitory action on alpha-tubulin, an essential component of the microtubular structure and, if present in excess, can be harmful to the integrity of the cell. Therefore, SIRT2 is also a potential therapeutic target for multiple sclerosis. The composition can advantageously inhibit NF-kappa B and MMP-9, inhibit SIRT2 activity and regulate SIRT3 which protects against apoptosis. Inhibition of SIRT2 has also been shown to rescue the toxicity of alpha-synuclein, a neurotoxic protein that produces neuronal apoptosis (Outieri, Science, 2007: vol 317 516-519). As a result of these findings, the composition can therefore be used in the treatment of multiple sclerosis. In addition, interferon-gamma (IFN-gamma, which is also inhibited by the use of the composition) phosphoryl Ef 4a. Phosphorylated ef 4a inhibits the function of neurons, astrocytes and glial cells. Once the function of the astrocytes is decreased, secretion of the leukemia inhibiting factor (LIF), from these cells is decreased. Since LIF is needed to stimulate the production of myelin oligodendrocytes, axon remyelination is also decreased. Therefore, indirectly, both SIRT2 and interferon-gamma negatively affect the remyelination process. Gamma interferon, which induces the demyelination of myelinated axons, therefore also indirectly inhibits remyelination. These phenomena are characteristic of multiple sclerosis. Inhibition of SIRT2 and also IFN-gamma by the composition may therefore provide a possible treatment for multiple sclerosis. Since SIRT2 adversely affects neurons associated with Parkinson's disease, Alzheimer's disease and multiple sclerosis together, it may be a common feature influencing the development of neurodegeneration.
[0156] [00156] The composition can be used in the prevention, improvement and / or treatment of mitochondriopathies, including neuromitochondriopathies. Advantageously, the composition can contribute to the repair of mitochondrial DNA by overregulating sirtuin 3 and thus favoring the interaction of sirtuin 3 with glycosylase 8-oxoguanine-DNA (OGG1), a DNA repair enzyme (Cheng et al., Cell Death Dis, 2013, 4e731).
[0157] [00157] In addition to the above, the composition can be used to reverse the degeneration associated with the senescence of cells, including stem cells, and those of the central and peripheral nervous systems. Underlying these properties is the observation that these compounds increase the cellular levels of sirtuin 3 (SIRT3) and decrease the level of sirtuin 2 (SIRT2). These proteins are known to regulate the processes that regulate cellular senescence, in which SIRT3 is associated with decreased SIRT2 and is associated with increased senescence. The well-known biomarker of p16 cell senescence can also be inhibited by using the composition (see Figure 2).
[0158] [00158] The safety of the composition when applied to human cells is evidenced by its effect on the XRCC 5 gene (see Figure 4), even under conditions when this gene was sublethally forced with oxidizer. XRCC5 is a double-stranded rupture repair gene that was not affected under stress conditions, indicating that the composition does not induce breaks in the double-stranded DNA. Human lymphocyte counts after stimulation with phytoaglutinin (PHA) mitogen did not decrease significantly during the experiments, further indicating the safety of the composition.
[0159] [00159] The use of the composition to inhibit major pro-senescence proteins and genes, including NF-cover B, pro-inflammatory cytokines, p16 INK4a and sirtuin 2, together with the super-regulation of sirtuin 3 may, for this reason, offer the prevention, improvement and / or treatment of a range of conditions and diseases in which they are overexpressed, including those of the skin and other tissues and organs. Overregulation of sirtuin 3 by the use of the composition may not provide a positive trend against the senescence process, but it may be able to reverse some of the cellular changes induced by the senescence process.
[0160] [00160] With reference to the Figures, at this point it is also provided the use of a composition as defined in the first aspect for the prevention, improvement and / or treatment of disorders and diseases involving the tension of the organ, tissue, cell caused by an inflammatory process , the composition comprising a conjugate of quinic acid with at least one molecule of caffeic acid, or a derivative, isomer, extract or its salt.
[0161] [00161] The composition can be used for the prevention, improvement and / or treatment of disorders or diseases associated with an increase in the expression of MMP proteins and / or genes. In a preferred embodiment, the composition inhibits MMPs, NF-cap B, and / or tissue inhibitors of matrix metalloproteinase activators (TIMP). In one embodiment, the disorder or disease is associated with an increase in the expression of MMP-9 and / or MMP-2. Typically, the composition inhibits MMP-9 and / or MMP-2. MMP-9 has been found to be present in increased concentrations in cells, tissues, organs or plasma under certain conditions and diseases.
[0162] [00162] The composition can be used for the prevention, improvement and / or treatment of conditions and diseases in which MMP-9 is overexpressed.
[0163] [00163] Advantageously, the composition can be used for the prevention, improvement and / or treatment of disease in which the inflammatory process is partly, or in acute or chronic form. In diseases in which there is an acute inflammatory reaction, particularly those caused by infecting organisms, the concentration of MMP-9 has been found to be increased in plasma, and this is often present in high concentrations. In diseases where there are signs of an inflammatory reaction, there is evidence that MMP-9 concentrations in tissue, organs and / or plasma are increased above constitutive levels. The inflammatory process evident in many diseases and disorders can be acute or chronic due to the presence of infectious organisms, for example, bacteria, viruses, and parasites, or they can be an integral part of an underlying disease. Some examples of diseases and disorders in which inflammation plays a role and in which MMP-9 is overexpressed include: conditions due to an infecting organism (for example, bacteria, viruses or parasites); osteoarthritis; rheumatoid arthritis; drop; Sjogren’s syndrome; synovitis; tendon, muscle, cartilage and bone injuries; laminal inflammation in horses; autoimmune disorders, including lupus erythematosus; Kawasaki disease; ulceration of the skin; burns; urticaria; periodontitis; bronchiectasis; bronchiolitis; chronic obstructive pulmonary disease; emphysema; atopic dermatitis; psoriasis; inflammation in stored blood; aneurysms; gastric and colon ulceration; Crohn's disease; colitis; pelvic inflammatory disease; appendicitis; pancreatitis; degenerative diseases of the central nervous system including focal and generalized cerebral ischemia; encephalitis; ophthalmopathy; uveitis; ocular surface disease, open angle; myocardial ischemia; infarction and fibrosis; coronary heart disease; cardiac insufficiency; atheromatous plaque instability; aneurysms and the inflammatory response seen in certain genetic disorders including Huntington's disease and motor neuron disease.
[0164] [00164] The use of the composition advantageously inhibits the major pro-inflammatory proteins, such as, TNF-alpha and MMP-9, and can be employed in the improvement and / or treatment of diseases and disorders involving the overexpression of MMPs, such as, chronic inflammatory disorders and conditions in which an inflammatory process is prevalent, or in metastasis and neoplastic progression.
[0165] [00165] The composition can be used for the prevention, improvement and / or treatment of a malignant or benign neoplasm. Preferably, the malignant neoplasm may be associated with breast, lung, colon, rectum, prostate, blood cells, oral cancer, skin cancer or melanoma, and / or leukemia.
[0166] [00166] In another modality, the composition can be used for the method of prevention, and / or treatment of cancer and cancer metastasis. An increased concentration of MMP-9 has been found in many cancers, for example, prostate and breast cancer, and melanoma. As mentioned earlier, MMP-9 is involved in the invasion of surrounding tissues by involving the extracellular matrix, and it is also involved in the growth of cancer cells in the lymph glands, organs and distant tissues. A large number of cancers have been shown to overexpress MMP-9 in the primary, invasive and metastatic stages of the disease. Most of the studies conducted have been on breast cancer, prostate cancer, colon cancer and melanoma. Other examples of cancers in which MMP-9 is overexpressed include leukemia, multiple myeloma, lung cancer, mesothelioma, hypopharyngeal and salivary gland cancers, esophageal cancer, gastric cancer, kidney cancer, bladder cancer, ovarian cancer, endometrial cancer , basal and scaly skin cancers.
[0167] [00167] The composition can be used for the treatment of cancer in combination with one or more anticancer drugs and / or treatment, including the use of radiotherapeutic, ultrasonic, phototherapeutic, chemotherapy, radiotherapy and / or surgery.
[0168] [00168] MMP-9 has been shown to be involved in the extension of a primary malignant neoplasm and metastasis. Although the composition is not an antimitotic drug per se, it can be used to inhibit MMP-9 secreted by the primary neoplasm, metastasis, and surrounding cells, thereby reducing or preventing it from another extension.
[0169] [00169] In the neoplastic process, MMP-9 can be over-regulated, thereby interrupting the extracellular architecture and creating a means for the proliferation of the cancer cell at the site of the primary tumor and in the metastatic disease.
[0170] [00170] Cancer is a major cause of death in industrialized countries and most deaths are from metastases, which are refractory to treatment. Most cancers, therefore, cannot be treated optimally today. In addition to the intrinsic properties of the cancer cell growing continuously, the development and progression of the primary tumor depends on the microenvironment of the malignant cells, which surprisingly can have all the characteristics of inflammation. One of the main factors in the inflammatory process has been shown to be NF-kappa B, which can indirectly affect the extracellular matrix architecture through MMP-9, allowing the primary tumor cell mass to expand further into this area. A continuous inflammatory process can therefore guarantee further expansion of the tumor. Controlling inflammation around the tumor mass can help to contain the tumor and reduce metastasis. Thus, the use of the composition may be useful for containing tumors due to the inhibition of NF-kB and MMP-9. The composition can be administered in combination with an antimitotic drug to offer a rational approach to treatment, which can advantageously have a lower level of toxicity for the patient. The composition can also be used to reduce metastatic spread of a tumor to lymph nodes, distant tissues and organs. Under normal conditions, NF-kappa B is kept limited in the cell cytoplasm by being bound to IKB kinase (IKK) in the IKK / NF-kappa B signaling module. NF-kappa B is activated by release from the module and is translocated from the cytoplasm to the cell nucleus, where it binds at relevant sites. NF-kappa B affects the transcription of genes that code for a number of important proteins in this process, including pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), Necrosis Factor Tumoral alpha (TNF-alpha) and interferon-gamma (IFN-gamma). MMPs, angiogenic factors and growth are even regulated in this process. Consequently, NF-kappa B mediates the process of cell proliferation, the promotion of tumors and the inflammatory process, together with the lymph and distant spread of cancer. This transcription factor is also linked to resistance to antimitotic therapy, both by drugs and radiation. Thus, NF-kappa B is a very important target for drugs in the treatment of cancer. The composition inhibits NF-kappa B, preventing the phosphorylation of serine 536 of the p65 subunit of NF-kappa B, thus preventing this transcription factor from binding to the relevant DNA site. Advantageously, the composition inhibits MMP-9, pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and IFN-gamma.
[0171] [00171] The use of the composition advantageously reduces the inflammatory component in muscular dystrophies, other muscular diseases and injuries, tendon, synovial and cartilage tissues.
[0172] [00172] The composition can be used for the improvement and / or treatment of muscular dystrophy which comprises a set of closely related genetic disorders, including Duchenne muscular dystrophy, where there is an absence of the dystrophin protein, and the lower part of the muscular dystrophy waists (DMC), where there is an absence of the protein related to fukutin protein (FKRP). In these conditions, the inflammation of the muscles occurs due to the infiltration of monocytes (macrophages) that secrete MMP-9, which results in an increased damage to the extracellular matrix of the muscle, thus attracting more extrinsic monocytes. This causes more inflammatory damage to lead to increased fibrosis of the affected muscle and increased physical disability. Effective inhibition of MMP-9 can break this cycle, to improve muscle damage and help slow the progression of this disease.
[0173] [00173] Duchenne muscular dystrophy is a genetic recessive disease linked to the X-chromosome that affects approximately 1 in 3500 male live births. Children with this disorder typically show the first signs of muscle degeneration that can progress to an inability to walk, which usually occurs before puberty. Patients with this condition usually die from respiratory and cardiac dysfunction at the age of 30. The dystrophin protein is essential for the structural integrity of the muscle and its normal functioning and is part of a complex of proteins that bind to the extracellular matrix (ECM) for the mechanical cytoskeleton of the muscle. Thus, this protein is involved in the provision of mechanical stability and is part of the signaling system between ECM for contractile elements. Mutations in the lead dystrophin gene lead to an absence of dystrophin protein in the protein chain complex, resulting in the clinical picture that was originally described by Duchenne. These disturbances in mechanical signaling cause other changes in the affected muscles, which can include severe damage to the muscle membrane that can allow the entry of several cells of the immune system, particularly macrophages. This can lead to a chronic inflammatory process, fibrosis and eventual degeneration of the muscles.
[0174] [00174] There are two pathological factors involved in Duchenne muscular dystrophy: first, the mutation in the dystrophin gene; and second, an ongoing inflammatory process resulting in decreased or absent muscle regeneration. Both of these factors contribute to the progression of the disease. It has been shown that the concentration of pro-inflammatory factor-alpha (TNF-alpha) cytokine tumor necrosis is regulated in the muscles of both animal models and those of patients with Duchenne muscular dystrophy, mainly due to the entry of inflammatory cells. TNF-alpha is a potent activator of NF-kappa B, the transcription factor that is closely involved in the inflammatory response. Persistent and chronic activation of NF-kappa B can produce pathological changes in different types of cells, tissues and different organs, as seen in several clinical diseases, and has been shown to be present in various conditions and diseases of skeletal muscle, including muscular atrophy, dystrophy Duchenne muscle and muscular dystrophy by pelvic and scapular girdle (LGMD). Complex IKK-NF-kappa B signaling has been shown to be important in muscular dystrophy and is therefore a legitimate target for possible pharmacological intervention. In addition, there are two components of this signaling process, one from damaged skeletal muscle and the other from immune cells that infiltrate damaged muscle. The process involves signaling downstream of MMP-9, which, due to involvement in the inflammatory process, is also a therapeutic target. The composition is able to inhibit NF-kappa B, MMP-9 and pro-inflammatory cytokines, in addition to the pro-apoptotic p16 gene, and therefore can be used in the improvement and / or treatment of Duchenne muscular dystrophy. Overexpression of NF-kappa B and MMP-9, with the associated downstream consequences, are also present in other muscular dystrophies, such as lower waist muscular dystrophy (DMC-2B), which condition is caused by an mutation in the gene. Although DMC-2B is different from Duchenne muscular dystrophy, due to the absence of a protein (FKRP), and may appear later than Duchenne muscular dystrophy, LGMD-2B involves the destruction of muscle fibers and a chronic inflammatory process , what factors are present in Duchenne muscular dystrophy. The composition is capable of modulating the deleterious effects of overexpression of NF-kappa B, MMP-9 and pro-inflammatory cytokines, thus helping to prevent, improve and / or treat DMC-2B.
[0175] [00175] Thus, the composition can be used to inhibit MMP and pro-inflammatory proteins and, in particular, TNF-alpha. The latter is known to activate NF-kappa B, which in turn regulates MMP-9, thus creating a pro-inflammatory and MMP-9 self-sustaining generation circuit. In turn, MMP-9 (an endopeptidase) can excise a terminal amino acid sequence from alpha-synuclein (a protein normally associated with the presynaptic region of neurons), giving rise to other forms of this protein, including insoluble compounds that are neurotoxic and found in Lewy body structures in Parkinson's disease. The activity and hyperactivity of MMPs can therefore be involved in the degenerative processes in diseases of the nervous system.
[0176] [00176] The composition can be used to prevent, improve and / or treat cells, tissues or organs in inflammatory diseases or disorders, in which MMPs are overexpressed, for example, in wound healing. The composition can also be employed in modulating or controlling overexpression of MMPs in secondarily affected cells, tissues or organs, for example, in conditions associated with an increase in blood-brain barrier permeability, or in conditions including stroke.
[0177] [00177] The composition can be used for the prevention, improvement and / or treatment of diseases of the musculoskeletal system in mammals, in which the inflammatory process is part.
[0178] [00178] The composition can be used for the prevention, improvement and / or treatment of muscular dystrophies, tendons, synovial membranes, cartilage and muscle injuries. Advantageously, the use of the composition can decrease, attenuate or inhibit the production of MMPs, preferably MMP-9, an enzyme that has been found to be present in increased concentrations in cells, tissues, organs or serum in certain conditions, disorders and diseases .
[0179] [00179] The composition can be used for the prevention, improvement and / or treatment of conditions or disorders associated with the intestine in which there is a chronic or acute inflammatory component. An acute inflammatory condition of the intestine can be produced by infection, usually by bacteria or parasites, such as, for example, in infection with Clostridium difficile; or in the chronic or acute stages of an underlying infectious pathology, such as, for example, Crohn's disease or ulcerative colitis. The composition can also be used to prevent, ameliorate and / or treat irritable bowel syndrome.
[0180] [00180] The composition can be used for the prevention, improvement and / or treatment of diseases of the eye. MMPs can be involved in acute and chronic diseases of the eye where there is an infectious or inflammatory component, or where MMP can be overexpressed as part of a disease process. These diseases can include, but are not limited to, conjunctivitis, blepharitis, dry eye, uveitis, macular degeneration, corneal opacities, glaucoma, lens and / or retina diseases.
[0181] [00181] The composition can be used for the prevention, improvement and / or treatment of diseases of the respiratory system in which there is an inflammatory component. Elevated levels of MMP-9 have been demonstrated in individuals with bronchiectasis, chronic obstructive pulmonary disease (COPD) and / or asthma.
[0182] [00182] The composition can be used for the prevention, improvement and / or treatment of rheumatoid arthritis and / or osteoarthritis.
[0183] [00183] The composition can be used for the prevention, improvement and / or treatment of Fragile X Syndrome (SXF) a disorder in which there is an absence of a protein called fragile X mental retardation protein (FMRP), in affected neurons. This condition is due to a mutation in the FMR1 gene, known to be due to methylation of the regulatory region, effectively silencing the gene. This results in deformities of the neuronal dendritic spines and subsequent loss of the ability to receive input signals from other neurons. Cognitive development is therefore significantly reduced. Inhibition of MMP-9 in knockout mice of the FMR1 gene has been shown to result in the maturation of dendritic spines, which points to a possible role for an MMP-9 inhibitor in the treatment of this disease.
[0184] [00184] In another modality, the composition can be used for the prevention, improvement and / or treatment of fatigue, in particular that of chronic fatigue syndrome (myalgic encephalomyelitis) and that, after viral infection (post- viral).
[0185] [00185] The compositions according to the invention are preferably used in human therapy, but can also be used in veterinary medicine. In the latter, applications can be applied to a mammal, either in the laboratory, in captivity or in nature, on a farm, in industrial, domestic or sport situations.
[0186] [00186] Other objectives, advantages and scope of the composition must be presented in the detailed description and must become understood by those versed in the technique, or ascertained by the practice in its use.
[0187] [00187] The results shown below in Figures 2 to 7 refer to the analysis of senescence tests on compound 2066 (1,5-Dicafeoylquinic acid or 1,5-DCQA). The experiments were conducted using Human Foreskin Fibroblasts (HFFs).
[0188] [00188] Figure 1 shows the results of a 1.5-DCQA WST-1 Cell Proliferation Assay in HFFs. The WST-1 Cell Proliferation Assay provides a sensitive and accurate assay for cell proliferation and cytotoxicity (cell viability). The WST assay is based on the cleavage of the tetrazolium salt WST-1 to formazan by mitochondrial cell dehydrogenases. The expansion in the number of viable cells results in an increase in the total activity of mitochondrial dehydrogenases present in the sample. The increase in enzyme activity results in an increase in the amount of formazan dye formed. The formazan dye produced by viable cells was quantified by a multi-well spectrophotometer measuring the absorbance of the dye solution at 440 nm. The compound provided was tested in the WST assay over a range of dilutions. The data generated indicated that 1,5-Dicafeoylquinic acid appeared to be beneficial for cell viability in dilutions of 1/1000 and 2/1000. Table 1 and Figure 1 show the results of the WST-1 Cell Proliferation Assay. The test results show the standard deviation (SD) for 1.5-DCQA (2066) and the control, and the mean values of 1.5-DCQA (2066) and the control.
[0189] [00189] In the experiments that follow, HFFs were stimulated for a period of two hours with 150 pM of hydrogen peroxide (H2O2), to stimulate premature senescence in the presence and absence of 1,5-Dicafeoilquinic acid (1/1000 dilution) , and subsequently tested by Taqman Real Time PCR for the expression of genes associated with major senescence.
[0190] [00190] Figure 2 shows the relative expression of p16 in HFFs incubated with 1,5-DCQA with and without tension-induced premature senescence with 150 pM H2O2. The results indicate that 1,5-Dicafeoylquinic acid having no tension effect on untreated cells (that is, without H2O2) gave excellent protection to the oxidative stimulus, as no increase in expression was observed after the insult.
[0191] [00191] Figure 3 shows the relative expression of p21 in HFFs incubated with 1,5-DCQA with and without tension-induced premature senescence with 150 pM H2O2. Since 1,5-DCQA-mediated inhibition is known to occur downstream of the p21 gene, expression levels are substantially unchanged after stress.
[0192] [00192] Figure 4 shows the relative expression of XRCC5 in HFFs with 1.5-DCQA with and without the tension-induced premature senescence with 150 pM H2O2. XRCC5 is a double strand break repair protein. The substantially unchanged expression of XRCC5, compared to the control data set, indicates that the compound does not induce DNA disruptions per se and mitigates against the effects of the oxidative stimulus.
[0193] [00193] These conclusions are supported by an analysis of the Protection of Telomeres (POT 1) gene. Figure 5 shows the relative expression of hPOT1 in HFFs incubated with 1.5-DCQA with and without tension-induced premature senescence with 150 μM H2O2. The results indicate a protective effect inducing the compound against oxidative stimulus, consistent with previous data sets.
[0194] [00194] Figure 6 shows the relative expression of Sirtuin 2 (SIRT2) in HFFs incubated with 1.5-DCQA with and without tension-induced premature senescence with 150 pM H2O2.
[0195] [00195] Figure 7 shows the relative expression of Sirtuin 3 (SIRT3) in HFFs incubated with 1.5-DCQA with and without tension-induced premature senescence with 150 μM H2O2. These genes are involved in regulating the cell cycle and mitochondrial tension responses. Stimulation with a lethal level close to oxidative stress typically induces an increase in SIRT2 and decreases in SIRT3 expression. The compound 1,5-DCQA induced a significant decrease in expression of SIRT2 without tension. This is indicative of each having a potential for stimulation of cell proliferation in the absence of an oxidizing stimulus. 1,5-DCQA induces an increase in SIRT3 expression after oxidative stimulation, indicating that it has a superior protective effect on cells.
[0196] [00196] Table 2 below shows a summary of the data obtained to generate the results shown in Figures 2 to 7.
[0197] [00197] The results shown in Table 2 and Figures 2 to 7 were generated using the polymerase chain reaction (PCR), in which the dCt and ddCT values are the results used in the statistical analysis. The abbreviation dCt refers to the "delta circle limit" and the abbreviation ddCt refers to the "delta cycle limit". In these experiments, HPRT (hypoxanthine phosphoribosyltransferase, a protein in the HPRT-1 gene) was employed as a control.
[0198] [00198] The results indicate that 1,5-DCQA has desirable properties as a protective agent during cell tension. This compound therefore protects mitochondria from tension, as determined by the level of expression of SIRT. The mode of action of this compound is understood to be downstream of p21 and appears to influence telomeric biology in a positive form of oxidative insult. The results indicate that in normal fibroblasts, the compound (1,5-DCQA) down-regulates SIRT2 expression to approximately 52%, but over-regulates SIRT3 expression to approximately 36% in senescent fibroblasts. Thus, the results shown in Table 2 and Figures 2 to 7 illustrate the beneficial properties of the composition. Advantageously, the use of the composition does not completely inhibit the expression of SIRT2, since some expression of SIRT2 is required for 'maintenance' activities within the cell.
[0199] [00199] Figure 8 shows the results of a Western blot that was performed on 50 μg of the extracts of the LNCaP cells and probed for p65, p65 (ser 536) and MMP-9 expression. Strips 1 and 2 of the West spot show the levels of expression of the Hela control lysates comprising TNF-alpha (TNFa), under stimulated and unstimulated conditions. Lanes 3 and 4 show the results of the LNCaP cell, under stimulated and unstimulated conditions. In this case, the vehicle used is ethanol. Lanes 5 to 10 show the results of the LNCaP cell incubated for 24 hours in 0.1, 1, 3, 10, 30,100 μM 1,4-DCQA, respectively. Tubulin (50kD) was used as a load control. P65 and Pp65 are shown to be part of the NF-kappa B gene. These results show the effect of 1-4-Dicafeoylquinic acid on p65 inhibition.
[0200] [00200] Figure 9 shows the results of a Western blot that was performed on 50 μg of extracts from LNCaP cells and probed for p65, Pp65 (ser 536) and MMP-9 expression. Strips 1 and 2 of the West spot show the levels of expression of the Hela control lysates comprising TNF-alpha (TNFa), under stimulated and unstimulated conditions. Lanes 3 and 4 show the results of the LNCaP cell, under stimulated and unstimulated conditions. In this case, the vehicle used is ethanol. Lanes 5 through 10 show the results of the LNCaP cell incubated for 24 hours in 0.1, 1, 3, 10, 30, 100 μM 1.5-DCQA, respectively. Tubulin (50kD) was used as a load control. The results show that 1,5-DCQA does not inhibit p65 expression, it does not inhibit p65 phosphorylation. Inhibition of MMP-9 is also clearly demonstrated at 0.1 μM to 100 μM.

权利要求:
Claims (13)
[0001]
Use of a conjugate of quinic acid with at least one molecule of caffeic acid, or an isomer or salt thereof, characterized by the fact that it is for the preparation of a composition for the prevention and / or improvement of cell or tissue senescence , in which the composition is for the prevention, improvement and / or treatment of senescence associated with degeneration in stem cells and other cells and tissues including those of the skin, hair follicle, nervous system, eyes and in transplants, in which senescence it can be induced by natural causes, or where senescence can be accelerated.
[0002]
Use, according to claim 1, characterized by the fact that the composition comprises a Dicafeoylquinic acid and / or a tricafeoylquinic acid, or an isomer or salt thereof.
[0003]
Use according to claim 1 or 2, characterized by the fact that the conjugate is selected from 1,3-Dicafeoylquinic acid, 1,4-Dicafeoylquinic acid, 1,5-Dicafeoylquinic acid, 3,4-Dicafeoylquinic acid , 3,5-Dicafeoylquinic acid, 4,5-Dicafeoylquinic acid, or 3,4,5-Tricafeoylquinic acid, or an isomer or salt thereof.
[0004]
Use according to any one of claims 1 to 3, characterized in that the composition inhibits the activity of MMP-9 (matrix metalloproteinase 9).
[0005]
Use according to any one of claims 1 to 4, characterized in that the composition improves the cohesion of the skin's extracellular matrix.
[0006]
Use according to any one of claims 1 to 5, characterized in that the composition stimulates the biosynthesis of fibrillar collagens, elastin and / or fibrillins, and / or inhibits the decomposition of elastin and / or type IV collagenase.
[0007]
Use according to any one of claims 1 to 6, characterized by the fact that the composition is for the prevention, amelioration and / or treatment of a condition associated with a loss of skin elasticity.
[0008]
Use according to any one of claims 1 to 7, characterized by the fact that the composition reduces the formation of wrinkles, reduces the redness of the skin, reduces the appearance of telangiectasias, delays the appearance of fine lines, and / or reduces the appearance of dark circles around the eyes.
[0009]
Use according to any one of claims 1 to 8, characterized by the fact that the composition is for the prevention and / or improvement of conditions associated with an excess of subcutaneous fat.
[0010]
Use according to any one of claims 1 to 9, characterized by the fact that the composition is for the prevention and / or amelioration of a condition associated with senescence of the hair and / or hair follicles.
[0011]
Use according to any one of claims 1 to 10, characterized in that the composition is administered in combination with an adjuvant treatment.
[0012]
Use according to any one of claims 1 to 10, characterized in that the composition is a plant extract, for example an artichoke extract.
[0013]
Use according to any one of claims 1 to 12, characterized in that the composition is incorporated into a food or drink.

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同族专利:

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公开号 | 公开日

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EP3052074A1|2016-08-10|

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BR112016006926A8|2020-02-27|

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GB201317286D0|2013-11-13|

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WO2015044649A1|2015-04-02|

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US20160228394A1|2016-08-11|

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BR112016006926A2|2017-08-01|

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FR3057772B1|2016-10-26|2020-10-02|Plant Advanced Tech Pat|POLYSUBSTITUTE QUINIC ACID DERIVATIVES AND THEIR USES|

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KR101852570B1|2017-03-14|2018-04-27|대한민국|Pharmaceutical composition for preventing or treating of bovine spongiform encephalopathy containing 1,5-Dicaffeoyl quinic acid as an active ingredient|

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KR102041485B1|2017-09-25|2019-11-06|제주대학교 산학협력단|Cosmetic composition comprising 3,4-dicaffeoylquinic acid for protecting skin against reactive oxygen species, ultraviolet ray or particulate matter|

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KR20200050068A|2018-10-31|2020-05-11|고려대학교 산학협력단|Composition Comprising the 3,5-Dicaffeoylquinic Acid for Recovery of Distrupted Skin Barrier and/or Alleviating Skin Inflammation|

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CN109674777A|2019-01-16|2019-04-26|中国科学院成都生物研究所|Application of the isochlorogenic acid class compound in preparation neurodegenerative disease and hypochondriacal drug|

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KR102338416B1|2021-04-28|2021-12-09|조선대학교 산학협력단|Pharmaceutical composition for preventing or treating osteoarthritis comprising 4,5-dicaffeoylquinic acid|

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KR102338415B1|2021-04-28|2021-12-09|조선대학교 산학협력단|Pharmaceutical composition for preventing or treating osteoarthritis comprising 3,4-dicaffeoylquinic acid|

法律状态:
2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-06-09| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-09-24| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/09/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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GBGB1317286.1A|GB201317286D0|2013-09-30|2013-09-30|Composition and Use|

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GB1317286.1|2013-09-30|

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PCT/GB2014/052863|WO2015044649A1|2013-09-30|2014-09-19|Compositions comprising a conjugate of quinic acid with caffeic acid, cosmetic and therapeutic uses|

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