UNITED STATES PATENT:
Non-Toxic Skin Cancer Therapy
with Copper Peptides (2017)
GHK and DNA: Resetting the
Human Genome to Health
BioMed Research International (2014)
The Effect of Human Peptide
GHK Relevant to
Nervous System Function
and Cognitive Decline
Brain Sciences (2017)
Tri-Peptide GHK-Cu and
Acute Lung Injury in Mice
Oncotarget (2016)
New Data of the Cosmeceutical
and TriPeptide GHK
SOFW Journal (2015)
Biomarkers Reveal Potential
Skin Toxicity Caused by
Certain Copper Compounds
Scientific Reports (2016)

GHK-Cu May Prevent
Oxidative Stress in Skin
by Regulating Copper and
Modifying Expression of
Numerous Antioxidant Genes Cosmetics (2015)
GHK Induces
Programmed Cell Death
in Neuroblastoma Cells
Biotech & Biomaterials (2012)
GHK Peptide as a
Natural Modulator of
Multiple Cellular Pathways
in Skin Regeneration (2015)
Emphysema-Related
Lung Destruction and
its Reversal by GHK
Genome Medicine (2012)
GHK:
The Human Skin Remodeling Peptide Induces Anti-Cancer
Expression and DNA Repair Analytical Oncology (2014)
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Copper Peptide Biochemistry Related to Tissue Regeneration

Study
Result Reference
Databank search for source of human GHK -  Effect of GHK-Cu on collagen synthesis
 Determined possible sources of GHK and effect of GHK-Cu on collagen synthesis in two strains of human fibroblasts and embryonic lung fibroblasts. GHK is a very rare sequence appearing in only 8 human proteins sequences as of 1990. It appears three times in collagen and also exist in several inflammatory proteins - All fibroblast lines stimulated collagen synthesis at 10exp (-12) M and maximally at 10exp (-9) M Glycyl-l-histidyl-l-lysine, a triplet from the a2 (I) chain of human type I collagen, stimulates collagen synthesis by fibroblast cultures Maquart, Gillery, Monboisse, Pickart, Laurent and Borel Ann. N.Y. Acad. Sci. 580:573-575, 1990
Search for source of GHK
Studies on a skin structural protein called SPARC. GHK and HGHK, two peptides with very high copper-binding affinity are angiogenic. They are generated by the breakdown of SPARC, a structural protein in skin which is rich in cysteine.  SPARC may  function at several levels to control the progression of neovessels. Proteolysis of SPARC by  plasmin results in the release of peptides containing the sequence  Gly-His-Lys, which are angiogenic in vitro and  in vivo. At later stages of angiogenesis when endothelial cell proliferation ceases, SPARC may exert inhibitory effects on angiogenesis.  Regulation of angiogenesis by extracellular matrix: the growth and the glue.  Sage and Vernon (University of Washington School of Medicine, Seattle, WA, USA)  J Hypertens Suppl 1994 12(10):S145-52
Effect of GHK on chemoattraction of healing associated immune cells 
Compared GHK to known potent chemoattractants and GHK analogs. GHK was most potent chemoattractant tested for mast cells, but Gly-His-Gly, His-Lys, and His-Gly-Gly were inactive.  Stimulation of rat peritoneal mast cell migration by tumor derived peptides. Poole and Zetter (Harvard Medical School)  Cancer. Res. 43, 5857-5861, 1983
Effect of GHK on chemoattraction of healing associated immune cells
Compared GHK to known potent chemoattractants and GHK analogs. An implantable device was used for the study of  leukocyte chemoattraction in rats for up to 18 days. GHK attracted wound healing immune cells (mast cells, macrophages, polymorphonuclear leukocytes)  at about 10exp (-10) M.  An in vivo assay for chemoattractant activity.  Zetter, Rasmussen and Brown (Harvard University Medical School, Boston, MA, USA)  Lab Invest 1985 53(3):362-8 
Heparin is felt to mediate some healing events
GHK-Cu and heparin which is a natural anti-coagulant and a  mediator of wound healing. GHK found to bind to heparin in nuclear magnetic resonance spectroscopy studies. Binding of the growth factor glycyl-L-histidyl-L-lysine by heparin. Rabenstein, Robert and Hari  (University of California at Riverside, USA)  FEBS Lett 1995, 376, pp. 216-20 
Angiogenesis in rabbit cornea model and capillary cell migration 
GHK-Cu tested for angiogenic activity. Copper complexes of glycyl-L-histidyl-L-lysine and heparin induced angiogenesis in rabbits. Copper deficient rabbits cannot induce angiogenesis.  Ceruloplasmin, copper ions, and angiogenesis. Raju, Alessandri, Ziche and Gullino (National Cancer Institute, Bethesda, MD, USA)  J Natl Cancer Inst 1982 69(5):1183-8 
Angiogenesis in rabbit cornea model and capillary cell migration
 GHK-Cu tested for angiogenic activity and effect on capillary cell migration. Increased angiogenesis in rabbit cornea model -  Increased in vitro migration of capillary cells by 8-fold Characterization of a chemoattractant for endothelium induced by angiogenesis effectors. Raju, Alessandri, Gullino (National Cancer Institute, Bethesda, MD, USA)  Cancer Res. 44:1579-1584, 1984 
Nerve Growth - comment

When wound healing is inadequate, the healed area is often devoid of sensory abilities.

 
Nerve Growth
Studied the effect of GHK on nerve growth. Gly-His-Lys supported chick neuron differentiation and viability in cell culture and increased nerve outgrowth . The optimum concentrations of GHK for neuron function were 100-400 ng/ml.  Effects of synthetic tripeptide on the differentiation of dissociated cerebral  hemisphere nerve cells in culture. Sensenbrenner; Jaros; Moonen,  Mandel (University of Strausbourg, France)  Neurobiology 1975 5(4):207-13 
Nerve Growth 

Studied the effect of GHK on nerve growth.

Gly-His-Lys supported chick neuron differentiation and viability in cell culture of various neurons -  chick embryo PNS (ganglion trigeminale) and from CNS of embryonal rats (hippocampus) and dissociated cells from chick embryo cerebral tissue.  The optimum concentrations of GHK for neuron outgrowth was 10 ng/ml. GHK increased the ratio of neurons to glial cell in culture. 

Uber die Wirkung eines synthetischen Tripeptids auf  in vitro kultiviertes Nervengewebe (The effect of a synthetic tripeptide nervous tissue cultured in vitro),  Lindner, Grosse, Halle and Henklein (Karl Marx University, Berlin, Germany)  Z Mikrosk Anat Forsch 1979;93(5):820-8 
Nerve Growth
Severed nerves are placed in a collagen tube impregnated with GHK. This caused an increased the production of Nerve Growth Factor and the neurotrophins NT-3 and NT-4 Ahmed MR, Basha SH, Gopinath D, Muthusamy J, Jayakumar RJ, Initial upregulation of growth factors and inflammatory mediators during nerve regeneration in the presence of cell adhesive peptide-incorporated collagen tubes, J Peripher Nerv Syst. 2005, 10:17-30
GHK was tested for maintaining fibroblast viability in serum free medium 
Chick fibroblast were maintained in serum free medium after the addition of GHK. The GHK containing culture medium allowed studies of factors affecting collagen metabolism without the complications of the proteins from serum.  An in vitro model of fibroblasia - Simultaneous quantification of fibroblast proliferation, migration, and collagen synthesis. Graham, Diegelmann and Cohen (Medical College of Virginia, Richmond, VA, USA) Proc Soc Exp Bio Med 176, 302-308, 1984
Collagen synthesis in cultured fibroblasts 
The effect of GHK-Cu was determined. GHK-Cu stimulated collagen synthesis in cultured fibroblasts.  The stimulation began between 10exp (-12) and 10exp (-11) M, maximized at 10exp (-9) M, and was independent of any change in cell number. The presence of a GHK triplet in the alpha 2(I) chain of type I collagen suggests that the tripeptide might be liberated by proteases at the site of a wound and exert in situ healing effects.  Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+.  Maquart, Pickart, Laurent, Gillery, Monboisse and Borel (Laboratoire de Biochimie, CNRS URA 84, Faculte de Medecine, Reims, France.  FEBS Lett 1988, 238(2):343-6 
Collagen synthesis in cultured fibroblasts 
The effect of GHK-Cu on collagen production was determined. GHK-Cu increased collagen synthesis at 10exp (-9) M Requirement of Copper and Tripeptide Glycyl-L-Histidyl-L-Lysine Complex Formation for Collagen Synthesis Activity in Normal Human Dermal Fibroblasts.  Oddos, T, Jumeau-Lafond, A ; Johnson & Johnson,  Val de Reuil, France, Ries, G,  Johnson & Johnson, Dusseldorf, Germany Abstract P72, American Academy of Dermatology Meeting, February 2002
Sulfated glycosaminoglycan (water-holding proteins) synthesis in cultured fibroblasts.
The effect of GHK-Cu on the synthesis of sulfated glycosaminoglycan (water-holding proteins) in cultured fibroblasts was determined. GHK-Cu induced a dose-dependent increase of the synthesis of total GAGs secreted into the culture medium and those associated with the cell layer. The effect of GHK-Cu increased with dosage and was optimal at 10exp (-9) to 10exp (-8) M. Higher concentrations had less effect  the rate of synthesis. GHK-Cu preferentially stimulated the synthesis of extracellular dermatan sulfate and cell layer associated heparin sulfate. Stimulation of sulfated glycosaminoglycans by the tripeptide copper complex glycyl-l-histidyl-l-lysine copper(II). Wegrowski, Maquart, Borel (University de Reims, France) Life Sci. 51, 1049-1056, 1992
The effects of GHK-Cu on the synthesis of glycosaminoglycans and small major proteoglycans was determined.
A study of the effects of GHK- Cu in vivo, using the wound chamber model. Stainless steel wire mesh cylinders were implanted subcutaneously on the back of rats.GHK-Cu  treated cultured fibroblasts and rat wound chambers had an increase in messenger RNA for decorin by not for biglycan. In both systems, GHK-Cu increased the synthesis of of decorin, dermatin sulfate and chondroitin sulfate. Expression of glycosaminoglycans and small proteoglycans in wounds: Modulation by the tripeptide copper complex glycyl-histidyl-lysine Cu(II).  Simeon, Wegrowski, Bontemps and Maquart J Invest Dermatol 2000 Dec;115(6):962-968
Wound healing events in "wound chambers" were studied in rats
A study of the effects of GHK- Cu in vivo, using the rat wound chamber model. GHK-Cu treated rat wounds had a concentration dependent increase of dry weight, DNA, total protein, collagen, and glycosaminoglycan. The stimulation of collagen synthesis was twice that of noncollagen proteins. Type I and type III collagen mRNAs were increased. An increase of the relative amount of dermatan sulfate was also found.  In vivo stimulation of connective tissue accumulation by the tripeptide- copper complex  glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds.  Maquart, Bellon, Chaqour, Wegrowski, Monboisse, Chastang, Birembaut and Gillery (Universite de Reims, France) J Clin Invest 92: 2368-76, 1993
Metalloproteinases that remove damaged proteins and scar tissue
Metalloproteinases are a family of proteins that remove damaged proteins and scar tissue. The expression and activation of matrix metalloproteinases where investigated in a model of experimental wounds in rats, and their modulation by GHK-Cu. Wound chambers were  inserted under the skin of rats and were injected daily with either injections of either 2 mg GHK-Cu or the same volume of saline. The wound fluid and the neosynthetized connective tissue deposited in the chambers were collected and analyzed for matrix metalloproteinase expression and/or activity. Interstitial collagenase increased in the wound fluid throughout the experiment and GHK-Cu did not alter its activity. Matrix metalloproteinase-9  (gelatinase B) and matrix metalloproteinase-2  (gelatinase A) were the two main gelatinolytic activities expressed during the healing process. Pro-matrix metalloproteinase-9 was strongly expressed during the early stages of wound healing (day 3) but decreased rapidly whereas in GHK-Cu treated chambers it persisted until day 22. Pro-matrix metalloproteinase-2 increased progressively until day 7, then decreased until day 18. Activated matrix metalloproteinase-2 increased until day 12, then decreased progressively whereas GHK-Cu increased pro-matrix  metalloproteinase-2 and activated matrix metalloproteinase-2 during the later stages of healing. GHK-Cu increased metalloproteinases activity up to 4-fold which may increase the activity of wound remodeling processes which remove damaged protein and scar tissue. Expression and activation of matrix metalloproteinases in wounds: modulation by the  tripeptide-copper complex  glycyl-L-histidyl-L-lysine- Cu2+,  Simeon; Monier; Emonard; Gillery; Birembaut, Hornebeck and Maquart (Faculte de Medecine, Reims, France)  J Invest Dermatol 1999 112(6):957-64 
Metalloproteinases and antiproteinases - comment
GHK-Cu increases MMP-2 in cultured fibroblasts but in rat wounds it decreases MMP-2 and MMP-9. GHK-Cu also increases inhibitors of metalloproteinases TIMP-1 and TIMP-2 in cultured fibroblasts. The overall actions would appear to reduce proteolysis but perhaps maintain it at a lower level than in early stage wounds.  
Metalloproteinases and antiproteinases that remodel tissue
The effect of GHK-Cu on the induction of metalloproteinases in cultured wound fibroblasts. GHK-Cu at 10exp(-10) M  increased MMP-2 mRNA and also inhibitors of metalloproteinases TIMP-1 and TIMP-2. The authors argue this indicate GHK-Cu modulates tissue remodeling. The tripeptide-copper complex GHK-Cu stimulates matrix metalloproteinases 2 expression by fibroblast cultures. Simeon, Emonard, Hornebeck & Maquart Laboratoire de Biochimie-UPRESA CNRS 6021, Faculte de Medecine, Reims, France. Life Sci 2000 Sep 22;67(18):2257-65
Metalloproteinases and antiproteinases that remodel tissue
GHK-Cu caused a significant decrease in wound area (64.5% GHK-Cu vs 28.2% control) by day 13. GHK-Cu also significantly lowered concentrations of TNF-alpha and MMP-2 and MMP-9. Canapp SO Jr, Farese JP, Schultz GS, Gowda S, Ishak A.M, Swaim SF, Vangilder J, Lee-Ambrose L, Martin FG, The effect of topical tripeptide-copper complex on healing of ischemic open wounds, Vet Surg. 2003 Nov-Dec;32(6):515-23

GHK and cellular energy production

GHK was tested for effects on phosphoylase A activation.

GHK stimulated in dose-dependent fashion the activity of phosphorylase a in isolated rat  hepatocytes. This  effect was associated with increases in both IP3 production and [Ca++]. These effects of Gly-His-Lys were antagonized by losartan, a nonpeptide angiotensin II receptor antagonist (AT1 selective), which  suggested that these receptors were involved in its effect. Binding competition experiments clearly indicated that Gly-His-Lys interacts with AT1 receptors. 
Glycyl-histidyl-lysine interacts with the angiotensin II AT1 receptor. Garcia-Sainz JA, Olivares-Reyes JA. Departamento de Bioenergetica, Universidad Nacional Autonoma de Mexico, Mexico D. F. Peptides 1995;16(7):1203-7
Review of Copper Peptide Tissue Regeneration - Year 2000

Overview of biological and clinical results. Link to abstract of talk

Prague, Czech Republic, May 19, 2000
GHK is a matrikine that stimulates tissue remodeling
The term of "matrikine" has been proposed to designate such ECM-derived peptides able to regulate cell activity. GHK is a matrikine and  a potent activator of ECM synthesis and remodeling Regulation de l'activite cellulaire par la matrice extracelulaire: le concept de matrikines. Maquart FX; Simeon A; Pasco S; Monboisse JC. J Soc Biol 1999;193(4-5):423-8
GHK-Cu and reduction of keloid scar formation
GHK-Cu was tested for effects on the production of the keloid-producing hormone TGF-beta1 by normal and keloid-producing fibroblasts. GHK-Cu, at 10exp (-9) M reduced the production of TGF-beta1 in both normal and keloid-producing fibroblasts. In contrast, retinoic acid (Retin-A, Tretinoin) increases the production of scar producing TGF-beta1 in these lines.  The effect of copper tripeptide and tretinoin on growth factor production in a serum-free fibroblast model. McCormack, M., Nowak KC, Koch, J.  Arch Facial Plast Surg 2001; 3: 28-32
Review of Copper Peptide Tissue Regeneration - Year 2002
Overview of biological and clinical results Pickart, L.  Copper Peptides for Tissue Regeneration.  Specialty Chemicals Oct. 9, 2002, 29-31. 

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