WO1992004039A1 - Regulation de la proliferation et de la differenciation de cellules grace a l'utilisation de peptides - Google Patents

Regulation de la proliferation et de la differenciation de cellules grace a l'utilisation de peptides Download PDF

Info

Publication number
WO1992004039A1
WO1992004039A1 PCT/US1991/006218 US9106218W WO9204039A1 WO 1992004039 A1 WO1992004039 A1 WO 1992004039A1 US 9106218 W US9106218 W US 9106218W WO 9204039 A1 WO9204039 A1 WO 9204039A1
Authority
WO
WIPO (PCT)
Prior art keywords
pth
human
peptide
enhancing
hair growth
Prior art date
Application number
PCT/US1991/006218
Other languages
English (en)
Inventor
Michael F. Holick
Original Assignee
Holick Michael F
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Holick Michael F filed Critical Holick Michael F
Publication of WO1992004039A1 publication Critical patent/WO1992004039A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/37—Parathyroid hormone [PTH]

Definitions

  • This invention relates to the regulation of cell differentiation and proliferation, e.g., for treating hyperproliferative skin disorders, such as psoriasis, for enhancing wound healing, and for stimulating hair growth.
  • Psoriasis is a disease of the epidermis and a major cause of disability and disfigurement for between 1 to 3% of the population of the world. In the United States
  • the disease is diagnosed by the presence of scaling, erythematous lesions on the scalp and extensor aspects of the anas and legs. Psoriatic lesions often are accentuated at sites of repeated trauma such as the elbows and knees. Furthermore, this skin disorder can afflict most of the areas of the skin of some individuals and can also cause internal damage such as arthritis. This disease is
  • UV-A predominately long wave length ultraviolet light
  • the skin is not only the site for the synthesis of vitamin D, but is also a target tissue for its biologically active form, 1,25- dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ).
  • a variety of tumor cells for example, HL-60, U937, and M-1
  • normal cells such as activated T-lymphocytes, monocytes, cultured skin fibroblasts, keratinocytes, and cells isolated from the skin of rats, mice, and humans contain a high affinity (1.0 x 10- 10 M), low capacity, protein which is a receptor for
  • 1,25(OH) 2 D 3 For tumor cells that possess a receptor for 1,25(OH) 2 D 3 , the hormone inhibits their proliferation and induces them to differentiate (Suda et al. in Vitamin D: Chemical, Biochemical and Clinical Update (Norman et al., ed.) Walter de Gruyter N.Y. 1985 pp. 187-196).
  • 1,25(OH) 2 D 3 inhibits the proliferation of cultured human fibroblasts and keratinocytes and induces keratinocytes to terminally differentiate (Smith et al., J. Invest. Dermatol. 86:709- 714, 1986).
  • 1,25(OH) 2 D 3 and its analog 1,24-dihydroxyvitamin D 3 are of value in the treatment of psoriasis when provided either orally or topically (Morimoto et al. Brit. J. Dermatol. 115:421-429, 1986; Kato et al. Brit. J. Dermatol. 115, 431-433, 1986).
  • Aging is associated with a variety of changes in the skin. There is an age-related decrease in epidermal
  • Thymidine labeling index (a measure of the proliferative activity of cells) of the epidermis in vivo has been reported to decline nearly 50% with age from approximately 5.1% in 19-25 year old men to approximately 2.85% in 69-85 year old men. Additional investigations have revealed that there is a 100% prolongation in stratum corneum replacement rate in old verses young men (Gilchrest, B. in Skin and Aging Processes, CRC Press, p. 21, 1984).
  • Parathyroid hormone a polypeptide 84 amino acids long, plays an important role in the maintenance of the concentration of ionized calcium in extracellular fluids within normal range. Parathyroid hormone acts directly to raise extracellular calcium by its effects on the bone and kidney, and indirectly by increasing the production of
  • osteosarcoma cells possess receptors for parathyroid hormone (Yamamoto, I. et al., J. Clin. Invest. 71:404-407, 1983; Goldring, S. et al., J. Clin. Endo. and Met. 46:425- 433, 1978).
  • a variety of in vitro and in vivo tests have been developed to assay for parathyroid hormone. These include the measurement of cyclic AMP production in isolated canine kidney membranes (Nissenson et al., J. Clin. Endo. and Met. 52:840, 1981) and in osteosarcoma cells (Lindall, A.W. et al., J. Clin. Endo. and Met. 57:1007, 1983) and human fibroblasts (Goldring et al., J. Clin. Endo. and
  • a cytochemical assay has also been developed to measure glucose-6-phosphate dehydrogenase activity in guinea pig kidney (Goltzman, D. J. et al.,
  • PTH 34-residue amino terminal fragment of the PTH molecule [PTH (1-34)] is biologically active in vitro and in vivo (Nussbaum, S. R. et al. J. Prot. Chem. 4:391-406, 1985).
  • Rat PTH (1-34) which has a 5 amino acid sequence difference from the- corresponding 1-34 region of both human and bovine PTH, has been found to be 8-10 fold more active than human PTH (1- 34) and 2-4 fold more active than bovine PTH (1-34) in the canine adenylate cyclase system (Keutmann, H.T. et
  • Keratinocyte-conditioned medium was harvested from confluent, first passage cultures. Conditioned medium from each of 10 keratinocyte cultures stimulated adenylate cyclase activity in a clonal ROS 17-2.8 cell assay. This biologically active substance is thought to be one of the factors responsible for causing humoral hypercalcemia in patients with a variety of malignancies.
  • This PTH-related protein was isolated from a human lung cancer cell line, and full-length complementary DNA clones encoding it have been inserted into expression vectors used to produce the peptide in mammalian cells.
  • the clones were found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids that has significant homology with parathyroid hormone in the amino terminal region; of the first 16 residues of this protein, 8 of the 16 were found to be identical to human PTH (Suva, L.J. et al. Science 232:893-896, 1987).
  • This invention arose in part out of the following discoveries: 1) when human cultured keratinocytes are incubated with human PTH (1-34) (herein, PTH (1-34)) at 10- 7 and 10 -8 M, this polypeptide fragment inhibits growth and induces terminal differentiation of these cells; 2) a synthetic fragment of hypercalcemic factor ([Tyr 34 ] calcemic factor fragment (1-34) amide (herein, CFF (1-34)) also inhibits the proliferation and induces terminal
  • PTH amide (herein, PTH (3-34)), like PTH (1-34), is an agonist, i.e., it inhibits proliferation and induces terminal differentiation of keratinocytes; 4) [Tyr 34 ] bovine PTH (7-34) amide (herein, PTH (7-34)) is an antagonist which blocks the antiproliferative and
  • the invention provides two important therapeutic methods, one involving inhibition of cell proliferation and enhancement of cell
  • the first method of the invention generally involves inhibiting proliferation and enhancing differentiation of a mammalian cell by contacting the cell with a peptide
  • the peptide is PTH (1-34), PTH (3-34), or CFF (1-34).
  • This method has particular application in the treatment of hyperproliferative skin disorders such as psoriasis.
  • the method may also be useful in the treatment of certain cancers, by the inhibition of cancer cell
  • the second method of the invention generally involves enhancing proliferation of a mammalian cell by contacting the cell with a peptide (preferably at least 3, and more preferably at least 8, amino acids long) which has 10% or greater (more preferably, 50% or greater, and most preferably 75% or greater) homology with a region
  • human parathyroid hormone or human hypercalcemic factor which is capable of blocking the differentiation or the inhibition of proliferation in vitro of cultured human keratinocytes by PTH (1-34) or 1,25(OH) 2 D 3 or CFF (1-34).
  • the peptide is PTH (7-34).
  • proliferation of a mammalian cell e.g., during wound healing, is enhanced by contacting the cell or wound with a peptide (preferably at least 3, and more preferably at least 8, amino acids long) which has 10% or greater (more preferably, 50% or greater, and most preferably, 75% or greater) homology with a region (preferably, within the amino-terminal 34 amino acid region) of human parathyroid hormone or human
  • the peptide is PTH (1-34), PTH (7-34), CFF (1-34), or CFF (7-34).
  • Hair growth is stimulated by administering to a mammal a peptide (preferably at least 3, and more preferably at least 8, amino acids long) which has 10% or greater (more preferably, 50% or greater, and most preferably, 75% or greater) homology with a region (preferably, within, the amino-terminal 34 amino acid region) of human parathyroid hormone or human hypercalcemic factor, and which is capable of stimulating hair growth in vitro.
  • a peptide preferably at least 3, and more preferably at least 8, amino acids long
  • a region preferably, within, the amino-terminal 34 amino acid region of human parathyroid hormone or human hypercalcemic factor
  • the peptide is PTH (7-34).
  • This method can have applications in the promotion of new hair growth or stimulation of the rate of hair growth, e.g., following chemotherapeutic treatment or for treating a form of alopecia, e.g., male pattern baldness.
  • Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
  • Fig. 1 is a comparison of the amino acid sequences of human PTH and hypercalcemic factor, taken from Suva et al., id.
  • Figs. 2, 3, 4, and 5 are bar graphs showing comparative proliferative effects of peptides of the invention.
  • Figs. 6 and 7 are graphs showing cell
  • Fig. 8 is a graph showing wound healing effects of peptides of the invention.
  • the peptides used in the methods of the invention are all easily synthesized, using recombinant DNA or solid phase peptide synthesis techniques, and some are available commercially as well, or can be derived from commercially available peptides. For example, there is reproduced below a section of the Bach Chem catalog, listing a number of available human, rat, and bovine analogs and fragments.
  • a preferred first step is to choose a peptide which includes a fragment which has at least 10%, and more preferably 50% or greater, homology with an 8 or greater amino acid long fragment within the amino terminal 34 amino acid region of human PTH or hypercalcemic factor.
  • homology is meant amino acid sequence identity.
  • the fragment can be modified in any of a variety of standard chemical ways, e.g., the carboxy-terminal amino acid residue can be made into a terminal amide group; the amino-terminal residue can be modified with groups to, e.g., enhance lipophilicity; the peptide can be chemically glycosylated to increase
  • D-amino acids can be substituted for L-isomers in the peptide.
  • Candidate peptides are tested for suitability as inhibitors of cell proliferation and enhancers of
  • Those peptides which inhibit proliferation and induce differentiation in cultured keratinocytes are those potentially useful as therapeutic agents in treating disorders, e.g., psoriasis and cancer, where suppression of cell proliferation is desired.
  • Candidate peptides may be tested for suitability as enhancers of cell proliferation using cultured human
  • keratinocytes Those peptides which block the effect of agonist peptides or 1,25(OH) 2 D 3 on cultured keratinocyte proliferation are those potentially useful as therapeutic agents in treating disorders, e.g., wounds, burns, or skin ulcerations, where maintenance or stimulation of cell proliferation is desired.
  • Candidate peptides may be tested for their ability to enhance wound healing by carrying out a skin punch biopsy test, described below.
  • Candidate peptides may be tested for suitability as stimulators of hair growth using an in vitro hair growth assay, such as is described below.
  • Those peptides which stimulate hair growth in vitro are those potentially useful for the stimulation of hair growth in vivo, e.g., for the stimulation or maintenance of hair growth during or
  • alopecia e.g., male pattern baldness
  • Peptides which block antiproliferative compounds can also be useful in conjunction with chemotherapeutic agents in the treatment of cancer; many chemotherapeutic agents are effective only against dividing cells, and the blocking peptides can have the effect of inducing division of
  • Blocking peptides can also be useful in promoting growth of new cells, e.g., skin cells, in topical skin creams. Differentiation-inducing peptides can be used as immunostimulants, by inducing maturation of monocytes and lymphocytes bearing PTH receptors, while blocking peptides can be used to inhibit lymphocyte maturation, and thus can be used to treat conditions, e.g., autoimmune diseases such as juvenile diabetes, rheumatoid arthritis, and allograft rejection, where mature lymphocytes are a causative agent. Keratinocyte Culture
  • Keratinocytes were grown in culture as follows. NIH 3T3 cells were plated at 0.5 x 10 5 cells per 35-mm tissue-culture dish, and two days later were lethally irradiated with a cobalt-60 source (5000 rads).
  • Keratinocytes were obtained from neonatal foreskin after overnight trypsinization at 4°C and treatment with 0.02% EDTA. Keratinocytes were plated in 2 ml of serum-free medium per dish on the lethally irradiated 3T3 cells. Each experiment was performed on primary or secondary
  • the serum-free medium consisted of Dulbecco's Modified
  • DMEM Eagle's Medium
  • M.A. Bioproducts, Walkersville, MD concentration of calcium
  • epidermal growth factor 25 ng/ml
  • hydrocortisone (203 ng/ml); insulin (5 ⁇ g/ml); prostaglandin E 1 (50 ng/ml); transferrin (5 ⁇ g/ml prostaglandin E 1 (50 ng/ml); cholera toxin (0.1 ⁇ g/ml); (Sigma Chemical Co., St. Louis, MO); and selenous acid (2 ng/ml) (Collaborative Research, Lexington, MA).
  • insulin 5 ⁇ g/ml
  • prostaglandin E 1 50 ng/ml
  • transferrin 5 ⁇ g/ml prostaglandin E 1 (50 ng/ml)
  • cholera toxin 0.1 ⁇ g/ml
  • selenous acid (2 ng/ml)
  • hydrocortisone and cholera toxin were removed from the medium, and the dishes were washed with 0.02% EDTA to remove any remaining 3T3 cells.
  • triplicate plates of keratinocytes were incubated with the aforementioned compounds or vehicle alone. After one week of dosing, the medium was removed from each culture and centrifuged, and the pellet was resuspended for the counting of the desquamated floater cells. A hemacytometer was used to count the different cell types under a phase-contrast microscope. The attached cells were then trypsinized for 30-40 min with 0.1 EDTA and 0.1% trypsin and then
  • the keratinocytes were pelleted and resuspended in a known volume of medium. Duplicate aliquots were taken for counting the basal (small, rounded) and squamous (larger, irregular-shaped, flattened) cells. The remaining cells were pelleted and treated with 10 mM Tris-HCl (pH 7.4) with 1% beta-mercaptoethanol and 1% sodium dodecyl sulfate (SDS) at room temperature for 10 min. Only cells with cornified envelopes were present after this treatment.
  • Figs. 6 and 7 represent the percent of control of the total number of cornified envelopes observed in the cultures. As can be seen in Fig. 6, 1,25(OH) 2 D 3 increased, in a dose-dependent manner, the total number of cornified envelopes. Similarly, PTH (1-34), PTH (3-34), and CFF (1- 34) also increased, in a dose-dependent manner, the number of cornified envelopes relative to the control cultures.
  • hyperproliferative diseases such as psoriasis and cancer
  • CFF (1-34) and PTH (3-34) have the same effect as PTH (1- 34) and are thus also candidates for hyperproliferative disease therapy
  • PTH (7-34) an antagonist to PTH action, has substantially no effect on proliferation or terminal differentiation by itself, but can block the
  • Figure 8 is a graphical represention of the percent wound healing exhibited by each of the test groups.
  • Peptides PTH (7-34) and PTH (1-34) are biologically identical.
  • Candidate peptides may be screened for their ability to stimulate hair growth as follows. Hair is obtained from human subjects, preferably from a group of at least 18 subjects, including men, some of whom exhibit varying degrees of male pattern baldness, and women, and including subjects from different age groups. Hair is sampled from 4 sites of the scalp (frontal, occipital, temporal, and nuchal) and the following body areas: beard, axilla, pubic, chest, forearm, and leg, using the method described by van Scott et al. (J. Invest. Derm. 29: 197, 1957). Immediately after plucking, the hairs are placed in chilled Krebs-Ringer phosphate buffer, pH 7.4. Growing (anagen) and resting (telogen) hairs are differentiated either by gross
  • telogen hairs are incubated in duplicate, in 2 ml. centrifuge tubes, in a total volume of 1 ml of incubation mixture consisting of Krebs-Ringer phosphate buffer, pH 7.4, glucose (9mM), and candidate peptide; control incubation mixture lacks peptide. Samples are incubated with shaking at 37°C in an air
  • DNA content is determined by the method of Kissane and Robins (J. Biol. Chem. 233: 184, 1958) as modified by Santoianni and Ayala (J. Invest. Derm. 4J5: 99, 1965).
  • the peptides are administered in therapeutically effective amounts to people in need of them.
  • the peptides are administered mixed with a pharmaceutically acceptable carrier substance, e.g., magnesium carbonate or lactose.
  • a pharmaceutically acceptable carrier substance e.g., magnesium carbonate or lactose.
  • the composition can be in the form of a pill, tablet, capsule, liquid, or sustained release tablet for oral administration; or a liquid for nasal, intravenous, subcutaneous, parenteral, or intraperitoneal administration.
  • the compounds can be used in a
  • pharmacologically inert topical carrier such as one
  • a gel comprising a gel, an ointment or a cream, including such carriers as water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters or mineral oils.
  • carriers include liquid petrolatum, isopropylpalmitate, polyethylene glycol ethanol 95%,
  • polyoxyethylene monolaurate 5% in water sodium lauryl sulfate 5% in water, and the like.
  • Materials such as anti- oxidants, humectants, viscosity stabilizers and the like may be added, if necessary.
  • the compounds can also be administered by means of subcutaneous pumps, patches, tapes or by means of liposomal carriers.
  • the peptides can be provided in the form of pharmaceutically acceptable salts.
  • preferred salts are those of therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic,
  • toluenesulfonic, or pamoic acid as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids such as hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid.
  • hydrohalic acids e.g., hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Dosage will be dependent upon the age, health, and weight of the recipient; kind of concurrent treatment, if any; frequency of treatment; and the nature of the effect desired. Generally, daily dosage will be from about 0.001 micrograms/kg to 10,000 micrograms/kg, preferably 0.1 to 10 micrograms per kg of body weight. Normally, from 0.1 to 1000 micrograms/kg per day, in one or more applications per day, will be effective to obtain the desired results.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Endocrinology (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention décrit des procédés qui servent à inhiber la prolifération et à améliorer la différenciation d'une cellule mammifère, à induire la prolifération d'une cellule mammifère, à améliorer la cicatrisation et à stimuler la croissance capillaire, grâce à l'utilisation d'un peptide qui possède une homologie de 10 % ou supérieure avec une région de l'hormone parathyroïde humaine ou du facteur hypercalcémique humain.
PCT/US1991/006218 1990-08-30 1991-08-30 Regulation de la proliferation et de la differenciation de cellules grace a l'utilisation de peptides WO1992004039A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57521990A 1990-08-30 1990-08-30
US575,219 1990-08-30

Publications (1)

Publication Number Publication Date
WO1992004039A1 true WO1992004039A1 (fr) 1992-03-19

Family

ID=24299414

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/006218 WO1992004039A1 (fr) 1990-08-30 1991-08-30 Regulation de la proliferation et de la differenciation de cellules grace a l'utilisation de peptides

Country Status (1)

Country Link
WO (1) WO1992004039A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034596A2 (fr) * 1995-05-03 1996-11-07 Holick, Michael, F. Utilisation d'huile d'emeu pour stimuler la croissance de la peau et des cheveux

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CLINICAL RESEARCH, Volume 37, No. 2, issued 1989, HOLICK et al., "Synthetic fragments of PTH-related peptide (PTHrp) inhibit the proliferation and induce terminal differentiation of cultured human keratinocytes: PTHrp may be an endogenous antiproliferation and differentiation factor for keratinocytes", page 529a. *
ENDOCRINOLOGY, Volume 118, No. 6, issued 1986, MAC DONALD et al., "Parathyroid hormone stimulates the Proliferation of Derived from Human Bone", pages 2445-2449. *
JOURNAL OF CELL BIOLOGY, Volume 107, No. 6, part 3, issued December 1988, HOLICK et al., "PTH related peptide (PTHrp) is a potent antiproliferation and differentiation factor: PTH (7-34) inhibits the antiproliferative and maturation activity of both PTHrp and 1,25 (OH) 2 d3", page 40a, Abstract #303. *
JOURNAL OF PROTEIN CHEMISTRY, Volume 4, No. 6, issued 1985, NUSSBAUM et al., "Design of analogues of parathyroid hormone: A conformational approach", pages 391-406. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA, Volume 83, issued October 1986, DOPPELT et al., "Inhibition of the in vivo parathyroid hormone-mediated calcemic response in rats by a synthetic hormone antagonist", pages 7557-7560. *
SCIENCE, Volume 220, issued 03 June 1983, HORIUCHI et al., "A Parathyroid hormone inhibitor in vivo: Design and biological evaluation of a hormone analog", pages 1053-1055. *
SCIENCE, Volume 231, issued 24 January 1986, MERENDINO et al., "A Parathyroid cell Hormone-Like Protein from cultured Human Keratinocytes", pages 388-390. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034596A2 (fr) * 1995-05-03 1996-11-07 Holick, Michael, F. Utilisation d'huile d'emeu pour stimuler la croissance de la peau et des cheveux
WO1996034596A3 (fr) * 1995-05-03 1997-03-27 Holick Michael F Utilisation d'huile d'emeu pour stimuler la croissance de la peau et des cheveux
US5744128A (en) * 1995-05-03 1998-04-28 Holick; Michael F. Use of emu oil for stimulating skin and hair growth

Similar Documents

Publication Publication Date Title
US5527772A (en) Regulation of cell proliferation and differentiation using peptides
US10844101B2 (en) Plant-derived elastin binding protein ligands and methods of using the same
EP3121196B1 (fr) Peptides dérivés de la famille wnt et leurs utilisations
AU2006325778A1 (en) Skin care compositions and treatments
EP0200757A4 (fr) Stimulation de la cicatrisation de plaies a l'aide du facteur de croissance de l'epiderme humain prepare a partir d'adn recombinant.
KR101092915B1 (ko) 성장인자―유래 펩타이드 및 이의 용도
JP2014177464A (ja) Ｍｎｔｆペプチドの美容および皮膚科用製剤
US7906480B2 (en) Use of a parathyroid hormone peptide analogs for the treatment of vaginal atrophy
EP0415924B1 (fr) Regulation de la proliferation et de la differenciation cellulaires par utilisation de peptides
Wang et al. Effect of 1, 25, 28‐trihydroxyvitamin D2 and 1, 24, 25‐trihydroxyvitamin D3 on intestinal calbindin‐D9K mRNA and protein: Is there a correlation with intestinal calcium transport?
WO1992004039A1 (fr) Regulation de la proliferation et de la differenciation de cellules grace a l'utilisation de peptides
WO2007043721A1 (fr) Compositions pour ameliorer l'etat de la peau et contenant une hormone de croissance humaine en tant qu'agent actif
US11793746B2 (en) Intense skin hydration systems and methods
KR101155151B1 (ko) 성장인자?유래 펩타이드 및 이의 용도
KR101155152B1 (ko) 성장인자?유래 펩타이드 및 이의 용도
JP2004512351A (ja) クロモラエナ・オドラータの使用に基づく肌手入れ用組成物及び方法
CN117599033A (zh) 一种抗皮肤老化制剂及其应用
KR20040076780A (ko) 재조합 인슐린 유사 성장인자를 함유하는 화장료 조성물

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA