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A copy of the license can be obtained by writing to: It covers the rights and obligations of the users and contributors to this document. Urinary Catheter with Infections Sub Group. Ongoing efficacy of the catheter care bundle in minimising line. Robert Wood Johnson University Hospital. Proteases are involved in a wide variety of biological processes.
Disruption of the balance between proteases and protease inhibitors is often associated with pathologic tissue destruction. Various studies have focused on the role of proteases in tissue injury, and it is thought that the balance between proteinases and proteinase inhibitors is a major determinant in maintaining tissue integrity.
Serine proteinases from inflammatory cells, including neutrophils, are implicated in various inflammatory disorders, such as pulmonary emphysema, arthritis, atopic dermatitis and psoriasis.
These and other inflammatory conditions are often associated with dysregulated levels of cytokines. Proteases also degrade the vascular basement membrane and participate in the remodeling of the extracellular matrix to facilitate cell migration and invasion to promote tumor angiogenesis. Proteases release angiogenic growth factors bound to the extracellular matrix and to generate chemotactically active fragments derived from extracellular matrix components, which in turn exert chemotactic and mitogenic, modulatory activates on endothelial cells, smooth muscle cells and fibroblasts to participate in angiogenic processes.
Risks associated with current cytokine blocking agents include serious infections, anaphylaxis, and lupus-like syndrome. In addition, there is observed loss of clinical benefit after the drugs are stopped, and a small proportion of patients develop antibodies to the biological agents, which is likely to limit their efficacy with repeated use. Synthetic and natural protease inhibitors have been shown to inhibit tumor promotion in vivo and in vitro.
Previous research investigations have indicated that certain protease inhibitors belonging to a family of structurally-related proteins classified as serine protease inhibitors or SERPINS, are known to inhibit several proteases including trypsin, cathepsin G, thrombin, tissue kallikrein, as well as neutrophil elastase.
Systemic delivery of purified protease inhibitors reduces joint inflammation and cartilage and bone destruction as well. Topical administration of protease inhibitors finds use in such conditions as atopic dermatitis, a common form of inflammation of the skin, which may be localized to a few patches or involve large portions of the body. The depigmenting activity of protease inhibitors and their capability to prevent ultraviolet-induced pigmentation have been demonstrated both in vitro and in vivo.
Also, protease inhibitors have been found to help wound healing http: Secretory leukocyte protease inhibitor was demonstrated to reverse the tissue destruction and speed the wound healing process when applied topically.
In addition, serine protease inhibitors can also help to reduce pain in lupus erythematosus patients See U. Naturally occurring protease inhibitors can be found in a variety of foods such as cereal grains oats, barley, and maize , Brussels sprouts, onion, beetroot, wheat, finger millet, and peanuts.
One source of interest is the soybean. The average level in soybeans is around 1. These low levels make it impractical to isolate the natural protease inhibitor for clinical applications.
Thus, there is a need for a method to produce large quantities of protease inhibitors that have desired characteristics of protein therapeutics, and for compositions that effectively deliver the protease inhibitor in a usable form.
The compositions and methods according to the invention fulfill some of the above needs and in particular offer an advantage in providing protease inhibitors that specifically target the activity of cytokines involved in pathologic and non-pathologic processes.
In one embodiment, the invention provides for a personal care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In other embodiments, the modified variant BBPI of the invention comprises a combination of amino acid substitutions chosen from the following combinations: In another embodiment, the invention provides for a personal care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In some embodiments, the modified variant BBPI comprised in the personal care composition of the invention, has greater trypsin inhibitory activity and production yield than the corresponding unmodified precursor variant inhibitor of said BBPI.
In other embodiments, the invention provides for a personal care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In some embodiments, the personal care composition is a skin care composition selected from the group consisting of skin creams, lotions, sprays, emulsions, colloidal suspensions, foams, aerosols, liquids, gels, sera, and solids.
In other embodiments, the skin care composition is chosen from moisturizing body washes, body washes, antimicrobial cleansers, skin protective creams, body lotions, facial creams, moisturizing creams, facial cleansing emulsions, facial gels, facial sera, surfactant-based facial cleansers, facial exfoliating gels, anti-acne treatments, facial toners, exfoliating creams, facial masks, after shave balms, pre-shave balms, tanning compositions, sunscreens, dipilatories, hair growth inhibitors and radioprotectives.
Typically, the radioprotective is a sunscreen that is chosen from non-water-resistant sunscreens, very water-resistant sunscreens, and water-in-silicone sunscreens. The skin care compositions may optionally include topically applied over-the-counter compositions, anti-fungal treatments, anti-acne treatments, skin protectants, sunscreens, deodorants, and antiperspirants. In some embodiments, the cosmetic compositions of the invention comprise at least one pigment.
Such cosmetic compositions include pressed powder formulations, and foundations. Cosmetic foundation compositions can be chosen from water-in-oil foundations, water-in-silicone foundations, oil-in-water foundations, anhydrous makeup sticks, and cream-to-powder foundations.
In other embodiments, the invention provides for a skin care composition for treating an angiogenic skin disorder. The hair care composition can be in the form of shampoos, conditioners, hair styling compositions, hair colorants, permanent wave formulations, creams, gels, mousses, sprays, emulsions, colloidal suspensions, liquids, foams, and solids.
In some embodiments, the hair care composition may also include a radiopretective. Examples of radioprotectives include sunscreens selected from non-water-resistant sunscreens, very water-resistant sunscreens, and water-in-silicone sunscreens. The hair care composition can be used to prevent hair growth. In other embodiments, the invention provides for a method for inhibiting hair growth by providing a personal composition that comprises a BBPI having an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: For example, the composition can be applied to inhibit facial hair, underarm hair, leg hair, torso hair, arm hair and head hair growth.
The angiogenic skin disorder can be chosen from psoriasis, scleroderma, venous ulcers, acne, rosacea, warts, eczema, hemangiomas and lymphangiogenesis. In other embodiments, the invention provides a personal care composition that comprises a Bowman Birk Protease Inhibitor BBPI having an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In some embodiments, the invention provides for a hair care composition comprising a Bowman Birk Protease Inhibitor BBPI having an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: The hair care composition can be used to promote hair growth.
In another embodiment, the invention provides for a method for promoting hair growth by providing a personal care composition that comprises a Bowman Birk Protease Inhibitor BBPI having an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: For example, the composition can be applied to promote the growth of facial hair, underarm hair, leg hair, torso hair, arm hair and head hair growth.
In some embodiments, the hair growth-promoting personal care composition can be used to treat a condition that involves hair loss. For example, conditions that involve hair loss and that can be treated using the hair care composition of the invention include inflammatory alopecias, pseudopelade, scleroderma, tick bites, lichen planus, psoriasis, lupus, seborrheic dermatitis, loose hair syndrome, hemochromatosis, androgenic alopecia, and alopecia greata.
In another embodiments, the invention the invention provides for a personal care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In some embodiments, the personal care composition is capable of promoting hair growth.
In other embodiments, the invention the invention provides for a hair care or a skin care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: The hair or skin care composition can be in the form of shampoos, conditioners, hair styling compositions, hair colorants, permanent wave formulations, creams, gels, mousses, sprays, emulsions, colloidal suspensions, liquids, foams, and solids.
In some embodiments, when the composition is a skin care composition, it can be in the form of moisturizing body washes, body washes, antimicrobial cleansers, skin protective creams, body lotions, facial creams, moisturizing creams, facial cleansing emulsions, facial gels, facial sera, surfactant-based facial cleansers, facial exfoliating gels, anti-acne treatments, facial toners, exfoliating creams, facial masks, after shave balms, pre-shave balms, tanning compositions, sunscreens, and radioprotectives.
The skin care composition can optionally further include topically applied over-the-counter compositions, anti-fungal treatments, anti-acne treatments, skin protectants, sunscreens, deodorants, and antiperspirants. The radioprotectives included in the skin or hair care composition are sunscreens that can be selected from non-water-resistant sunscreens, very water-resistant sunscreens, and water-in-silicone sunscreens.
In other embodiments, the invention provides for a cosmetic composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: Examples of cosmetic compositions include mascaras, eyeliners, pressed powder formulations, and foundations.
In other embodiments, the invention provides for a hair care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: Examples of radioprotectives that can be included in the hair care composition are sunscreens such as very water-resistant sunscreens, and water-in-silicone sunscreens.
The hair care composition is capable of promoting hair growth. In another embodiment, the invention provides for a method for promoting hair growth by providing a personal care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In some embodiments, the skin disorders that can be treated with the composition include psoriasis, scleroderma, and skin cancer.
The personal care composition can be used to promote hair growth. In another embodiment, the invention provides for a hair care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In some embodiments, the hair care composition is capable of promoting hair growth in a subject suffering from psoriasis.
In some embodiments, the hair care composition further comprises a radioprotective. Examples of radioprotectives include sunscreens such as non-water-resistant sunscreens, very water-resistant sunscreens, and water-in-silicone sunscreens. In some embodiments, the hair care composition is capable of promoting hair growth.
In another embodiment, the invention provides for a skin care composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: In some embodiments, the skin care composition can be in the form of skin creams, lotions, sprays, emulsions, colloidal suspensions, foams, aerosols, liquids, gels, sera, and solids.
Alternatively, the skin care composition is in the form of moisturizing body washes, body washes, antimicrobial cleansers, skin protective creams, body lotions, facial creams, moisturizing creams, facial cleansing emulsions, facial gels, facial sera, surfactant-based facial cleansers, facial exfoliating gels, anti-acne treatments, facial toners, exfoliating creams, facial masks, after shave balms, pre-shave balms, tanning compositions, skin lightening compositions, skin redness reduction compositions, sunscreens, depilatories, and radioprotectives.
Optionally, the skin care composition further comprises topically applied over-the-counter compositions, anti-fungal treatments, anti-acne treatments, skin protectants, sunscreens, deodorants, and antiperspirants.
In another embodiment, the invention provides for a cosmetic composition that comprises a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: The cosmetic composition is selected from mascaras, eyeliners, pressed powder formulations, and foundations. In some embodiments, the cosmetic composition is a cosmetic composition that comprises at least one pigment.
A cosmetic composition that comprises at least one pigment is a mascara, and the mascara is selected from non-waterproof mascaras, waterproof mascaras, volumizing mascaras, lengthening mascaras, curling mascaras, anhydrous waterproof mascaras, water-based mascaras, and eyelash or eyebrow treatments.
In other embodiments, the cosmetic composition is a cosmetic composition selected from a pressed powder formulation selected from loose powders, blushes, eye shadows, and bronzing powders. In yet other embodiments, the cosmetic composition is a foundation selected from water-in-oil foundations, water-in-silicone foundations, oil-in-water foundations, anhydrous makeup sticks, and cream-to-powder foundations. In another embodiment, the invention provides for a method for promoting hair growth of a subject suffering from psoriasis that includes the steps of providing a personal care composition comprising a modified variant Bowman Birk Protease Inhibitor BBPI that comprises an amino acid substitution at least at one amino acid position chosen from positions equivalent to 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55, and 65 of the variant BBI of SEQ ID NO: The fraction of active 2BBIck81 is indicated at the top of the bars.
The binding competition with the CK peptide is shown for comparison and the binding with the wild-type BBI is included as a negative control. Site-saturation libraries were constructed at all the numbered amino acids. The trypsin inhibitory loop and the VEGF binding peptide loop in italics are indicated and disulfide bonds are shown by the connecting lines. BCE activity ratios for each amino acid substitution made at position The ratios were averaged from quadruplicate cultures grown in microtiter plates in the absence white bars or presence black bars of 2-mercaptoethanol.
The activity ratios for sBBI are included for comparison as a positive control. BCE activity ratios for the amino acid substitutions made at position 50 A and position 37 B white bars. The ratios were averaged from quadruplicate cultures in the presence of 2-mercaptoethanol. The activity ratios for sBBI are included as a positive control for comparison black bars. The ratios were determined in quadruplicate in the presence of 2-mercaptoethanol individual data points shown.
In all scaffolds, the binding peptides replaced the chymotrypsin inhibitory loop. The numbered residues identify the amino acids that are substituted to generate the modified variant BBPIs of the invention. A The stimulation indices SI values for all 71 donors were averaged and are shown, with standard deviations in error bars. B The percent responders to each peptide in the 20 wt BBI peptide set are shown.
Unless otherwise indicated, the practice of the present invention involves conventional techniques commonly used in molecular biology, microbiology, protein purification, protein engineering, protein and DNA sequencing, and recombinant DNA fields, which are within the skill of the art.
Such techniques are known to those of skill in the art and are described in numerous standard texts and reference works. All patents, patent applications, articles and publications mentioned herein are hereby expressly incorporated herein by reference in their entirety.
Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Various scientific dictionaries that include the terms included herein are well known and available to those in the art.
Although any methods and materials similar or equivalent to those described herein find use in the practice or testing of the present invention, some preferred methods and materials are described. Accordingly, the terms defined immediately below are more fully described by reference to the Specification as a whole. It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described, as these may vary, depending upon the context they are used by those of skill in the art.
All patents, patent applications, and other publications, including all sequences disclosed within these references, referred to herein are expressly incorporated by reference, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. All documents cited are, in relevant part, incorporated herein by reference. However, the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
Numeric ranges are inclusive of the numbers defining the range. It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein.
Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein.
Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. The headings provided herein are not limitations of the various aspects or embodiments of the invention which can be had by reference to the Specification as a whole.
Accordingly, as indicated above, the terms defined immediately below are more fully defined by reference to the specification as a whole. In some embodiments, at least one amino acid is substituted to generate the modified protease inhibitor.
In some embodiments, the modified variant PI comprises an amino acid substitution at least at one position equivalent to positions 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, and 65 of SEQ ID NO: In other embodiments, the modified variant PI comprises a combination of substitutions as described herein.
In yet other embodiments, the modified variant PI comprises an insertion. The modified protease inhibitors herein encompass the substitution of any of the nineteen naturally occurring amino acids at any one of the amino acid residues in regions other than the reactive loops e.
In some embodiments, the scaffold is a variant scaffold, which has either the first protease inhibitory loop e. Bowman Birk Inhibitor The binding peptide does not need to be of the same length as the protease inhibitory loop sequence it is replacing in the scaffold, and it differs from the protease inhibitory loop sequence of the wild-type BBPI by at least two amino acids.
The binding peptide sequence is heterologous to that of the protease inhibitor. Binding peptides bind to target proteins. A formulation may include more than one type of modified variant BBPI i. The second protease inhibitory loop or chymotrypsin loop of a variant BBPI e. In some embodiments, the substitution involves the replacement of a naturally occurring residue or base. In some embodiments, two or more amino acids are substituted to generate a modified BBPI that comprises a combination of amino acid substitutions.
In some embodiments, combinations of substitutions are denoted by the amino acid position at which the substitution is made. For example, a combination denoted by means that three amino acids at positions 25, 50 and 52 are substituted. In other embodiments, the combination of substitutions is denoted by the amino acid position and the amino acid resulting from the substitution.
For example, a modified BBPI that comprises the combination of substitutions 13ILTA is a modified BBPI wherein the amino acid at position 13 has been substituted with an isolucine, the amino acid at position 25 has been substituted with a leucine, the amino acid at position 50 has been substituted with a threonine, and the amino acid at position 52 has been substituted with an alanine.
In some embodiments, the combination of substitutions is given in the context of the scaffold in which the substitutions are made. In some embodiments, the original and substituted amino acid are indicated e. In some embodiments, the modification involves the replacement of a naturally occurring residue or base.
In other embodiments, the modification comprises a combination of at least one amino acid substitution. In yet other embodiments, the modification comprises an insertion with or without the insertion being combined with at least one amino acid substitution. After aligning the conserved cysteine residues, allowing for insertions and deletions in order to maintain alignment i.
For example, in FIG. A comparison of these sequences shows that the invariant cysteine residues are conserved. While the primary sequence is the preferred structure for determining the position of equivalent amino acids in the BBPIs of the invention, equivalent residues may also be identified by determining homology at the level of tertiary structure for a protein BBPI protein.
Equivalent amino acid positions are defined as those for which the atomic coordinates of two or more of the main chain atoms of a particular amino acid residue of the protein having putative equivalent residues and the protein of interest N on N, CA on CA, C on C and O on O are within 0. Alignment is achieved after the best model has been oriented and positioned to give the maximum overlap of atomic coordinates of non-hydrogen protein atoms of the proteins analyzed.
The crystal structure of the Bowman Birk inhibitor from soybean has been determined Hwang et al. In some embodiments, the fusion polypeptides include a spacer peptide positioned between the secretory sequence and a secreted polypeptide.
In some embodiments, the fusion protein is processed by host cell enzymes e. In some embodiments, the activity is biological activity. In further embodiments, activity encompasses binding of proteins to receptors which results in measurable downstream effects e. The process includes both transcription and translation. The greater the production yield, the greater the level or amount of protease inhibitor that is produced.
It will be understood that, as a result of the degeneracy of the genetic code, a multitude of nucleotide sequences encoding a given protein may be produced. In some embodiments, the DNA construct comprises a sequence of interest e. In some embodiments, the sequence is operably linked to additional elements such as control elements e.
In some embodiments, the DNA construct comprises sequences homologous to the host cell chromosome. In other embodiments, the DNA construct comprises non-homologous sequences. Once the DNA construct is assembled in vitro it may be used to mutagenize a region of the host cell chromosome i. In some embodiments, a heterologous DNA sequence is a chimeric DNA sequence that is comprised of parts of different genes, including regulatory elements.
Vectors include cloning vectors, expression vectors, shuttle vectors, and plasmids. Many prokaryotic and eukaryotic expression vectors are commercially available. Selection of appropriate expression vectors is within the knowledge of those of skill in the art. Such methods for introduction include but are not limited to protoplast fusion, transfection, transformation, conjugation, and transduction See e.
The percent identity shared by polynucleotide or polypeptide sequences is determined by direct comparison of the sequence information between the molecules by aligning the sequences and determining the identity by methods known in the art. In some embodiments, the alignment includes the introduction of gaps in the sequences to be aligned. In addition, for sequences which contain either more or fewer nucleotides or amino acids than those of the candidate polynucleotide or polypeptide sequences, it is understood that the percentage of homology will be determined based on the number of homologous nucleotides or amino acids in relation to the total number of nucleotides or amino acids.
Thus, for example, homology of sequences shorter than those of the sequences identified herein will be determined using the number of nucleosites or amino acids in the shorter sequence. This homology is determined using standard techniques known in the art See e.
Analogous sequences are determined by known methods of sequence alignment. A commonly used alignment method is BLAST, although as indicated above and below, there are other methods that also find use in aligning sequences. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments. It can also plot a tree showing the clustering relationships used to create the alignment.
The adjustable parameters are set with the following values: The HSP S and HSP S2 parameters are dynamic values and are established by the program itself depending upon the composition of the particular sequence and composition of the particular database against which the sequence of interest is being searched.
However, the values may be adjusted to increase sensitivity. A suitable host cell may be a naturally occurring or wild-type host cell, or it may be an altered host cell. In one embodiment, the host cell is a Gram positive microorganism.
In some preferred embodiments, the term refers to cells in the genus Bacillus. It is recognized that the genus Bacillus continues to undergo taxonomical reorganization. Thus, it is intended that the genus include species that have been reclassified, including but not limited to such organisms as B. In preferred embodiments, it is operably linked to a DNA sequence encoding the fusion polypeptide.
Such linkage comprises positioning of the promoter with respect to the translation initiation codon of the DNA sequence encoding the fusion DNA sequence. In particularly preferred embodiments, the promoter sequence contains transcription and translation control sequences which mediate the expression of the fusion DNA sequence. For example, DNA encoding a secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
Operably linked DNA sequences are usually contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
Thus, for example, recombinant cells express genes that are not found in identical form within the native non-recombinant form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all as a result of deliberate human intervention. In some embodiments, the personal care composition is in the form of an emulsified vehicle, such as a nutrient cream or lotion, a stabilized gel or dispersioning system, such as skin softener, a nutrient emulsion, a nutrient cream, a massage cream, a treatment serum, a liposomal delivery system, a topical facial pack or mask, a surfactant-based cleansing system such as a shampoo or body wash, an aerosolized or sprayed dispersion or emulsion, a hair or skin conditioner, styling aid, or a pigmented product such as makeup in liquid, cream, solid, anhydrous or pencil form.
However, it is not intended that the present invention be limited to any particular form, as various forms find use in the present invention. In some embodiments, the modified variant BBPI is added to a personal care composition such as a hair care composition, a skin care composition, a nail care composition, a cosmetic composition, or any combinations thereof. In some particularly preferred embodiments, the present invention provides skin care compositions that improve skin tone.
In these embodiments, the improvement comprises lessening of wrinkles, smoothing skin texture, modifying skin coloration, and other desired cosmetic benefits. Thus, cosmetics are defined by their intended use, as articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering appearance.
These compositions provide non-therapeutic benefits and are not regulated as pharmaceuticals. However, in some situations, cosmetic compositions are incorporated into pharmaceutical compositions to provide cosmetic benefits e. Cosmetic compositions include makeup compositions as defined herein. Also, it is intended that the present invention encompass the use of cosmetics on animals other than humans. Thus, drugs are defined as articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, and articles other than food intended to affect the structure or any function of the body of man or other animals.
In some preferred embodiments, rinse-off compositions are formulated so as to deposit an effective amount of active s on the area treated. Cosmetic benefits include but are not limited to improvements in the condition of skin, hair, nails, and the oral cavity. In preferred embodiments, at least one cosmetic benefit is provided by the skin care, hair care, nail care, and makeup compositions of the present invention. UV radiation sunscreens and sunblocks. Oftentimes, the etiology of the angiogenic disease is unknown.
However, whether angiogenesis is an actual cause of a disease state or is simply a condition of the disease state is unimportant, but the inhibition of angiogenesis in treating or reversing the disease state or condition is an important aspect of the present invention.
Thus, it is not intended that the present invention be limited to any particular mechanisms of action. Examples of angiogenic skin disorders which are suitable for treatment utilizing compounds of the present invention include, but are not limited to psoriasis, acne, rosacea, warts, eczema, hemangiomas and lymphangiogenesis, Sturge-Weber syndrome, neurofibromatosis, tuberous sclerosis, chronic inflammatory disease, and arthritis.
Any skin disorder which has as a primary or secondary characterization, increased vascularization, is considered an angiogenic skin disorder herein. Rosacea may vary from very mild but persistent erythema to extensive hyperplasia of the sebaceous glands with deep-seated papules and pustules and be accompanied by telangiectasia at the affected erythematous sites. It is intended that the term encompass all of the various forms of the condition. Although it is not intended that the present invention be limited to any particular body area, psoriatic lesions typically occur on the elbows, knees, scalp and trunk.
Microscopically, these lesions demonstrate characteristic parakeratosis and elongation of rete ridges. Although there are numerous forms of acne, the most common form is known as acne simplex or acne vulgaris which is characterized by eruptions of the face, upper back and chest and is primarily comprised of comedones, cysts, papules and pustules on an inflammatory base.
The condition occurs primarily during puberty and adolescence due to an overactive sebaceous apparatus which is believed to be affected by hormonal activity. These conditions are often followed by lichenification, scaling and occasionally, by duskiness of the erythema and, infrequently, hyperpigmentation.
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