Bioactive nut peptides and compositions for skin treatment

Abstract

Bioactive Walnut Peptides and Compositions for Skin Treatment: Bioactive walnut peptides and their use for topical application to the skin are described. Bioactive walnut peptides can be incorporated into pharmaceutical or cosmetic compositions and are useful for improving skin barrier function. Figure for abstract: none

Description

Title of the invention: Bioactive nut peptides and compositions for skin treatment SCOPE OF DISCLOSURE

[0001] This disclosure relates to bioactive nut peptides and the use of nut peptides for skin treatment. Nut peptides and compositions containing them are particularly useful for improving skin barrier function and treating damaged, inflamed, and injured skin. CONTEXT

[0002] The skin is a complex organ composed of several types of cells and microstructures that work together to perform critical functions and support the body's homeostasis. It is the outermost composite layer of our body and is primarily responsible for the permeability barrier, protecting against external aggressions and preventing water loss from the inside. Our understanding of the organization, functionality, and underlying mechanisms of the skin barrier has evolved considerably over the years. The formation of an intact and well-maintained stratum corneum, where the permeability barrier resides, depends heavily on the differentiation of epidermal keratinocytes and the synthesis, release, localization, and binding of lipids, which primarily include ceramides, cholesterol, and free fatty acids.Extensive research on the stratum corneum barrier, its disruption in disease pathogenesis, and barrier responses to environmental aggressions has led to the development of modern treatments and topical care routines.

[0003] The epidermis maintains its homeostasis and performs essential functions through a dynamic self-renewal process during which basal keratinocytes divide and migrate through the spinous and granular layers while progressively differentiating. When the keratinocytes reach the top of the granular layer, the terminal differentiation process occurs, during which the keratinocytes undergo programmed cell death and flatten to form the stratum corneum. During this process, the lamellar bodies of the keratinocytes in the granular layer fuse with the plasma membranes and release their predominantly lipid contents into the intercellular spaces of the nascent stratum corneum.An interaction of hydrolytic enzymes and their inhibitors, also secreted via the lamellar bodies, participates in the elaboration of the layered intercellular lipid structure and, ultimately, is involved in . Cellular desquamation occurs on the surface of the skin. Simultaneously with the accumulation of extracellular lipids, significant changes occur in keratinocytes during the formation of the stratum corneum. Transglutaminase-1-mediated cross-linking of cytoplasmic proteins at the cell periphery leads to the formation of highly insoluble cornified envelopes of stratum corneum cells, subsequently called corneocytes. This is followed by covalent binding to these structures of a ceramide monolayer, replacing the phospholipid plasma membranes of living cells. These newly formed lipid cornified envelopes provide the scaffolding for the subsequent stacking and organization of intercellular lipids.The composite structure of the stratum corneum, made up of corneocytes interspersed with polar lipids, can be compared to a brick and mortar wall forming the permeability barrier of the stratum corneum.

[0004] To fulfill its function as a permeability barrier, the epidermis must remain mechanically resistant while being sufficiently flexible to adapt to skin movements and the flow of keratinocytes through successive layers, like a conveyor belt. Cell-cell and cell-substrate junctions play a central role in maintaining the mechanical properties of the epidermis. Desmosomes, which interconnect individual cell cytoskeletons into a superstructure, evolve throughout the epithelial tissue and modify their location, protein composition, and glycan distribution according to the stage of cell differentiation and the onset of mechanical stress. In this process, adherens junctions linked to the actin cytoskeleton participate in the dynamics of desmosome and tight junction expression.During the formation of the stratum corneum, these junctions are cross-linked to the cornified envelopes and contribute to strengthening the physical resistance of the functional barrier of the stratum corneum. The mechanical properties of the stratum corneum show a significant increase in stiffness between deep and superficial corneocytes. The mechanical integrity of the stratum corneum also depends on the direction of the applied shear forces, as lateral, side-by-side adhesion between cells is stronger than that between successive layers of corneocytes.

[0005] The relative impermeability of the stratum corneum, and therefore its barrier function, depends essentially on intercellular lipids, although these represent only 15% of the stratum corneum's weight. Near-equimolar proportions of ceramides, cholesterol, and free fatty acids appear to be essential for the proper self-assembly of the intercellular lipid multilayers within the stratum corneum. The composition of the stratum corneum lipids is further subdivided into free fatty acids (10%), cholesterol (27%), cholesterol esters (10%), and cholesterol sulfate. (3%) and ceramides (50%). These lipids, organized in multiple double layers parallel to the corneocyte surfaces, can assemble within the layers into domains with different densities. A dense orthorhombic lateral lining of lipid molecules and a more fluid hexagonal format predominate in normal human skin. Effective filling of the stratum corneum interstices is essential to prevent excessive water loss and the penetration of contaminants / environmental aggressors.

[0006] The formation and restoration of a disrupted stratum corneum barrier is a dynamic, finely regulated process, subject to the influence of intrinsic and environmental factors. In addition to diseases and severe environmental exposures to ultraviolet radiation or pollution, events occurring in daily life can also negatively impact the skin barrier. The importance of the stratum corneum in maintaining skin homeostasis, coupled with the prevalence and severity of internal and external factors that can alter its permeability, underscores the need for topical products to support the skin barrier. Understanding the structure, composition, and function of the epidermal permeability barrier provides a solid foundation for the knowledge-based development of topical treatments aimed at maintaining and improving the skin of patients, whether healthy or diseased.The formulation of pharmaceutical and cosmetic compositions to improve barrier integrity has continued as knowledge of the skin barrier continually evolves. Efforts are currently underway to address the need to enhance barrier function and regeneration. DISCLOSURE SUMMARY

[0007] This disclosure relates to bioactive walnut peptides and the use of walnut peptides for topical application to the skin. Bioactive walnut peptides, which can be incorporated into a pharmaceutical or cosmetic composition, improve skin barrier function and skin re-epithelialization, repair damaged skin, and enhance wound healing. For example, walnut peptides and compositions containing them are useful for improving the skin barrier function of healthy skin and for treating skin that has suffered physical, chemical, environmental, sun damage, and damage caused by disease, including inflammation.

[0008] Walnuts are one of the most widespread and oldest nuts in the world. They have high nutritional value and are rich in oleic acid, linoleic acid, alpha-linolenic acid, and other unsaturated fatty acids, vitamins, and proteins. Walnuts are commonly used to make walnut oil because They have a high lipid content. The residue remaining after lipid extraction is considered a by-product, although it contains nut proteins and other useful components. Nut protein is primarily composed of albumin, globulin, gliadin, and glutenin.

[0009] Bioactive nut peptides can be derived from nut proteins or can be synthesized. For example, nut peptides are obtained by enzymatic hydrolysis, fermentation hydrolysis, or chemical hydrolysis of nut proteins or produced synthetically, for example, by solid-phase synthesis. Bioactive peptides that are particularly useful according to the present disclosure typically have a molecular weight of less than 6,000 Da and often less than 1,000 Da. These nut peptides may have from 2 to 50 amino acid residues, but typically have from 2 or 3 amino acid residues to about 20 amino acid residues.

[0010] Preferably, bioactive nut peptides have a minimum of 2 or 3 amino acid residues up to about 20 amino acid residues and confer a positive physiological or dermatological effect on skin cells. Bioactive peptides include amino acids joined by covalent bonds, also called amide or peptide bonds, while proteins are polypeptides of higher molecular weight (MW), i.e., having more than 50 amino acid residues. Bioactive nut peptides usually exhibit hormonal or drug-like activities and are classified according to their mode of action. Many bioactive peptides share certain structural characteristics, for example, an amino acid residue length of 2 to 20 amino acids.

[0011] The useful bioactive nut peptides described in this disclosure often include one or more amino acid residues selected from leucine, proline, or combinations thereof. In other embodiments, the nut peptides include three or more amino acid residues selected from leucine, proline, or combinations thereof. Non-limiting examples of amino acid residues within nut peptides that include leucine and proline include Leu-Pro-Leu (LPP), Leu-Leu-Pro, Pro-Pro-Leu (PPL), and Pro-Leu-Pro (PLP). Other non-limiting examples of amino acid sequences that may be included in bioactive nut peptides include Thr-Trp-Leu-Pro-Leu-Pro-Arg (TWLPLPR), Tyr-Val-Leu-Leu-Pro-Ser-Pro-Lys (YVLLPSPK), Lys-Val-Pro-Pro-Leu-Leu-Tyr (KVPPLLY), and their combinations.

[0012] In various embodiments, one or more of the following nut peptides are preferred:

[0013] Peptide I Thr-Trp-Leu-Pro-Leu-Pro-Arg (TWLPLPR),

[0014] Peptide II Tyr-Val-Leu-Leu-Pro-Ser-Pro-Lys (YVLLPSPK), and / or

[0015] Peptide III Lys-Val-Pro-Pro-Leu-Leu-Tyr (KVPPLLY).

[0016] As already mentioned, bioactive walnut peptides are particularly useful for topical application to the skin. Accordingly, this disclosure relates to the use of walnut peptides in skin treatment processes. In various embodiments, one or more walnut peptides are applied to the skin in a pharmaceutical or cosmetic composition, which typically includes a physiologically acceptable carrier, for example, water, and optionally water-soluble solvents. The pharmaceutical or cosmetic composition includes a sufficient quantity of the one or more bioactive walnut peptides to ensure that a therapeutically effective amount of the one or more walnut peptides is delivered to the skin during use.

[0017] Bioactive nut peptides are useful for treating skin inflammation. For example, bioactive nut peptides remarkably and advantageously reduce, treat, or prevent pro-inflammatory cytokines in the skin. In addition, bioactive walnut peptides are useful in the treatment of skin conditions, diseases, or disorders such as psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, eczema, spongiosis, edema, hereditary ichthyosis, senile xerosis, palmar hyperkeratosis, plantar hyperkeratosis, cuts, bruises, pore size, skin cancer, wound healing or re-epithelialization disorders, keloids, hypertrophic scars, cellulite, orange peel skin, elastosis, actinic elastosis, keratosis, rosacea, telangiectasia, couperose, or combinations thereof.

[0018] In various embodiments, the use of two or more bioactive nut peptides is preferred. These two or more bioactive nut peptides may have similar activities or may offer different activities beneficial to the skin. In other embodiments, the use of three or more bioactive nut peptides is preferred. The use of multiple bioactive peptides allows for the modification of more than one physiological mechanism in skin treatment. For example, one or more bioactive nut peptides may be useful for preventing and / or treating age-related inflammation, while another bioactive nut peptide may be useful for stimulating fibroblasts that produce collagen and elastin to clarify, thicken, and firm the skin.Moreover, combinations of bioactive nut peptides can interact synergistically and provide benefits that exceed the sum of the individual contributions of the peptides. For example, the synergistic activity of a combination can be at least 5%, at least 10%, or at least 25% greater than the sum of the individual activities of the corresponding amounts of the bioactive nut peptides.

[0019] One or more bioactive nut peptides are often incorporated into a pharmaceutical or cosmetic composition for application to the skin. Pharmaceutical and cosmetic compositions typically include one or more bioactive nut peptides and one or more physiologically acceptable carriers, such as water. Non-limiting examples of physiologically acceptable carriers include water, water-soluble solvents such as alcohols, polyols, and glycols, fatty compounds such as oils, triglycerides, fatty acids, fatty alcohols, and the like. Pharmaceutical and cosmetic compositions include lotions, creams, serums, sprays, emulsions, gels, powders, dispersions, ointments, sticks, pastes, and foams. Brief description of the designs

[0020] An implementation of this technology is described, by way of example only, with reference to the accompanying figures, in which:

[0021] [Fig-1] [Fig.1] is a heat map showing genes with expression differential in adult human epidermal keratinocytes treated with walnut peptides; and

[0022] [Fig.2] [Fig.2] is a heat map showing differentially expressed genes in reconstructed human epidermis treated with walnut peptides.

[0023] The various aspects of disclosure are not limited to the results, arrangements and representations shown in the drawings. DETAILED DESCRIPTION OF THE INVENTION

[0024] This disclosure relates to bioactive walnut peptides and their topical use for skin treatment. The bioactive walnut peptides comprise two to several dozen amino acids linked together by peptide bonds. Their molecular weight is generally less than 6,000 Da, preferably less than 3,000 Da, and more preferably less than 1,000 Da. The term "peptide" in accordance with this disclosure is a compound that includes an unbroken sequence of at least two amino acids within its structure and has a maximum of about 50 amino acids. The terms "di-peptide" or "dipeptide" as used herein refer to a compound that includes an unbroken sequence of two amino acids within its structure. The terms "tri-peptide" or "tripeptide" as used herein refer to a compound that includes an unbroken sequence of three amino acids within its structure.As used here, a "tetrapeptide" or "tetrapeptide" is a compound that includes an unbroken sequence of four amino acids within its structure. These amino acids are indicated here using a traditional one-letter convention from left (N-terminal end) to right (C-terminal end). In this nomenclature, G is glycine, H is histidine, K is lysine, E is glutamic acid, and so on, according to a well-known and accepted nomenclature in art.

[0025] A "bioactive" peptide, as defined in this disclosure, has a minimum of 2 or 3 amino acid residues up to approximately 20 amino acid residues in length and has a measurable physiological effect on skin cells. Bioactive peptides include amino acids linked by covalent bonds, also known as amide or peptide bonds, whereas proteins are polypeptides with a higher molecular weight (MW) and generally more than 50 amino acid residues. Bioactive peptides typically exhibit hormonal or drug-like activities and are classified according to their mechanism of action. Many bioactive peptides share certain structural features, which include, for example, a peptide residue length of 2 to 20 amino acids.

[0026] The term "amino acid" as used herein includes and encompasses all natural amino acids, in the D or L configuration if optically active, and known non-native, synthetic, and modified amino acids, such as homocysteine, omithine, norleucine, and p-valine. A list of non-natural amino acids can be found in *The Peptides*, Vol. 5 (1983), Academy Press, Chapter VI, by D.C. Roberts and F. Vellaccio. The amino acids in the peptides of the present invention may be present in their natural L configuration, their non-natural D configuration, or as a racemic mixture.

[0027] As used herein, the term "peptide" also refers to the salts, deproteinized forms, acylated forms of the peptide, deacylated forms of the peptide, enantiomers, diastereomers, racemates, prodrugs, and hydrates of the peptide mentioned above. Diastereomers of the peptide are obtained when the stereochemical or chiral center of one or more amino acids is changed. The enantiomer exhibits the opposite stereochemistry in all chiral centers. In various embodiments, the C-terminus of a peptide is synthesized as an amide to neutralize a negative charge created by the C-terminal COOH. This modification may be added to help prevent enzymatic degradation.

[0028] The term “prodrug” refers to any precursor compound that can generate or release the aforementioned peptide under physiological conditions. Such prodrugs are, for example, larger peptides that are selectively cleaved to form the peptide of the invention. Other prodrugs are protected amino acids having protecting groups at the carboxylic acid and / or amino group. Suitable protecting groups for amino groups include, for example, benzyloxycarbonyl, t-butyloxycarbonyl (BOC), formyl, and acetyl or acyl groups. Suitable protecting groups for the carboxylic acid group are esters such as benzyl esters or t-butyl esters.

[0029] Epidermal deterioration can result from acute injury or exposure. Virtually all dysfunctions of the epidermis, whether congenital or Acquired skin conditions are associated with significant alterations in the skin barrier. This is particularly evident in dermatoses with a substantial inflammatory component. In many cases, barrier dysfunction can cause skin disease, as is the case in atopic dermatitis, and contributes to the vicious cycle of a given pathology by inducing an inflammatory response. Deficient expression of the epidermal protein filaggrin, due to loss-of-function genetic mutations, has been found to be responsible for the development of atopic dermatitis in up to 50% of cases in Northern Europe.

[0030] Filaggrin is produced in granulocytic stratum keratinocytes, and its catabolic processing in the stratum corneum leads to an abundance of hydrophilic amino acids that constitute the bulk of the so-called natural moisturizing factor (NMF). The absence or marked reduction of the natural moisturizing factor compromises the hydration of the stratum corneum and, consequently, its barrier function. Interestingly, the same filaggrin mutations present on both alleles of the gene result in a phenotype of ichthyosis vulgaris, most frequently associated with atopy. In ichthyosis, the epidermis must compensate for the permeable barrier with hyperkeratosis. The accumulation of comeocytes is probably favored by a particularly low degree of hydration of the stratum corneum, which may inhibit the activity of hydrolytic enzymes in the stratum corneum.This putative mechanism could exacerbate the favorable environment for desquamation of serine protease activation due to a more alkaline (optimal) intracellular pH in amino acid-deficient tissue. Nanomechanical and ultrastructural studies of the elastic properties of filaggrin-deficient corneocytes demonstrate a significant reduction in cell stiffness and delayed comeodesmosome degradation, both potential indicators of stratum corneum functionality. In addition to altered filaggrin expression, atopic dermatitis of the epidermis also exhibits a significant reduction in key TJ proteins and, more importantly, ceramides, including EOS ceramides.

[0031] Regarding changes in ceramides, decreased levels and shortened acyl chains have been observed in skin not affected by atopic dermatitis, independently of filaggrin mutations, which may have etiological significance. Altered ceramide expression levels and their lamellar and lateral organization are correlated with disease activity. Even lower levels of free ceramides and sterols have been reported in atopic dermatitis lesions, with a concomitant increase in sphingosine and sphinganine-based ceramides.

[0032] In psoriasis, inflammatory skin lesions induced by Thl7 lymphocytes recruited by interleukin 23 are characterized by hyperproliferation Keratinocytes and incomplete terminal differentiation result in an ineffective permeability barrier function. Although the immune cell subsets and cytokines involved in atopic dermatitis and psoriasis pathogenesis differ considerably, the deleterious vicious cycle of barrier disruption / inflammation is always present in the latter. The incomplete terminal differentiation of psoriatic lesion keratinocytes is induced by T-cell-mediated skin inflammation, which significantly impacts ceramide expression compared to normal or uninvolved skin. Similar to atopic dermatitis, ceramide species exhibit shorter fatty acid chains in psoriasis lesions.Clinical observations of improvement in psoriasis vulgaris lesions under simple occlusion and in atopic dermatitis lesions with topical emollient therapy alone clearly indicate that restoration or compensation of the stratum corneum barrier helps to interrupt the vicious cycle of pathogenic self-propagation.

[0033] To fulfill its protective functions, the epidermis must continuously adapt to changes in environmental conditions. These include climate / seasonal factors such as relative humidity, ambient temperature, and sun exposure, as well as environmental aggressions due to the widespread use of chemicals, the presence of air pollutants, and changes in the composition and abundance of the skin's surface microbiota, the latter being largely linked to the aforementioned factors.

[0034] Humidity influences the renewal of the stratum corneum by changing the rate of corneocyte desquamation. Specifically, it promotes a rapid rise in the pH of the stratum corneum, leading to increased activity of kallikreins, the main serum proteases of the stratum corneum involved in desquamation. Furthermore, exposure to water facilitates the accessibility of corneodesmosomes to proteolytic enzymes, which otherwise remain encapsulated within the largely hydrophobic extracellular spaces, thus promoting the release of cells onto the skin surface. Conversely, corneodesmosomes persist in the outer stratum corneum of xerotic winter skin compared to normal skin. Moreover, it is known that cold and dry weather increase the prevalence and risk of relapse in patients with atopic dermatitis.

[0035] Environmental factors leading to a degradation of the skin barrier function include exposure to irritants and allergens. In industrialized societies, the skin barrier is affected by the daily use of detergents and disinfectants, combined with the harmful effects of air pollutants that vary according to geographical location and source. These pollutants contain solid and liquid particles suspended in the air and Various gases, such as ozone, nitrogen oxides, volatile organic compounds, and carbon monoxide, are present. Particles vary in number, size, shape, surface area, and chemical composition, while both particles and gases can vary in solubility and toxicity. Occupational factors also play a role, as they increase risks in specific subpopulations. In healthcare professionals, intensive glove use leads to occlusion, which significantly exacerbates the negative effect of detergents / soaps on the skin barrier function. Published data indicate that a dose-response relationship is important with respect to the duration of occlusion. This is particularly relevant for workplaces where it is common to switch between wearing gloves and washing hands.

[0036] The present disclosure includes methods for improving the skin barrier function. Such methods include treating the skin by topical application of a therapeutically effective amount of one or more walnut peptides to the skin. In various embodiments, the one or more bioactive walnut peptides have a molecular weight of less than 10,000 Da. In other embodiments, the one or more bioactive walnut peptides have a molecular weight of less than 8,000 Da, less than 6,000 Da, less than 5,000 Da, less than 4,000 Da, less than 3,000 Da, less than 2,000 Da, less than 1,000 Da, and even less than 500 Da. Preferably, the one or more bioactive walnut peptides have a molecular weight of less than 5,000 Da, more preferably less than 2,000 Da, and even more preferably less than 1,000 Da.

[0037] The number of amino acid residues in the one or more bioactive nut peptides will vary and may be limited depending on the molecular weights described above. Nevertheless, in various embodiments, the one or more bioactive nut peptides comprise from 2 to approximately 50 amino acid residues.In other embodiments, the bioactive peptide(s) have from 2 to approximately 25 amino acid residues, from approximately 2 to approximately 20 amino acid residues, from approximately 2 to approximately 18 amino acid residues, from approximately 2 to approximately 15 amino acid residues, from approximately 2 to approximately 12 amino acid residues, from approximately 2 to approximately 10 amino acid residues, from approximately 3 to approximately 25 amino acid residues, from approximately 3 to approximately 20 amino acid residues, from approximately 3 to approximately 18 amino acid residues, from approximately 3 to approximately 18 amino acid residues, from approximately 3 to approximately 15 amino acid residues, from approximately 3 to approximately 12 amino acid residues, or from approximately 3 to approximately 10 amino acid residues. amino acid. Preferably, the one or more bioactive peptides comprise 2 to 20 amino acid residues, more preferably 2 to about 15 amino acid residues, and even more preferably 3 to about 12 amino acid residues.

[0038] In various embodiments, the one or more bioactive nut peptides include one or more amino acid residues selected from leucine, proline, and combinations thereof. In another embodiment, the one or more bioactive nut peptides include three or more amino acid residues selected from leucine, proline, or one of their combinations. Non-limiting examples of a bioactive peptide of three or more amino acid residues selected from leucine, proline, and their combinations include Leu-Pro-Leu, Leu-Leu-Pro, Pro-Pro-Leu, and Pro-Leu-Pro. For example, the one or more bioactive nut peptides may comprise an amino acid sequence selected from Thr-Trp-Leu-Pro-Leu-Pro-Arg, Tyr-Val-Leu-Leu-Pro-Ser-Pro-Lys, or Lys-Val-Pro-Pro-Leu-Leu-Tyr.As already mentioned, bioactive nut peptides include salts, deprotected forms, acylated forms, deacylated forms, enantiomers, diastereomers, racemates, prodrugs, and hydrates of a particular amino acid sequence.

[0039] In a preferred embodiment, at least one, and preferably all, of one or more bioactive nut peptides are selected from peptide I, peptide II and peptide III, including their salts, their deprotected forms, their acylated forms, their deacylated forms, their enantiomers, their diastereomers, their racemates, their prodrugs and their hydrates.

[0040] Peptide I TWLPLPR (Thr-Trp-Leu-Pro-Leu-Pro-Arg),

[0041] Peptide II YVLLPSPK (Tyr-Val-Leu-Leu-Pro-Ser-Pro-Lys), and

[0042] Peptide III KVPPLLY (Lys-Val-Pro-Pro-Leu-Leu-Tyr).

[0043] In various embodiments, the use of two bioactive nut peptides or More is desirable. Two or more bioactive nut peptides may share similar activities or may offer different activities beneficial to the skin. In other embodiments, the use of three or more bioactive nut peptides is preferred. The use of multiple bioactive peptides allows for leveraging more than one physiological mechanism for skin treatment. For example, one or more bioactive nut peptides may be useful for preventing and / or treating inflammation, while another bioactive nut peptide may be useful for stimulating fibroblasts that produce collagen and elastin to clarify, thicken, and firm the skin. Moreover, as shown later, combinations of bioactive nut peptides interact synergistically to provide benefits that go beyond the sum of the individual peptide contributions.For example, the synergistic activity of a combination of bioactive nut peptides may be at least 5%, preferably at least 10%, and more preferably at least 25% greater than the sum of the activities of the corresponding individual amounts of the bioactive nut peptides.

[0044] Combinations of peptide I, peptide II, and peptide III are particularly useful. For example, a combination of peptide I and peptide II, a combination of peptide I and peptide III, a combination of peptide II and peptide III, or a combination of peptide I, peptide II, and peptide III can be used. The peptides in the combinations can be included in various weight ratios relative to each other as described below.

[0045] Peptide I and peptide II can be used together in a weight ratio of about 1:10 to about 10:1. In other embodiments, peptide I and peptide II can be used together in a weight ratio of about 8:1 to about 1:8, about 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1:1.

[0046] Peptide I and peptide III can be used together in a weight ratio of about 1:10 to about 10:1. In other embodiments, peptide I and peptide III can be used together in a weight ratio of about 8:1 to about 1:8, about 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1:1.

[0047] Peptide II and peptide III can be used together in a weight ratio of about 1:10 to about 10:1. In other embodiments, peptide II and peptide III can be used together in a weight ratio of about 8:1 to about 1:8, about 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1:1.

[0048] In various embodiments, this disclosure relates to the use of one or more nut peptides or a pharmaceutical or cosmetic composition comprising one or more nut peptides to improve skin barrier function or skin re-epithelialization. Accordingly, the disclosure encompasses methods for improving skin barrier function or skin re-epithelialization that include applying a therapeutically effective amount of one or more nut peptides or a composition comprising them to the skin, including damaged and undamaged skin.

[0049] In various embodiments, this disclosure relates to the use of one or more nut peptides or a pharmaceutical or cosmetic composition comprising one or more nut peptides to treat or repair damaged skin. Accordingly, the disclosure encompasses methods for treating or repairing damaged skin, including the application of a therapeutically effective amount of one or more nut peptides or a composition comprising them to skin in need. In other embodiments, the damaged skin has been physically damaged, chemically damaged, damaged by the environment, damaged by the sun, or damaged due to disease.

[0050] In other embodiments, the disclosure relates to the use of one or more nut peptides or a pharmaceutical or cosmetic composition comprising one or more nut peptides for wound healing. For example, the disclosure relates to methods for enhancing wound healing and methods for treating or improving the appearance of skin due to the wound-healing properties conferred by nut peptides and compositions comprising them. Such methods include: (i) damaging skin tissue using a chemical, a laser, or physical force; and (ii) applying a therapeutically effective amount of one or more bioactive nut peptides to the damaged skin.Non-limiting examples of cosmetic procedures that damage the skin include ablative laser procedures, non-ablative laser procedures, microneedling procedures, cryotherapy procedures, radiofrequency microneedling procedures, dermabrasion, chemical peels, exfoliants or mechanical or energy-based devices, or any chemical procedure that damages the skin (e.g., chemical peels, etc.).

[0051] In various embodiments, this disclosure relates to the use of one or more nut peptides or a pharmaceutical or cosmetic composition comprising one or more nut peptides to improve skin barrier function. Accordingly, the disclosure encompasses methods for improving skin barrier function, including the application of a therapeutically effective amount of one or more nut peptides or a composition comprising them to skin in need. In various embodiments, the skin barrier function of healthy, undamaged skin is improved. In other embodiments, the skin barrier function of damaged skin is improved.

[0052] In various embodiments, this disclosure relates to the use of one or more nut peptides or a pharmaceutical or cosmetic composition comprising one or more nut peptides to treat dry or itchy skin. Accordingly, the disclosure encompasses methods for treating dry or itchy skin, including the application of a therapeutically effective amount of one or more nut peptides or a composition comprising them to skin in need.

[0053] In various embodiments, the present disclosure relates to the use of one or more nut peptides or a pharmaceutical or cosmetic composition comprising one or more nut peptides to treat a condition, a disease or a skin disorder chosen from psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, eczema, spongiosis, edema, hereditary ichthyosis, senile xerosis, palmar hyperkeratosis, plantar hyperkeratosis, cuts, bruises, pore size, skin cancer, wound healing or re-epithelialization disorders, keloids, hypertrophic scars, cellulite, orange peel skin, elastosis, actinic elastosis, keratosis, rosacea, telangiectasia, couperose, or combinations thereof.Accordingly, the disclosure encompasses methods for treating a skin condition, disease, or disorder selected from psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, eczema, spongiosis, edema, hereditary ichthyosis, senile xerosis, palmar hyperkeratosis, plantar hyperkeratosis, cuts, bruises, pore size, skin cancer, wound healing or re-epithelialization disorders, keloids, hypertrophic scars, cellulite, orange peel skin, elastosis, actinic elastosis, keratosis, rosacea, telangiectasia, couperose, or combinations thereof, including the application of a therapeutically effective amount of one or more nut peptides or a composition comprising them to skin that requires it.

[0054] In other embodiments, this disclosure relates to the use of one or more nut peptides or a pharmaceutical or cosmetic composition comprising one or more nut peptides for treating skin suffering from inflammation or an inflammatory disorder, and to methods for treating skin suffering from inflammation or an inflammatory disorder. Non-limiting examples of inflammatory disorders include atopic dermatitis, psoriasis, or combinations thereof.

[0055] In various embodiments, this disclosure relates to the use of one or more walnut peptides or a pharmaceutical or cosmetic composition comprising one or more walnut peptides to enhance terminal differentiation and keratinization of skin cells. Similarly, the disclosure relates to methods for enhancing terminal differentiation and keratinization of skin cells comprising the application of a therapeutically effective amount of one or more walnut peptides to skin in need.

[0056] One or more walnut peptides are often combined with one or more additional skin-active agents. Non-limiting examples of skin-active agents include anti-atrophy agents, antioxidants, depigmenting agents, or combinations thereof. More specific but non-limiting examples include ceramides, alpha-hydroxy acids, beta-hydroxy acids, vitamin A, vitamin C, vitamin D, vitamin E, niacinamide, caffeine, ferulic acid, salicylic acid, madecassoside, retinoic acid, benzoyl peroxide, or combinations thereof. In a preferred embodiment, one or more walnut peptides are combined with one or more ceramides, by For example, one or more ceramides chosen from among free ceramides, for example, Ceramide EOP, Ceramide AS, Ceramide AP, Ceramide NS, Ceramide NP, Ceramide NH, Ceramide AH, Ceramide EOH, Ceramide EOS, Ceramide AdS, Ceramide NdS and Ceramide EOdS, protein-bound ceramides, phytosphingosine, sphingosine, ceramide precursors, fatty acids, fatty alcohols, cholesterol, cholesterol sulfate, or combinations thereof.

[0057] One or more nut peptides can be combined with cholesterol.

[0058] One or more nut peptides can be combined with one or more Sphingolipids. Sphingolipids are a class of lipids containing a sphingoid base skeleton, which are a set of amino aliphatic alcohols that include sphingosine. One or more walnut peptides can be combined with sphingosine-1-phosphate.

[0059] One or more bioactive nut peptides are often incorporated into a pharmaceutical or cosmetic composition for application to the skin. Pharmaceutical and cosmetic compositions typically include one or more bioactive nut peptides and a physiologically acceptable carrier. A "physiological carrier," as used here, is a carrier that is suitable and safe for application to human skin. A particularly common physiologically acceptable carrier is water. However, physiologically acceptable carriers may include oils, fats, organic solvents, and the like, provided they are suitable and safe for application to the skin.Non-limiting examples of physiologically acceptable carriers include water, water-soluble solvents such as alcohols, polyols, and glycols, fatty compounds such as oils, triglycerides, fatty acids, fatty alcohols, petrolatum, and the like. The pharmaceutical and cosmetic compositions disclosed herein may be lotions, creams, serums, sprays, emulsions, gels, powders, dispersions, ointments, sticks, pastes, or foams.

[0060] Bioactive nut peptides can be obtained by hydrolyzing nut proteins into small molecular peptides with molecular weights between the molecular weights of individual amino acids and the molecular weights of proteins. This can be achieved using biological or chemical processes. For example, bioactive peptides can be prepared by enzymatic procedures, fermentation, and chemical processes.

[0061] Bioactive nut peptides can be synthesized by coupling the carboxyl group or C-terminus of one amino acid to the amino group or N-terminus of another. Due to the possibility of unforeseen reactions, protecting groups are sometimes necessary. The chemical synthesis of peptides begins at the C-terminus of the peptide and ends at the N-terminus. Peptides can be synthesized either by solid-phase peptide synthesis, liquid-phase peptide synthesis, or by condensation of fragments. In principle, the seemingly simple formation of a peptide bond can be accomplished using any of the procedures available in organic chemistry for the synthesis of carboxylic acid amides.

[0062] The general process for synthesizing peptides in the solid phase (e.g., a resin) begins with the attachment of the first amino acid, the C-terminal residue, to the resin. To prevent polymerization of the amino acid, the alpha-amino group and the reactive side chains are protected by a temporary protecting group. Once the amino acid is attached to the resin, the resin is filtered and washed to remove excess byproducts and reagents. Next, the N-alpha protecting group is removed in a deprotection process, and the resin is washed again to remove excess byproducts and reagents. Then, the next amino acid is coupled to the attached amino acid. This is followed by another washing procedure, which leaves the resin-peptide assembly ready for the next coupling cycle. The cycle is repeated until the peptide sequence is complete.Next, typically, all the protecting groups are removed, the peptide resin is washed away, and the peptide is cleaved from the resin.

[0063] Enzymatic hydrolysis involves the use of commercial enzymes to obtain bioactive peptides. The enzymes are responsible for cleaving the peptide bonds established in the protein, thereby releasing the encrypted peptide. For the enzyme to exert its activity, it is important that the enzyme binds to the substrate and proceeds with enzymatic catalysis. The enzyme possesses specific active sites containing residues that form temporary bonds with the substrate and residues that catalyze the reaction with the substrate. In this way, binding sites and catalytic sites are formed, respectively. The bonds forming the enzyme-substrate complex are usually hydrogen bonds, hydrophobic interactions, or Van der Waals interactions.Enzymatic hydrolysis can generally be carried out in three ways: (i) under traditional batch conditions; (ii) using immobilized enzymes; or (iii) using ultrafiltration membranes. Many proteolytic enzymes are known and include those described, for example, in Cruz-Casas et al., Enzymatic Hydrolysis and Microbial Fermentation: The Most Favorable Biotechnological Methods for the Release of Bioactive Peptides (Food Chem (Oxf). 3:100047, Dec. 30, 2021).

[0064] Microbial fermentation is a biotechnological process that yields bioactive peptides. This process involves the use of microorganisms capable of producing proteolytic enzymes, with the aim of having these enzymes hydrolyze proteins into shorter peptides. The microorganisms generally used are bacteria, fungi, or yeasts, which may be present microbial cultures can be introduced into the substrate naturally or added as starter cultures. The microbial fermentation process can be divided into several systems. However, immersion fermentation and solid-state fermentation are the most widely used.

[0065] Immersion fermentation uses a culture of microorganisms in a liquid medium containing nutrients. This system is suitable for microorganisms with high water-level activity, such as bacteria, and offers the advantage that the generated bioactive peptides are easy to purify. Solid-state fermentation uses microbial growth on nutrient-rich solid substrates. It has the advantage of releasing nutrients in a controlled manner and is suitable for fungi and microorganisms with lower moisture requirements.

[0066] Bioactive nut peptides can be produced using any process known to those skilled in the art, such as those disclosed in Merrifield, RB, Solid Phase Peptide Synthesis L, J. AM. CHEM. SOC. 85:2149-2154 (1963); Carpino, LA et al., [(9-Fluorenylmethyl)Oxy] Carbonyl (Fmoc) Amino Acid Chlorides: Synthesis, Characterization, And Application To The Rapid Synthesis Of Short Peptides, J. ORG. CHEM. 37:51:3732-3734; Merrifield, RB et al., Instrument For Automated Synthesis Of Peptides, ANAL. CHEM. 38:1905-1914 (1966); or Kent, SBH et al., High Yield Chemical Synthesis Of Biologically Active Peptides On An Automated Peptide Synthesizer OfNovel Design, IN: PEPTIDES 1984 (Ragnarsson U., ed.) Almqvist and Wiksell Int., Stockholm (Sweden), p. 185-188.

[0067] The therapeutically effective amount of one or more bioactive nut peptides will vary depending on the specific bioactive nut peptide and the combination of bioactive nut peptides. Nevertheless, in various embodiments, the therapeutically effective amount can range from approximately 1 pg to approximately 50 mg (50,000 pg) per cm² of skin. In other embodiments, the therapeutically effective amount of one or more walnut peptides is approximately 1 pg to approximately 40 mg, approximately 1 pg to approximately 30 mg, approximately 1 to approximately 20 mg, approximately 1 pg to approximately 10 mg, approximately 1 pg to approximately 8,000 pg, approximately 1 pg to approximately 5,000 pg, approximately 1 pg to approximately 2,000 pg, approximately 1 pg to approximately 1,000 pg, approximately 10 pg to approximately 40 mg, approximately 10 pg to approximately 30 mg, approximately 10 to approximately 20 mg, approximately 10 pg to approximately 10 mg, approximately 10 pg to approximately 8,000 pg, approximately 10 pg to approximately 5,000 pg, from approximately 10 pg to approximately 2000 pg, from approximately 10 pg to approximately 1000 pg,from approximately 100 pg to approximately 50 mg, from approximately 100 pg to approximately 40 mg, from approximately 100 pg to approximately 30 mg, from approximately 100 pg to approximately 20 mg, from approximately 100 pg to approximately 10 mg, from approximately 100 pg to approximately 8,000 pg, from approximately 100 pg to approximately 5,000 pg, from approximately 100 pg to approximately 2,000 pg, from approximately 100 pg to approximately 1,000 pg, from approximately 500 pg to approximately 50 mg, from approximately 500 pg to approximately 40 mg, from approximately 500 pg to approximately 30 mg, , from about 500 pg to about 30 mg, from about 500 |ig to about 20 mg, from about 500 |ig to about 10 mg, from about 500 to about 8,000 |ig, from about 500 pg to about 5,000 |ig, from about 500 |ig to about 2,000 pg or from about 500 |ig to about 1,000 |ig per cm2 of skin.

[0068] Bioactive nut peptides are typically formulated with a physiologically acceptable carrier and applied to the skin in the form of a pharmaceutical or cosmetic composition. The amount of one or more bioactive nut peptides will vary depending on their activity, use, and interaction with additional bioactive nut peptides that may optionally be included in the pharmaceutical or cosmetic composition. Nevertheless, in various embodiments, the pharmaceutical or cosmetic composition includes from approximately 0.01 to approximately 10% by weight of one or more bioactive nut peptides, relative to the total weight of the pharmaceutical or cosmetic composition.

[0069] In other embodiments, the pharmaceutical or cosmetic composition includes approximately 0.01 to approximately 8% by weight, approximately 0.01 to approximately 5% by weight, approximately 0.01 to approximately 3% by weight, approximately 0.01 to approximately 1% by weight, approximately 0.01 to approximately 0.5% by weight, approximately 0.1 to approximately 10% by weight, approximately 0.1 to approximately 8% by weight, approximately 0.1 to approximately 5% by weight, approximately 0.1 to approximately 3% by weight, approximately 0.1 to approximately 1% by weight, approximately 0.5 to approximately 10% by weight, approximately 0.5 to approximately 8% by weight, approximately 0.5 to approximately 5% by weight, approximately 0.5 to approximately 3% by weight, approximately 0.5 at about 2% by weight, from about 1 to about 10% by weight, from about 1 to about 8% by weight, from about 1 to about 5% by weight, from about 1 to about 3% by weight, or from about 0.1 to about 2% by weight of one or more bioactive nut peptides, relative to the total weight of the pharmaceutical or cosmetic composition.

[0070] Pharmaceutical and cosmetic compositions including one or more bioactive nut peptides may be formulated in various forms, for example, lotions, creams, serums, sprays, emulsions, gels, powders, dispersions, ointments, sticks, pastes, and foams. In addition to a physiologically acceptable carrier, the pharmaceutical and cosmetic composition may optionally include one or more of the following: • Active desquamating agents, keratolytic agents and exfoliating agents, • Suspension agents, • Emulsifying agents, • Thickeners, and / or • Antihistamines. Skin-active agents

[0071] Non-limiting examples of cutaneous active agents include rosacea-inhibiting agents (e.g., metronidazole, sulfacetamide, sodium sulfacetamide, sulfur, dapson, doxycycline, minocycline, clindamycin, clindamycin phosphate, erythromycin, tetracyclines, azelaic acid, calcium dobesilate, maleic acid and any compatible combination thereof);alpha-adrenergic receptor agonists (e.g., clonidine, amphetamine, doxtroamphetamine, apraclonidine, dipivefrine, alpha-methyldopa, oxymetazoline, oxymetazoline hydrochloride, methoxamine, metaraminol, medetomidine, dexmedetomidine, ethylnorepinephrine, guanfacine, guanabenz, phenylephrine, phenylephrine hydrochloride, ephedrine, epinine, epinephrine, ethylnorepinephrine, levarterenol, lofexidine, norepinephrine, norphenylephrine, norephredine, phenylpropanolamine, pemoline, propylhexadrine, pseudoephedrine, methamphetamine, alpha-methylnorepinephrine, methylphenidate, mephentermine, midodrine, mivazerol, moxonidine, desglymidodrine, tetrahydrozoline, tetrahydrozoline hydrochloride, cirazolin, amidephrine, brimonidine, brimonidine tartrate, naphazoline, isoproterenol, xylazine, xylometazoline and / or tizanidine);Chemicals and botanical extracts with vasoconstrictive properties, including, but not limited to, corticosteroids, ephedrine, pseudoephedrine, caffeine and / or escin; extracts of ephedra, phedra sinica, hamamelis virginiana, hydrastis canadensis, lycopus virginicus, aspidosperma quebracho, cytisus scoparius, raphanus sativus linn (radish leaf extracts), horse chestnut, etc.;

[0072] In a preferred embodiment, the cutaneous active agents are selected from ceramides, ceramide precursors, free fatty acids, linoleic / oleic acids, cholesterol, cholesterol sulfate, beta-glucan, carob seed extract, Eperua falcata extract, amino acids, niacinamide and its derivatives, hyaluronic acid and its derivatives, glycerin, allantoin, squalane, omega fatty acids, or combinations thereof.

[0073] Additional non-limiting examples include chemicals or botanical extracts with anti-inflammatory properties (e.g., corticosteroids (for short-term use)), non-steroidal anti-inflammatory drugs, linoleic acid, linolenic acid, bisabolol, glycyrrhetinic acid, glycerin, plant extracts with anti-inflammatory properties (e.g., tea extracts, chamomile extracts), anti-inflammatory interleukins (e.g., II-IRA); isoprenylcysteine ​​analogs (i.e., N-acetyl-S-farnesyl-L-cysteine), aromatic aldehydes with anti-inflammatory properties (e.g., 4-ethoxybenzaldehyde), etc., and any compatible combination thereof); chemicals or botanical extracts with antimicrobial properties (e.g., antibiotics including, without limitation, gentamicin, penicillins, cephalosporins, quinolones, ciprofloxacin and / or novobiocin); chemicals or botanical extracts with antifungal properties (e.g., ketoconazole, naphtifine hydrochloride, oxyconazole nitrate, sulconazole nitrate, urea, terbinafine hydrochloride, selenium sulfide, etc.); chemicals or botanical extracts with antidandruff properties; chemicals or botanical extracts with antiseborrheic properties; keratolytic agents or botanical extracts with keratolytic properties (i.e., alpha-hydroxy acids; beta-hydroxy acids, polyhydroxy acids, urea, salicylic acid, etc.); chemicals with astringent properties; serine protease inhibitors; saturated dicarboxylic acids; alpha-hydroxy acids (e.g., glycolic acid, lactic acid, malic acid, citric acid, tartaric acid, etc.); beta-hydroxy acids (e.g., camitine, 3-hydroxybutyric acid, 3-hydroxypropionic acid, 3-hydroxy-3-methylbutyric acid, salicylic acid, etc.).

[0074] Additional non-limiting examples of cutaneous active agents include retinoic acid, tretinoin, isotretinoin, adapalene, retinol and / or their derivatives; benzoyl peroxide; dapsone; kinetin (N6-furfuryladenine) and their derivatives (e.g., furfurylaminotetrahydropyranyladenine); niacinamide (nicotinamide), and their combinations.

[0075] Additional non-limiting examples of cutaneous active agents include metronidazole, sulfacetamide, sodium sulfacetamide, sulfur, tetracyclines, doxycycline, clindamycin, clindamycin phosphate, erythromycin and / or minocycline, azelaic acid, calcium dobesylate, caffeine, theobromine, theophylline and / or one of their derivatives (i.e., xanthines), vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E and vitamin K, creatine, camitine, and essential fatty acids such as linoleic acid and / or linolenic acid, zinc salts such as, by For example, zinc sulfate, zinc chloride, zinc glycinate, zinc gluconate, zinc histidine, zinc L-2-pyrrolidone-5-carboxylate (zinc PCA), a zinc salt of linoleic acid,a zinc salt of linolenic acid, a zinc salt of azelaic acid, zinc peptides, zinc oxide, copper salts including, but not limited to, copper sulfate, copper chloride, copper glycinate, copper gluconate, copper histidine, copper L-2-pyrrolidone-5-carboxylate (copper PCA), a copper salt of linoleic acid, a copper salt of linolenic acid, a copper salt of azelaic acid, copper peptides, ,

[0076] Non-limiting examples of cutaneous active agents include madecassoside, retinoic acid, benzoyl peroxide, sulfur, vitamin B6 (pyridoxine or chloride), selenium, salicorne, cinnamon extract mixtures, zinc gluconate, zinc pyrrolidonecarboxylate (or zinc pidolate), zinc lactate, zinc aspartate, zinc carboxylate, zinc salicylate, zinc cystate, pidoiferous copper as Cuivridone Solabia, the extracts of plants of Arnica montana, Cinchona succirubra, Eugenia caryophyllata, Humulus lupulus, Hypericum perforatum, Mentha piperita, Rosmarinus officinalis, Salvia officinalis, Thymus officinalis and extracted from Thymus (Spiraea ulmaria), and their mixtures.

[0077] In various embodiments, one or more cutaneous active agents may be selected from adenosine, 2-[4-(2-hydroxyethyl)piperazin-l-yl]ethanesulfonic acid (HEPES), hyaluronic acid, lanolin, citric acid, malic acid, lactic acid, tartaric acid, salicylic acid, vitamin C, a vitamin, a retinoid, retinal, retinoic acid, a carotenoid, an amino acid, a protein, an enzyme, and a coenzyme. In some cases, the active ingredient is adenosine.

[0078] In one embodiment, the composition includes one or more skin-active agents selected from humectants and moisturizing ingredients, a depigmenting agent or an agent that treats oily skin.

[0079] Humectants and moisturizing ingredients may include, in particular, glycerol and its derivatives, urea and its derivatives, in particular Hydrovance marketed by National Starch, lactic acid, hyaluronic acid, AHA, BHA, sodium pidolate, xylitol, serine, sodium lactate, ectoine and its derivatives, chitosan and its derivatives, collagen, plankton, an extract of Imperata cylindra sold under the name Moist 24 by Sederma, acrylic acid homopolymers such as Lipidure-HM from NOF Corporation, beta-glucan and in particular sodium carboxymethyl beta-glucan from Mibelle-AG-Biochemistry, a blend of passionflower, apricot, corn and rice bran oils sold by Nestlé under the name NutraLipids, a C-glycoside derivative,in particular C-13-D-xylopyranoside-2-hydroxypropane in the form of a 30% by weight solution of active ingredient in a water / propylene glycol mixture (60 / 40% by weight) such as the product manufactured by Chimex under the trade name "Mexoryl SBB", a rosehip oil marketed by Nestle, a zinc-enriched extract of Porphyridium cruentum microalgae marketed under the name Vincience Algualane Zinc, marine collagen and chondroitin sulfate spheres (Atelocollagen) sold by Engelhard Lyon under the name Marine Filling Spheres, hyaluronic acid spheres such as those marketed by Engelhard Lyon, and arginine.

[0080] Depigmenting agents include vitamin C and its derivatives, and in particular vitamin CG, CP and 3-O ethyl vitamin C, alpha and beta-arbutin, ferulic acid, lucinol and its derivatives, kojic acid, resorcinol and its derivatives, acid tranexamic acid and its derivatives, gentisic acid, homogentisic acid, gentisate or methyl homogentisate, dioic acid, D-panthetin calcium sulfonate, lipoic acid, ellagic acid, vitamin B3, linoleic acid and its derivatives, ceramides and their homologues, plant derivatives such as chamomile, bearberry, the aloe family (vera, ferox, bardensis), blackberry, skullcap, a kiwi fruit (Actinidia chinensis) marketed by Gattefosse, a Paeonia suffruticosa root extract, such as that sold by Ichimaru Pharcos under the name Liquid Botanpi Be, a brown sugar extract (Saccharum officinarum) such as the molasses extract marketed by Taiyo Kagaku under the name Liquid Molasses, without this list being exhaustive.Specific depigmenting agents include vitamin C and its derivatives, notably vitamin CG, CP and 3-0 ethyl vitamin C, alpha and beta arbutin, ferulic acid, kojic acid, resorcinol and its derivatives, panthetin D calcium sulfonate, lipoic acid, ellagic acid, vitamin B3, a kiwi fruit (Actinidiadia chinensis) marketed by Gattefosse, and a Paeonia suffruticosa root extract, such as that sold by Ichimaru Pharcos under the name Botanpi Liquid B.

[0081] Useful cutaneous active agents include adenosine and its derivatives and retinol and its derivatives, such as retinyl palmitate, ascorbic acid and its derivatives such as magnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and its derivatives such as tocopheryl acetate, nicotinic acid and its precursors such as nicotinamide; ubiquinone; glutathione and its precursors such as L-2-oxothiazolidine-4-carboxylic acid, C-glycoside compounds and their derivatives as described in particular in EP-1345919, in particular C-beta-D-xylopyranoside-2-hydroxy-propane as described in particular in EP-1345919, plant extracts including sea fennel and olive leaf extracts, and their plants and hydrolysates such as rice protein hydrolysates or soy proteins;extracts of algae, and in particular kelp, bacterial extracts, sapogenins such as diogenin, and extracts of Dioscorea plants, in particular wild yam, including: α-hydroxy acids, 3-hydroxy acids, such as salicylic acid and n-octanoyl-5-salicylic oligopeptides and pseudodipeptides and their acyl derivatives, in particular {2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-methyl-}acetic acid and lipopeptides marketed by the company under the trade names SEDERMA Matrixyl 500 and Matrixyl 3000; lycopene, manganese salts and magnesium salts, in particular gluconates, and mixtures thereof.

[0082] Adenosine derivatives include in particular non-phosphate adenosine derivatives, such as in particular, 2'-deoxyadenosine, 2',3'-adenosine isopropylidene; toyocamycin, 1-methyladenosine, N-6-methyladenosine; Adenosine N-oxide, 6-methylmercaptopurine riboside and 6-chloropurine riboside.

[0083] Other derivatives include adenosine receptor agonists such as phenylisopropyl adenosine (“PIA”), 1-methylisoguanosine, N6-cyclohexyladenosine (CHA), N6-cyclopentyladenosine (CPA), 2-chloro-N6-cyclopentyladenosine, 2-chloroadenosine, N6-phenyladenosine, 2-phenylaminoadenosine, MECA, N6-phenethyladenosine, 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS-21680), N-ethylcarboxamidoadenosine (NECA), 5'(N-cyclopropyl)-carboxamidoadenosine, DPMA (PD 129.944) and the metrifudil.

[0084] In one embodiment, the composition comprises an active ingredient that treats oily skin. These active ingredients may be sebum-regulating or anti-seborrheic agents capable of regulating the activity of the sebaceous glands. These include: retinoic acid, benzoyl peroxide, sulfur, vitamin B6 (pyridoxine chloride), selenium, glasswort—mixtures of cinnamon extract, tea, and octanoylglycine such as Seppic's Sepicontrol A5 TEA—the cinnamon, sarcosine, and octanoylglycine mixture marketed by Seppic under the trade name Sepicontrol A5—zinc salts such as zinc gluconate, zinc pyrrolidone carboxylate (or zinc pidolate), zinc lactate, zinc aspartate, zinc carboxylate, zinc salicylate, zinc cysteate, and derivatives, particularly copper and copper pidolate, such as Cuivridone Solabia—plant extracts of Arnica montana, Cinchona succirubra, Eugenia caryophyllata, Humulus lupulus, and Hypericum perforatum.Extracts of Mentha piperita, Rosmarinus officinalis, Salvia officinalis, and Thymus vulgaris, all marketed, for example, by Maruzen; extracts of meadowsweet (Spiraea ulmaria), such as those sold under the name Sebonormine by Silab; extracts of the seaweed Laminaria saccharina, such as those sold under the name Phlorogine by Biotechmarine; extracts of mixed burnet roots (Sanguisorba officinalis / Poterium officinale), ginger rhizomes (Zingiber officinalis), and cinnamon bark (Cinnamomum cassia), such as those sold under the name Sebustop by Solabia; extracts of flaxseed, such as those sold under the name Linumine by Lucas Meyer; and extracts of Phellodendron, such as those sold under the name Phellodendron extract BG by Maruzen or Oubaku Liquid B by Ichimaru. Pharcos—argan oil blend extract,Extracts of Serenoa serrulata (saw palmetto) and sesame seeds, such as those sold under the name Regu SEB by Pentapharm; mixtures of willowherb, Terminalia chebula, nasturtium, and bioavailable zinc extracts (microalgae), such as that sold under the name Seborilys Green Tech; extracts of Pygeum afrianum, such as that sold under the name Pygeum afrianum sterolic lipid extract by Euromed; extracts of Serenoa serrulata, such as those sold under the name Viapure Sabal by Actives International, and those sold by Euromed—extracts of mixtures of plantain, Berberis aquifolium and sodium salicylate such as that sold under the name Seboclear Rahn—clove extract such as that sold under the name Clove extract powder by Maruzen—argan oil such as that sold under the name Lipofructyl by Laboratoires Sérobiologiques—lactic protein filtrates, such as that sold under the name Normaseb by Sederma—kelp extracts, such as that sold under the name Laminarghane by Biotechmarine—oligosaccharides from the seaweed Laminaria digitata, such as that sold under the name Phycosaccharide AC by Codif—sugar cane extracts such as that sold under the name Policosanol by Sabinsa, sulfonated shale oil,such as that sold under the name Ichthyol Pale by Ichthyol—meadowsweet (Spiraea ulmaria) extracts such as that sold under the name Cytobiol Ulmaire by Libiol—sebacic acid, notably sold as a sodium polyacrylate gel under the name Sebosoft by Sederma—glucomannans extracted from konjac tuber and modified with alkylsulfonate chains such as that sold under the name Biopol Beta by Arch Chemical—Sophora angustifolia extracts, such as that sold under the name Sophora powder or Sophora extract by Bioland—Cinchona succirubra bark extracts such as that sold under the name Red Bark HS by Alban Muller—Quillaja saponaria extracts such as that sold under the name Panama wood HS by Alban Muller—glycine grafted onto an undecylenic chain, such as that sold under the name Lipacide UG OR by SEPPIC - the mixture of oleanolic acid and nordihydroguaiaretic acid,such as that sold as a gel under the name AC. Net by Sederma; phthalimidoperoxyhexanoic acid; tri(C12-C13) citrate sold under the name COSMACOL ECI by Sasol; trialkyl (C14-C15) citrate sold under the name COSMACOL ECL by Sasol; hydroxydecanoic acid, including mixtures of hydroxydecanoic acid, sebacic acid, and 1,10-decanediol such as that sold under the name Acnacidol BG by Vincience, and mixtures thereof.

[0085] Other cutaneous active agents useful here include those selected from N-acetyl D-glucosamine, panthenol (e.g., DL panthenol available from Alps Pharmaceutical Inc.), tocopheryl nicotinate, benzoyl peroxide, 3-hydroxybenzoic acid, flavonoids (e.g., flavanone, chalcone), famesol, phytantriol, glycolic acid, lactic acid, 4-hydroxybenzoic acid, acetylsalicylic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters (e.g., retinyl propionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopherol and its esters (e.g., tocopheryl acetate: DL-α-tocopheryl acetate available from Eisai), acid azelaic acid, arachidonic acid, tetracycline, ibuprofen, naproxen, ketoprofen, hydrocortisone, acetominophene, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neomycin sulfate, theophylline, and mixtures thereof.

[0086] In various embodiments, the total amount of cutaneous active agents in the pharmaceutical or cosmetic composition of the disclosure, other than one or more bioactive nut peptides, may be included in an amount of more than zero to about 9% by weight, more than zero to about 8% by weight, more than zero to about 7% by weight, more than zero to about 6% by weight, more than zero to about 5% by weight, more than zero to about 4% by weight, more than zero to about 3% by weight, more than zero to about 2% by weight;from about 10 ppm to about 10% by weight (100,000 ppm), from about 10 ppm to about 5% by weight (50,000 ppm), from about 10 ppm to about 2.5% by weight (25,000 ppm), from about 10 ppm to about 1% by weight (10,000 ppm), from about 10 ppm to about 0.5% by weight (5,000 ppm), from about 10 ppm to about 0.3% by weight (3,000 ppm), from about 10 ppm to about 0.2% by weight (2,000 ppm), from about 10 ppm to about 0.1% by weight (1,000 ppm), from about 10 ppm to 500 ppm; from about 0.1 to about 10% by weight, from about 0.1 to about 5% by weight, from about 0.1 to about 2.5% by weight, from about 0.1 to about 1% by weight, from about 0.1 to about 0.5% by weight; from about 1 to about 10% by weight, from about 1 to about 8% by weight, from about 1 to about 6% by weight, from about 1 to about 5% by weight, from about 1 to about 4% by weight, from about 1 to about 3% by weight;from about 2 to about 10% by weight, from about 2 to about 8% by weight, from about 2 to about 6% by weight, from about 2 to about 5% by weight, from about 2 to about 4% by weight; from about 3 to about 10% by weight, from about 3 to about 8% by weight, from about 3 to about 6% by weight, from about 3 to about 5% by weight; from about 4 to about 10% by weight, from about 4 to about 8% by weight or from about 4 to about 6% by weight, relative to the total weight of the pharmaceutical or cosmetic composition. Emollients

[0087] One or more emollients may also optionally be included in the pharmaceutical or cosmetic composition described herein. An emollient generally refers to an ingredient that can help maintain a soft, smooth, and supple appearance of the skin. Emollients usually remain on the skin's surface or in the stratum corneum and act as a moisturizer or lubricant and reduce destratification. Non-limiting examples of emollients include acetylarginine, acetylated lanolin, seaweed extract, and polyethylene glycol-6 esters derived from oil. apricot kernel, polyethylene glycol-11 esters from avocado oil, bis-polyethylene glycol-4 dimethicone, butoxyethyl stearate, glycol esters, alkyl glycol esters, cetyl laurate, polyethylene glycol-10 esters from coco, alkyl tartrates, diethyl sebacate, dihydrocholesteryl butyrate, dimethiconol, dimyristyle tartrate, 5-lauroyl glutamate distearate, etilavokadate, ethylhexyl myristate, glyceryl isostearate, glyceryl oleate, geksildetsilstearate, geksilizostearate, hydrogenated palm glycerides, hydrogenated soybean glycerides, hydrogenated fat glycerides isostearylneopentanoate, isostearyl palmitate, isostearylsilizononanoate, laureth-2 acetate, lauryl polyglyceryl-6 cetearyl glycol ether, methylglyutset-20 benzoate, mineral oil, palm oil, coconut oil, miret-3 palmitate, octyldecanol, octyldodecanol,Odontella aurita oil, 2-oleamido-l,3-octadecanediol, commercial PAL glycerides, avocado polyethylene glycol glycerides, castor oil polyethylene glycol, polyethylene glycol-2 / dodecyl glycol copolymer, shea butter polyethylene glycol glycerides, phytol, raffinose, stearyl citrate, sunflower seed oil glycerides, non-ointment, small tocopherol glucoside. Suspenders

[0088] The pharmaceutical or cosmetic composition of the present invention may optionally include one or more suspending agents, preferably in a concentration effective for suspending the water-insoluble material in a dispersed form within the compositions or for modifying the viscosity of the composition. These concentrations will vary. However, in some embodiments, the pharmaceutical and cosmetic composition includes from about 0.1% to about 10%, more preferably from about 0.25% to about 5.0% of one or more suspending agents, by weight of the total composition. Non-limiting examples include vinyl polymers, such as cross-linked acrylic acid polymers, known as carbomers, cellulose derivatives, and modified cellulose polymers such as methylcellulose, ethylcellulose, nitrocellulose, carboxymethylcellulose, crystalline cellulose, and cellulose powder.polyvinylpyrrolidone, polyvinyl alcohol, guar gum, hydroxypropyl guar gum, gum arabic, galactan, locust bean gum, pectin, agar, starch (rice, corn, potato, wheat), algal colloids (algal extract), microbiological polymers such as dextran, succinoglycan, pullulan, starch-based polymers such as carboxymethyl starch, methyl starch, alginic acid polymers such as sodium alginate, propylene glycol esters of alginic acid, acrylate polymers such as sodium polyacrylate, polyacrylate, polyacrylamide, polyethyleneimine and materials, water-soluble inorganic materials such as bentonite, aluminum magnesium silicate, laponite, hectorite, and anhydrous silicic acid.

[0089] Other optional suspending agents include crystalline suspending agents that can be resolved into acyl derivatives, long-chain amine oxides, long-chain acyl derivatives, and mixtures thereof. Said preferred suspending agents include fatty acid ethylene glycol esters, fatty acid alkanolamides, long-chain fatty acid esters (e.g., stearyl stearate, cetyl palmitate, etc.); long-chain esters of long-chain alkanolamides (e.g., stearamide distearate diethanolamide, stearamide stearate monoethanolamide); and glyceryl esters (e.g., glyceryl distearate, trihydroxystearine, tribhengen).Other suitable suspending agents include primary amines containing a fatty alkyl fragment with at least about 16 carbon atoms, examples of which include palmitamine or stearamine, and secondary amines containing two fatty alkyl fragments, each with at least about 12 carbon atoms, examples of which include dipalmitoylamine or di(hydrogenated fat)amine. Other suitable suspending agents include phthalic acid diamide (hydrogenated fat) and a crosslinked maleic anhydride / methyl vinyl ether copolymer. Emulsifying agents

[0090] Non-limiting examples of emulsifying agents include condensation products of alkylene oxides with fatty acids (i.e. fatty acid alkylene oxide esters), condensation products of alkylene oxides with 2 moles of fatty acids (i.e. fatty acid alkylene oxide diesters), condensation products of alkylene oxides with fatty alcohols (i.e. fatty alcohol alkylene oxide esters), condensation products of alkylene oxides with both fatty acids and fatty alcohols [i.e. where a portion of the alkylene polyoxide is esterified at one end with a fatty acid and esterified (i.e., via an ether bond) at the other end with a fatty alcohol].Non-limiting examples of nonionic surfactants derived from said alkylene oxide include ceteth-6, ceteth-10, ceteth-12, cetetareth-6, cetetareth-10, cetetareth-12, steareth-6, steareth-10, steareth-12, steareth-21, PEG-6 stearate, PEG-10 stearate, PEG-100 stearate, PEG-12 stearate, PEG-20 glyceryl stearate, PEG-80 glyceryl tallowate, PEG-10 glyceryl stearate, PEG-30 glyceryl cocoate, PEG-80 glyceryl cocoate, tallowate of PEG-200 glyceryl, PEG-8 dilaurate, PEG-10 distearate, and mixtures thereof. Other applicable nonionic surfactants include polyhydroxyamide fatty acid surfactants. A particularly preferred surfactant corresponding to the above structure is N-methylglucoside alkylamide. coco. The preferred surfactants among nonionic surfactants are those selected from the group consisting of steareth-21, ceteareth-20, ceteareth-12, sucrose cocoate, steareth-100, PEG-100 stearate, and mixtures thereof. Other nonionic surfactants suitable for use in this application include sugar esters and polyesters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters, C1-C30 fatty alcohols, alkoxylated C1-C30 ester derivatives, C1-C30 fatty alcohol fatty acids, alkoxylated C1-C30 fatty alcohol esters, polyglyceryl C1-C30 fatty acid esters, C1-C30 polyol esters, C1-C30 polyol esters, alkyl phosphates, polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl lactylates, and mixtures thereof.Non-limiting examples of these emulsifiers include: polyethylene glycol 20 sorbitan monolaurate (polysorbate 20), polyethylene glycol 5 soy sterol, steareth-20, ceteareth-20, PPG-2 methyl glucose ether distearate, ceteth-10, polysorbate 80, cetyl phosphate, cetyl phosphate, cetyl phosphate, cetyl phosphate, cetyl phosphate, polysorbate 60, glyceryl stearate, polyoxyethylene 20 sorbitan triolcat (polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ether sodium stearate, polyglyceryl-4 isostearate, hexyl laurate, PPG-2 methyl glucose ether distearate, PEG-100 and their PEG-100. Another group of useful nonionic surfactants here is a mixture of fatty acid esters based on a mixture of sorbitan or a fatty acid ester of sorbitol and a fatty acid ester of sucrose, where the fatty acid in each example is preferably C8-C24, more preferably C10-C20. Thickeners

[0091] Thickeners suitable for inclusion in pharmaceutical or cosmetic compositions are described here.Non-limiting examples include acrylamide copolymer, agarose, amylopectin, bentonite, calcium alginate, calcium carboxymethylcellulose, carbomer, carboxymethylchitin, cellulose gum, dextrin, gelatin, hydroxymethyl hydroxycellulose hydroxypropyl, hydroxyethyl hydroxypropyl hydroxypropyl, hydroxyethyl hydroxypropyl, hydroxyethyl hydroxypropyl, hydroxyethyl hydroxypropyl, hydroxyethyl hydroxypropyl, hydroxyethyl hydroxypropyl, hydroxypropyl; Magnesium alginate, methylcellulose, microcrystalline cellulose, pectin, various polyethylene glycols, polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, various isopropylene glycols, sodium acrylate copolymers, sodium carrageenan, xanthan gum and / or yeast beta-glucan, or mixtures thereof.

[0092] More generally, carboxylic acid polymers are useful thickeners. Carboxylic acid polymers are crosslinked compounds containing one or Several monomers derived from acrylic acid, substituted acrylic acids, and salts and esters of said acrylic acids and substituted acrylic acids, wherein the crosslinking agent contains two or more carbon-carbon double bonds and is derived from a polyhydric alcohol. Examples of commercially available carboxylic acid polymers useful here include carbomers, which are homopolymers of acrylic acid crosslinked with allyl ethers of sucrose or pentaerythritol. Carbomers are available in BF Goodrich's Carbopol® 900 series (e.g., Carbopol® 954). In addition, other suitable carboxylic acid-based polymeric agents include C10-30 alkyl acrylate copolymers with one or more monomers of acrylic acid, methacrylic acid, or esters of one of its short chains (i.e., a Cl-4 alcohol), the crosslinking agent being an allyl ether of sucrose or pentaerythritol.These copolymers are known as C10-C30 acrylate / alkyl acrylate crosslinked polymers and are commercially available under the names Carbopol® 1342, Carbopol® 1382, Pemulen TR-1 and Pemulen TR-2. Goodrich. Examples of preferred carboxylic acid polymer-based thickeners useful in this application include carbomer-selected thickeners, C10-C30 acrylate / alkyl acrylate crosslinked polymers, and mixtures thereof.

[0093] Furthermore, according to certain embodiments, the thickeners are selected from polysaccharides. Non-limiting examples of polysaccharide thickeners include cellulose, carboxymethyl hydroxyethyl cellulose, cellulose acetate propionate carboxylate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium methyl hydroxyethyl cellulose, and hydroxyethyl methyl hydroxyethyl cellulose. Alkyl-substituted celluloses are also useful. In these polymers, the hydroxy groups of the cellulosic polymer are hydroxylated (preferably hydroxyethylated or hydroxypropylated) to form hydroxylated cellulose, which is then further modified with a straight-chain or C10-30 branched alkyl group via an ether bond.Typically, these polymers are straight-chain or branched-chain esters of C10-30 alcohols and hydroxyalkyl celluloses. Examples of alkyl groups applicable in this application include groups selected from stearyl, isostearyl, lauryl, myristyle, cetyl, isocetyl, cocoyl (e.g., an alkyl group derived from coconut oil alcohols), palmityl, oleyl, linoleyl, retinoyl, behenyl, and mixtures thereof. A preferred alkylhydroxyalkyl cellulose ester is a material called cetyl hydroxyethyl cellulose, which is an alcohol ester. cetyl and hydroxyethyl cellulose, in accordance with the Perfume and Cosmetics and Perfume Association (CTFA). The stated material is sold under the trade name Natrosol® CS Plus by Aqualon Corporation (Wilmington, Delaware). Other examples can be found in the International Cosmetic Ingredient Dictionary and Handbook, the Cosmetic Bench Reference - Directory of Cosmetic Ingredients, offered by the United States Pharmacopeia (USP) and the National Formulary (NF), and other references to known cosmetic and pharmaceutical ingredients in the art. Other useful polysaccharides include scleroglucans, which are straight-chain (1-3) glucose units linked (1-6), where one in three glucose units is linked; a commercially available example is Clearogel™ CS 11 by Michel Mercier Products Inc. (Mountainside, New Jersey).

[0094] Other useful thickeners include those derived from natural sources. Non-limiting examples include acacia gum, agar-agar, algin, alginic acid, ammonium alginate, amylopectin, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextrin, gelatin, gellan gum, guar gum hydrochloride, gydrohydrochloride, hyaluronic acid, hydrated silicon dioxide, hydroxypropyl chitosan, hydroxypropyl gum, karaya gum, kelp, fruit tree resin, natto gum, potassium alginate, potassium carrageenan, propylene glycol alginate, sclerotium gum, sodium carboxymethyl dextran, dextran, sodium carrageenan, tragacanth gum, xanthan gum and / or mixtures thereof.

[0095] Furthermore, the compositions may optionally contain polyacrylamide polymers, in particular nonionic polyacrylamide polymers, including substituted branched or unbranched polymers. Other polyacrylamide polymers useful here include acrylamides and acrylic acid-substituted acrylamides multiblock copolymers and substituted acrylic acids. Antihistamines

[0096] Antihistamines, also called histamine antagonists, are substances that inhibit the action of histamine by blocking its binding to histamine receptors or by inhibiting the enzymatic activity of histidine decarboxylase, which catalyzes the conversion of histidine to histamine, and similar agents. Non-limiting examples of antihistamines include acrivastine, azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine, chlorodiphenhydramine, cimetidine, clemastine, cyproheptadine, desloratine, and dimendenine. dimendenine EXAMPLES

[0097] Various changes can be made to the compositions and processes described above without departing from the scope of the invention. Accordingly, it is intended that any disclosure contained in the above description and in the examples given below should be interpreted in an illustrative and not limiting sense. Example 1 Differential gene expression

[0098] Peptides I, II and III were studied for their ability to influence gene expression at a concentration of 100 pM to 500 pM for cells and 250 pM for reconstructed human epidermis (EHR).

[0099] Normal adult human epidermal keratinocytes

[0100] Normal adult human epidermal keratinocytes (lot 80819221, passage 3, ATCC) cells were expanded and seeded in a 6-well plate at a density of 300,000 cells / well. The cells were cultured in basal dermal cell medium (ATCC PCS-200-030) supplemented with keratinocyte growth kit (ATCC PCS-200-040). The cells were fixed overnight, and the culture medium was aspirated and replaced with medium containing either 100 pM or 500 pM of peptide I, peptide II, or peptide III. The cells were cultured for 4 days with treatment and regeneration of the treatment medium every two days, except on weekends. After the 7-day incubation period, the cells were trypsinized, and the cell pellet was flash-frozen using liquid nitrogen. The cells were then subjected to T-RNA sequencing.The relative log2 change for each treatment group compared to untreated control samples for differentially expressed genes (DEGs) related to the skin barrier was analyzed. The relative change was plotted using a heat map to show the upregulation or downregulation of these genes. Microsoft Excel and GraphPad Prism were used for further data analysis and presentation. The results are shown on the heat map in [Fig. 1]. The data... show that peptide II and peptide III provide a powerful benefit to the skin barrier at the cellular level at both concentrations tested, while peptide I showed an influence at the highest concentration. Reconstructed human epidermis

[0101] Reconstructed human epidermis (RHE) (EPISKIN / S / 13, Episkin) was received and samples were prepared for use. Upon arrival, the inserts containing the RHE were removed from the multiplate and placed in a 12-well plate containing the preservation medium. The untreated control tissues were placed in standard preservation medium; the treatment groups were placed in preservation medium containing 250 µM of peptide I, II, or III in combination. The medium was aspirated and replaced every two days, except on weekends. The RHE was cultured at the air-liquid interface at 37 °C, 5% CO2, and saturated humidity for 7 days. Following culture, the samples were flash-frozen in liquid nitrogen and sent for RNA sequencing.The relative log2 change for each treatment group compared to untreated control samples for differentially expressed genes (DEGs) related to the skin barrier was analyzed. The relative change was plotted using a heat map to show the upregulation or downregulation of these genes. Microsoft Excel and GraphPad Prism were used for further data analysis and presentation, shown on the heat map in [Fig. 2]. The data show that a combination of the three peptides provides enhanced skin barrier function for EHR. Example 2 Facial treatment

[0102] An example of a facial treatment containing about 0.01 to about 1% by weight of peptide I, peptide II, peptide III, or combinations thereof, is shown below.

[0103] [Tables] Table 6 INGREDIENTS % by weight PEPTIDE I, II, III OR THEIR COMBINATIONS 0.01 - 10 METHYLPARABEN 0.3 2-PHENOXYETHANOL 0.5 SODIUM POLYACRYLATE 0.8 XANTHAN GUM 0.2 WATER / AQUA 98.2

[0104] The preceding description illustrates and describes the disclosure. Furthermore, the disclosure shows and describes only the preferred embodiments. However, as mentioned above, it should be understood that it is suitable for use in several other combinations, modifications, and environments, and that it is suitable for changes or modifications in the scope of the inventive concepts as expressed herein, in accordance with the teachings above and / or the skills or knowledge of the relevant art. The embodiments described herein are further intended to explain the best known means to the applicant and to enable others skilled in the art to use the disclosure in such or other embodiments, and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein.Similarly, the annexed claims are to be interpreted as including variant embodiments.

[0105] As used herein, the terms "comprising", "having" and "including" are used in their broad and non-limiting sense.

[0106] The terms "a," "an," "the," and "the" are understood to encompass both the plural and the singular. Thus, the phrase "one of their mixtures" also refers to "their mixtures." Throughout the disclosure, the phrase "one of their mixtures" is used, following a list of items, as shown in the following example where the letters A through F represent the items: "one or more items selected from the group consisting of A, B, C, D, E, F, and one of their mixtures." The phrase "one of their mixtures" does not require that the mixture include all of the items A, B, C, D, E, and F (although all of the items A, B, C, D, E, and F may be included). Rather, it indicates that a mixture of two or more of A, B, C, D, E, and F may be included. In other words, it is equivalent to the formulation "one or more elements chosen from the group consisting of A, B, C, D, E, F, and a mixture of two or more of A, B, C, D, E and F".

[0107] Similarly, the expression "one of their / its salts" also refers to "their / its salts". Thus, when the disclosure refers to "an item selected from the group consisting of A, B, C, D, E, F, one of their salts, and one of their mixtures", it indicates that one or more of A, B, C, D and F may be included, one or more of a salt of A, a salt of B, a salt of C, a salt of D, a salt of E and a salt of F may be included, or a mixture of any two of A, B, C, D, E, F, a salt of A, a salt of B, a salt of C, a salt of D, a salt of E and a salt of F may be included.

[0108] The salts referred to throughout the disclosure may include salts having a counterion such as an alkali metal counterion, an alkali- metal counterion earthy or ammonium. This list of counterions, however, is not exhaustive. The appropriate counterions for the components described here are known in art.

[0109] The expression "one or more" means "at least one" and therefore includes individual components as well as mixtures / combinations.

[0110] The term “plurality” means “more than one” or “two or more”.

[0111] Except in operational examples, or unless otherwise indicated, all numbers expressing quantities of ingredients and / or reaction conditions can be modified in all cases by the term "approximately", meaning to within + / - 5% of the number indicated.

[0112] All percentages, parts and ratios herein are based on the total weight of the compositions of the present invention, unless otherwise indicated.

[0113] Some of the various identified component categories may overlap. In such cases where an overlap may exist and the composition includes both components (or the composition includes more than two overlapping components), an overlapping compound does not represent more than one component. For example, some compounds may be considered both an emollient and a nonionic surfactant. If a particular composition includes both an emollient and a nonionic surfactant, a single compound will serve only as an emollient or only as a nonionic surfactant (the single compound does not simultaneously serve as both an emollient and a nonionic surfactant).

[0114] As used herein, all provided ranges are intended to include each specific range within the given ranges, as well as each combination of intermediate subranges. Thus, a range of 1 to 5 specifically includes 1, 2, 3, 4, and 5, as well as subranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, 1 to 4, etc. All ranges and values ​​disclosed herein are inclusive and combinable. For example, any value or point described herein that falls within a range described herein can serve as a minimum or maximum value for inferring a subrange, etc.

[0115] The expression "substantially free" or "essentially free" as used here means that less than about 2% by weight of a specific material is added to a composition, relative to the total weight of the compositions. However, the compositions may include less than about 1% by weight, less than about 0.5% by weight, less than about 0.1% by weight, or none at all of the specified material.

[0116] All components presented positively in this disclosure may be excluded negatively from the claims, for example, a claimed composition may be "free", "substantially free" (or "substantially free") of one or more components that are presented positively in this disclosure.

Claims

Demands

1. Bioactive walnut peptides, or a composition comprising at least one bioactive walnut peptide, for its use in improving skin barrier function or improving re-epithelialization or improving skin wound healing.

2. Peptide or composition for its use according to claim 1, wherein said wound results from damage to the skin tissue by means of a chemical, a laser or a physical force.

3. Peptide or composition for its use according to claim 2, wherein the skin tissue is damaged by means of an ablative laser procedure, a non-ablative laser procedure, a microneedling procedure, a cryotherapy procedure, a radiofrequency microneedling procedure, dermabrasion, chemical peel, exfoliant or mechanical device.

4. Peptide or composition for its use according to any of the preceding claims, in which the skin is inflamed or suffers from an inflammatory condition.

5. Peptide or composition for its use according to claim 4, wherein the inflammatory condition is selected from atopic dermatitis, psoriasis or one of their combinations.

6. Peptide or composition for its use according to claim 1, for the treatment of a skin condition, disease or disorder selected from psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, eczema, spongiosis, edema, hereditary ichthyosis, senile xerosis, palmar hyperkeratosis, plantar hyperkeratosis, cuts, bruises, pore size, skin cancer, wound healing or re-epithelialization disorders, keloids, hypertrophic scars, cellulite, orange peel skin, elastosis, actinic elastosis, keratosis, rosacea, telangiectasia, couperose, or combinations thereof.

7. Peptide or composition for its use according to any of the preceding claims, wherein one or more nut peptides are combined with one or more additional skin-active agents.

8. Peptide or composition for its use according to claim 7, wherein one or more additional cutaneous active agents are chosen from among anti-atrophy agents, antioxidants, depigmenting agents, or combinations thereof.

9. Peptide or composition for its use according to any of the preceding claims, wherein the bioactive nut peptide has a molecular weight of less than 5,000 Da, preferably less than 2,000 Da, more preferably less than 1,000 Da.

10. Peptide or composition for its use according to any one of the preceding claims, wherein the bioactive nut peptide has 2 to 20 amino acid residues, preferably 3 to 15 amino acid residues, more preferably 3 to about 10 amino acid residues.

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