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			{{more medical citations needed|date=August 2018}}
	{{chembox		{{chembox
			| Verifiedfields = changed
	| verifiedrevid = 450540996
			| Watchedfields = changed
	| Name = Copper Peptide GHK-Cu
			| verifiedrevid = 451242710
	| ImageFile = StructureofGHKMolecule.jpg
			| ImageFile = Glycyl-L-histidyl-L-lysine.svg
	| ImageSize = 200px
			| ImageSize = 200px
	| IUPACName = <nowiki>6-amino-2--3-(1H-imidazol-5-yl)propanoyl]amino]hexanoic acid; copper</nowiki>
			| ImageCaption = Tripeptide
	| OtherNames = Glycyl-L-Histidyl-L-Lysine, Cu-GHK, Lysine, glycylhistidyl-, monocopper salt
			| ImageFile1 =
	| Section1 = {{Chembox Identifiers
			| ImageSize1 = 200px
	| CASNo = 49557-75-7
			| ImageCaption1 = Copper complex
	| PubChem = 378611 <ref>http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=378611&loc=ec_rcs</ref>
			| IUPACName = 6-Amino-2-<nowiki>-3-(1''H''-imidazol-5-yl)propanoyl]amino]hexanoic acid
	| SMILES = C1=C(NC=N1)CC(C(=O)NC(CCCCN)C(=O)O)NC(=O)CN.
			| OtherNames = Glycyl-<small>L</small>-Histidyl-<small>L</small>-Lysine; Growth-modulating peptide; Kollaren; Liver cell growth factor; Liver growth factor Cu-GHK; Glycyl-histidyl-lysine, monocopper salt, Prezatide copper<ref>{{cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/Prezatide-copper | title=Prezatide copper }}</ref>
	| MeSHName =
			|Section1={{Chembox Identifiers
			| CASNo = 49557-75-7
			| CASNo_Ref = {{cascite|correct|??}}
			| CASNo1 = 89030-95-5
			| CASNo1_Ref = {{cascite|correct|CAS}}
			| index1_label = (Cu complex)
			| ChEBI = 95185
			| ChemSpiderID = 66263
			| ChemSpiderID1 = 335491
			| UNII_Ref = {{fdacite|correct|FDA}}
			| UNII = 39TG2H631E
			| UNII1_Ref = {{fdacite|correct|FDA}}
			| UNII1 = 6BJQ43T1I9
			| PubChem = 342538
			| PubChem1 = 378611
			| StdInChI=1S/C14H24N6O4/c15-4-2-1-3-10(14(23)24)20-13(22)11(19-12(21)6-16)5-9-7-17-8-18-9/h7-8,10-11H,1-6,15-16H2,(H,17,18)(H,19,21)(H,20,22)(H,23,24)
			| StdInChIKey = MVORZMQFXBLMHM-UHFFFAOYSA-N
			| SMILES = O=C(N(CC1=CN=CN1)C(N(CCCCN)C(O)=O)=O)CN
			| InChI1=1S/C14H24N6O4.Cu/c15-4-2-1-3-10(14(23)24)20-13(22)11(19-12(21)6-16)5-9-7-17-8-18-9;/h7-8,10-11H,1-6,15-16H2,(H,17,18)(H,19,21)(H,20,22)(H,23,24);
			| InChIKey1 = DIWZQABMLHSNJR-UHFFFAOYSA-N
			| SMILES1 = C1=C(NC=N1)CC(C(=O)NC(CCCCN)C(=O)O)NC(=O)CN.
	}}		}}
	| Section2 = {{Chembox Properties		|Section2={{Chembox Properties
	| Formula = C<sub>14</sub>H<sub>24</sub>CuN<sub>6</sub>O<sub>4<sub>		| Formula = C<sub>14</sub>H<sub>24</sub>N<sub>6</sub>O<sub>4</sub><br>C<sub>14</sub>H<sub>22</sub>CuN<sub>6</sub>O<sub>4</sub> (Cu complex)
	| MolarMass = 403.92416 g/mol		| MolarMass = 340.38 g/mol
	| ExactMass =		| Appearance =
	| Appearance =		| Density =
	| Density =		| MeltingPt =
	| MeltingPt =		| BoilingPt =
			| Solubility = 130.98 g/L <ref>{{cite web |url=http://www.mcbiotec.com/file/msds%20copper%20peptide.pdf |title=Archived copy |access-date=2011-05-15 |url-status=dead |archive-url=https://web.archive.org/web/20120324030906/http://www.mcbiotec.com/file/msds%20copper%20peptide.pdf |archive-date=2012-03-24 }}</ref>
	| BoilingPt =
	| Solubility = 130.98 g/L <ref>http://www.mcbiotec.com/file/msds%20copper%20peptide.pdf</ref>
	}}		}}
	| Section3 = {{Chembox Hazards		|Section3={{Chembox Hazards
	| MainHazards =		| MainHazards =
	| FlashPt =		| FlashPt =
	| Autoignition =		| AutoignitionPt =
	}}		}}
	}}		}}
	'''The copper peptide GHK-Cu''' is a naturally occurring copper complex of a glycyl-L-histidyl-L-lysine ]. Since it has three amino acids it is called tripeptide. The GHK-Cu tripeptide has strong affinity for ] (II) and was first isolated from human ]. It can be found also in ] and ].		'''Copper peptide GHK-Cu''' is a naturally occurring copper complex of the ] glycyl-<small>L</small>-histidyl-<small>L</small>-lysine. The tripeptide has strong affinity for ](II) and was first isolated from human ]. It can be found also in ] and ].
	==Overview==		==Overview==
	The copper peptide GHK-Cu is a naturally occurring human tripeptide. In plasma, the level of GHK-Cu is about 200&nbsp;ng/ml at age 20. By the age of 60, the level drops to 80&nbsp;ng/ml. Scientific studies conducted in different research laboratories around the world have established that human tripeptide GHK-Cu possesses a plethora of biological actions including activation of ], attraction of ], ] and ] effects, stimulation of ] and ] synthesis in skin ] and promotion of blood vessels growth. Recent studies indicate its important role in ] biology and ] defense. Since GHK-Cu plays an important role in skin biology, it is widely used in cosmetics as a reparative and ] ingredient.<ref>Pickart L. The human tri-peptide GHK and tissue remodeling. J. Biomater. Sci. Polymer Edn. 2008; 19(8):969-988</ref>		Several copper(II)-peptide complexes occur naturally.<ref>{{Cite web |url=http://www.copper-peptides.com/Science.html |title=The Magic of Copper Peptides Science |access-date=2012-05-16 |archive-date=2013-01-19 |archive-url=https://archive.today/20130119163206/http://www.copper-peptides.com/Science.html |url-status=dead }}</ref> In human plasma, the level of GHK-Cu is about 200&nbsp;ng/ml at age 20. By the age of 60, the level drops to 80&nbsp;ng/ml. In humans, GHK-Cu is proposed to promote ], attraction of ], ] and ] effects, stimulation of ] and ] synthesis in skin ] and promotion of blood vessels growth. Recent studies revealed its ability to modulate expression of a large number of human genes, generally reversing gene expression to a healthier state. Synthetic GHK-Cu is used in cosmetics as a reparative and ] ingredient.<ref>{{cite journal | last1 = Pickart | first1 = L | year = 2008 | title = The human tri-peptide GHK and tissue remodeling | journal = Journal of Biomaterials Science, Polymer Edition| volume = 19 | issue = 8| pages = 969–988 | doi=10.1163/156856208784909435| pmid = 18644225 | s2cid = 9354138 }}</ref>
	==History==		==History==
	Copper peptide GHK-Cu was isolated from human plasma ] in 1973 by Loren Pickart.<ref>		Loren Pickart (1938-2023) isolated the copper peptide GHK-Cu from human plasma ] in 1973.<ref>
	{{cite journal |last1=Pickart |first1=L |last2=Thaler |first2=MM |title=Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver |journal=Nature New Biol |year=1973 |volume=243 |issue=124 |pages=85–87 |pmid=4349963 }}</ref> Pickart noticed that liver tissue obtained from patients aged 60 to 80 years had an increased level of ]. However, when liver cells from old patients were incubated in the blood from the younger group, the older cells started functioning in nearly the same way as the younger liver tissue.<ref>{{cite journal |last1=Pilgeram |first1=L |last2=Pickart |first2=L |title=Control of fibrinogen biosynthesis; the role of free fatty acids |journal=J Atheroscler Res |year=1968 |volume=8 |pages=155–166}}</ref><ref>{{cite journal |last1=Pilgeram |first1=L |title=Control of fibrinogen biosynthesis; role of FFA/Albumin Ratio |journal=Cardiovasc Eng |year=2010 |volume=10 |issue=2 |pages=78–83 |doi=10.1007/s10558-010-9092-1}}</ref> It turned out that this effect was due to a small peptide factor that behaved similarly to the synthetic peptide glycyl-L-histidyl-L-lysine (GHK). Pickart proposed that this activity in human plasma albumin was a tripeptide glycyl-L-histidyl-L-lysine and that it might function by ] metal ions.<ref>		{{cite journal |last1=Pickart |first1=L |last2=Thaler |first2=MM |title=Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver |journal=Nature New Biology |year=1973 |volume=243 |issue=124 |pages=85–87 |pmid=4349963 }}</ref> It was noticed that liver tissue obtained from patients aged 60 to 80 years had an increased level of ]. However, when liver cells from old patients were incubated in the blood from the younger group, the older cells started functioning in nearly the same way as the younger liver tissue.<ref>{{cite journal |last1=Pilgeram |first1=L |last2=Pickart |first2=L |title=Control of fibrinogen biosynthesis; the role of free fatty acids |journal= Journal of Atherosclerosis Research|year=1968 |volume=8 |issue=1 |pages=155–166 |doi=10.1016/s0368-1319(68)80089-4|pmid=5642099 }}</ref><ref>{{cite journal |last1=Pilgeram |first1=L |title=Control of fibrinogen biosynthesis; role of FFA/Albumin Ratio |journal= Cardiovascular Engineering |year=2010 |volume=10 |issue=2 |pages=78–83 |doi=10.1007/s10558-010-9092-1|pmid=20383582 |pmc=2885297 }}</ref> It turned out that this effect was due to a small peptide factor that behaved similarly to the synthetic peptide glycyl-L-histidyl-L-lysine (GHK). Pickart proposed that this activity in human plasma albumin was a tripeptide glycyl-L-histidyl-L-lysine and that it might function by ] metal ions.<ref>
	{{cite |last=Pickart |first=L |title=A tripeptide in human plasma that increases the survival of hepatocytes and the growth of hepatoma cells |year=1973 |location=Ph.D. Thesis in Biochemistry |publisher=University of California, San Francisco}}</ref>		{{citation |last=Pickart |first=L |title=A tripeptide in human plasma that increases the survival of hepatocytes and the growth of hepatoma cells |year=1973 |location=Ph.D. Thesis in Biochemistry |publisher=University of California, San Francisco}}</ref>
			In 1977, the growth modulating peptide was shown to be a glycyl-<small>L</small>-histidyl-<small>L</small>-lysine.<ref>{{cite journal |last1=Schlesinger |first1=DH |last2=Pickart |first2=L |last3=Thaler |first3=MM |title=Growth-modulating serum tripeptide is glycyl-histidyl-lysine |journal=Cellular and Molecular Life Sciences |year=1977 |volume=33 |issue=3 |pages=324–325 |doi=10.1007/BF02002806 |pmid=858356 |s2cid=29422959 }}</ref> It is proposed that GHK-Cu modulates copper intake into cells.<ref>{{cite journal |last1=Pickart |first1=L |last2=Freedman |first2=JH |last3=Loker |first3=WJ |title=Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells |journal=Nature |year=1980 |volume=288 |pages=715–717 |doi=10.1038/288715a0 |pmid=7453802 |issue=5792|display-authors=etal|bibcode=1980Natur.288..715P |s2cid=4304271 }}</ref>
	In 1977, David Schlesinger of the Harvard University Chemistry Department confirmed that the growth modulating peptide isolated by Pickart was a glycyl-L-histidyl-L-lysine peptide.<ref>
	{{cite journal |last1=Schlesinger |first1=DH |last2=Pickart |first2=L |last3=Thaler |first3=MM |title=Growth-modulating serum tripeptide is glycyl-histidyl-lysine |journal=Cellular and Molecular Life Sci |year=1977 |volume=33 |issue=3 |pages=324–325 |doi=10.1007/BF02002806 }}</ref>
			==Wound healing ==
	Further research established that GHK peptide has a strong ] for copper and exists in two forms – GHK and GHK-Cu. On the basis of the available data, Pickart proposed that GHK-Cu functions by modulating copper intake into cells.<ref>{{cite journal |last1=Pickart |first1=L |last2=Freedman |first2=JH |last3=Loker |first3=WJ |last4=et al |title=Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells |journal=Nature |year=1980 |volume=288 |pages=715–717 |doi=10.1038/288715a0 |issue=5792}}</ref>
			===Biochemical studies===
	==Wound Healing ==
			In the late 1980s, copper peptide GHK-Cu started attracting attention as a promising ] agent. At picomolar to nanomolar concentrations, GHK-Cu stimulated the synthesis of ] in skin ], increased accumulation of total proteins, ] (in a biphasic curve) and DNA in the dermal wounds in rats. They also found out that the GHK sequence is present in collagen and suggested that the GHK peptide is released after tissue injury.<ref>{{cite journal | last1 = Maquart | first1 = FX | last2 = Pickart | first2 = L | last3 = Laurent | first3 = M | last4 = Gillery | first4 = P | last5 = Monboisse | first5 = JC | last6 = Borel | first6 = JP | year = 1988 | title = Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ | journal = FEBS Letters| volume = 238 | issue = 2| pages = 343–6 | doi=10.1016/0014-5793(88)80509-x| pmid = 3169264 | s2cid = 19289897 | doi-access = free | bibcode = 1988FEBSL.238..343M }}</ref><ref>{{Cite journal |doi = 10.1016/0024-3205(92)90504-i|pmid = 1522753|title = Stimulation of sulfated glycosaminoglycan synthesis by the tripeptide-copper complex Glycyl-L-histidyl-L-lysine-Cu2+|journal = Life Sciences|volume = 51|issue = 13|pages = 1049–1056|year = 1992|last1 = Wegrowski|first1 = Y.|last2 = Maquart|first2 = F.X.|last3 = Borel|first3 = J.P.}}</ref> They proposed a class of emergency response molecules which are released from the ] at the site of an injury.<ref>{{cite journal | last1 = Maquart | first1 = FX | last2 = Bellon | first2 = G | last3 = Pasco | first3 = S | last4 = Monboisse | first4 = JC | year = 2005 | title = Matrikines in the regulation of extracellular matrix degradation | journal = Biochimie | volume = 87 | issue = 3–4| pages = 353–60 | doi=10.1016/j.biochi.2004.10.006| pmid = 15781322 }}</ref>
	===Biochemical Studies===
			GHK-Cu also increased synthesis of ] – a small ] involved in the regulation of collagen synthesis, wound healing regulation and anti-tumor defense.<ref>{{cite journal | last1 = Siméon | first1 = A | last2 = Wegrowski | first2 = Y | last3 = Bontemps | first3 = Y | last4 = Maquart | first4 = FX | year = 2000 | title = Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+) | journal = The Journal of Investigative Dermatology| volume = 115 | issue = 6| pages = 962–8 | doi=10.1046/j.1523-1747.2000.00166.x| pmid = 11121126 | doi-access = free }}</ref>
	In the late 1980s, copper peptide GHK-Cu started attracting attention as a promising ] agent. Pioneers in this field were J.P Borel and F. Maquart from Université de Reims Champagne-Ardenne (France). Between 1988 and 2000, they found that GHK-Cu stimulated the synthesis of ] in the skin ], increased accumulation of total proteins, ] and DNA in the dermal wounds in rats. They also found out that the GHK sequence is present in collagen and suggested that the GHK peptide is released after tissue injury. <ref>Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+.FEBS Lett. 1988; 10;238(2):343-6</ref> <ref>Wegrowski Y, Maquart FX, Borel JP. Stimulation of sulfated glycosaminoglycan synthesis by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. Life Sci. 1992;51(13):1049-56</ref> They proposed a class of an emegency response molecules called matrikines, which are released from the ] at the site of an injury <ref>Maquart FX, Bellon G, Pasco S, Monboisse JC. Matrikines in the regulation of extracellular matrix degradation. Biochimie. 2005 Mar-Apr;87(3-4):353-60</ref>.
	GHK-Cu also increased synthesis of ] – a small ] involved in the regulation of collagen synthesis, wound healing regulation and anti-tumor defense.<ref>Siméon A, Wegrowski Y, Bontemps Y, Maquart FX.Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+).J Invest Dermatol. 2000;115(6):962-8</ref>
	The same group established that GHK-Cu stimulated both the synthesis of ], the enzymes which break down dermal proteins, and their inhibitors (anti-proteases). The fact that GHK-Cu not only stimulates the production of dermal components, but also regulates their breakdown suggests its regulatory role in the skin remodeling process.<ref>Siméon A, Emonard H, Hornebeck W, Maquart FX. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci. 2000; 22;67(18):2257-65</ref>		It was also established that GHK-Cu stimulates both the synthesis of ], the enzymes which break down dermal proteins, and their inhibitors (anti-proteases). The fact that GHK-Cu not only stimulates the production of dermal components, but also regulates their breakdown suggests that it should be used with caution.<ref>{{Cite journal |doi = 10.1016/s0024-3205(00)00803-1|pmid = 11045606|title = The tripeptide-copper complex glycyl-L-histidyl-L- lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures|journal = Life Sciences|volume = 67|issue = 18|pages = 2257–2265|year = 2000|last1 = Siméon|first1 = Alain|last2 = Emonard|first2 = Hervé|last3 = Hornebeck|first3 = William|last4 = Maquart|first4 = François-Xavier}}</ref>
	===Wound healing in animals===		===Wound healing in animals===
			A series of animal experiments established pronounced wound healing activity of GHK-Cu. In the dermal wounds of rabbits GHK-Cu facilitated wound healing, causing better wound contraction, faster development of granular tissue and improved ]. It also elevated the level of antioxidant ].<ref>{{cite journal | last1 = Gul | first1 = NY | last2 = Topal | first2 = A | last3 = Cangul | first3 = IT | last4 = Yanik | first4 = K | year = 2008 | title = The effects of topical tripeptide copper complex and helium-neon laser on wound healing in rabbits | journal = Veterinary Dermatology| volume = 19 | issue = 1| pages = 7–14 | doi=10.1111/j.1365-3164.2007.00647.x| pmid = 18177285 }}</ref><ref>{{cite journal | last1 = Cangul | first1 = IT | last2 = Gul | first2 = NY | last3 = Topal | first3 = A | last4 = Yilmaz | first4 = R | year = 2006 | title = Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits | journal = Veterinary Dermatology| volume = 17 | issue = 6| pages = 417–23 | doi=10.1111/j.1365-3164.2006.00551.x| pmid = 17083573 }}</ref>
	A series of animal experiments established pronounced wound healing activity of copper peptide GHK-Cu.
	In the dermal wounds of rabbits GHK-Cu facilitated wound healing, causing better wound contraction, faster development of granular tissue and improved ]. It also elevated the level of antioxidant ].<ref>Gul NY, Topal A, Cangul IT, Yanik K The effects of topical tripeptide copper complex and helium-neon laser on wound healing in rabbits. Vet Dermatol. 2008;19(1):7-14.</ref> <ref>Cangul IT, Gul NY, Topal A, Yilmaz R. Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Vet Dermatol. 2006;17(6):417-23</ref> <br />
	GHK-Cu has been found to induce a systemic enhancement of healing in rats, mice, and pigs; that is, the GHK-Cu peptide injected in one area of the body (such as the thigh muscles) improved healing at distant body areas (such as the ears). These treatments strongly increased healing parameters such as collagen production, angiogenesis, and wound closure in both wound chambers and full thickness wounds.<ref>Pickart L. Compositions for accelerating wound healing in mammals containing cupric salt or complexes with amino acid or peptide. US Patent 5,164,367, 1992.</ref> <br />
	Biotinylated GHK-Cu was incorporated into a collagen membrane, which was used as a wound dressing. This GHK-Cu enriched material stimulated wound contraction and ], as well as increased expression of antioxidant enzymes. The same material was tested for wound healing in diabetic rats. GHK-Cu treatment resulted in faster wound contraction and epithelization, higher level of ] and ], increased synthesis of collagen, and activation of fibroblasts and ].<ref>V, Kartha R, Jayakumar R.A therapeutic approach for diabetic wound healing using biotinylated GHK incorporated collagen matrices. Life Sci. 2007 ;2;80(4):275-84</ref> Ischemic open wounds in rats treated with GHK-copper healed faster and had decreased concentration of metalloproteinases 2 and 9 as well as of TNF-beta (a major inflammatory cytokine) compared with vehicle alone or with untreated wounds.<ref>Canapp SO Jr, Farese JP, Schultz GS, Gowda S, Ishak AM, 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;32(6):515-23</ref>
			GHK-Cu has been found to induce a systemic enhancement of healing in rats, mice, and pigs; that is, the GHK-Cu peptide injected in one area of the body (such as the thigh muscles) improved healing at distant body areas (such as the ears). These treatments strongly increased healing parameters such as collagen production, angiogenesis, and wound closure in both wound chambers and full thickness wounds.<ref>Pickart L. Compositions for accelerating wound healing in mammals containing cupric salt or complexes with amino acid or peptide. US Patent 5,164,367, 1992.</ref> In one study, full‐thickness wounds of 6 millimeters in diameter were created in an ischemic skin flap on the backs of rats, and for 13 days the wound sites were then treated daily with topical GHK or topical ] vehicle, or given no treatment. At the end of the study, the wound size had decreased by 64.5% in the GHK group; by 45.6% in the vehicle-treated group; and by 28.2% in the control group.<ref name="Canapp2003">{{cite journal|last1=Canapp SO Jr, Farese JP, Schultz GS, Gowda S, Ishak AM, Swaim SF, Vangilder J, Lee-Ambrose L, Martin FG|title=The effect of topical tripeptide-copper complex on healing of ischemic open wounds|journal= Veterinary Surgery|date=Nov–Dec 2003|volume=32|issue=6|pages=515–23|doi=10.1111/j.1532-950x.2003.00515.x|pmid=14648529}}</ref> The difference between the GHK group's wounds and those of the control group was significant, and was accompanied by significantly lower levels of ] and elastin-degrading ]s.<ref name="Canapp2003"/>
	===Human Trials===
	A 2% GHK gel showed promising results in treatment of 120 diabetic patients, increasing the percentage of ulcer closure from 60.8% to 98.5%, and decreasing the percentage of infection from 34% to 7%. The rate of healing was three times greater with GHK.<ref>{{cite journal |first1=Gerit D. |last1=Mulder DPM1 |first2=Leonard M. |last2=Patt PhD2 |first3=Lee |last3=Sanders DPM |last4=et al |title=Enhanced healing of ulcers in patients with diabetes by topical treatment of glycyl-l-histidyl-l-lysine
	|journal=Wound Repair Regen |year=1994 |volume=2 |issue=4 |pages=259–269 |doi=10.1046/j.1524-475X.1994.20406.x}}</ref> However, a 0.4% GHK-Cu cream failed to reach therapeutic goal in treatment of venous ulcers.<ref>{{cite journal |last1=Bishop |first1=JB |last2=Phillips |first2=LG |last3=Mustoe |first3=TA |last4=VanderZee |first4=AJ |last5=Wiersema |first5=L |last6=Roach |first6=DE |last7=Heggers |first7=JP |last8=Hill Jr |first8=DP |last9=Taylor |first9=EL |last10=Robson |first10=MC |title=A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers |journal=J Vasc Surg |year=1992 |month=Aug |volume=16 |issue=2 |pages=251–257 |pmid=1495150}}
	</ref> It is possible that that failure was due to a presence of bacterial film on hospital wounds that led to a fast degradation of the peptide. Recently, a second generation of breakdown resistant copper peptides was developed.<ref>{{cite |last=Pickart |first=L |title=Breakdown resistant copper peptides with improved wound healing actions |publisher=Wound Healing Society Meeting |location=Dallas, Texas |year=2009 |month=April |pages=26–29}}</ref>
			Biotinylated GHK-Cu was incorporated into a collagen membrane, which was used as a wound dressing. This GHK-Cu enriched material stimulated wound contraction and ], as well as increased expression of antioxidant enzymes. The same material was tested for wound healing in diabetic rats. GHK-Cu treatment resulted in faster wound contraction and epithelization, higher level of ] and ], increased synthesis of collagen, and activation of fibroblasts and ].<ref>{{cite journal | last1 = Kartha | first1 = R | last2 = Jayakumar | first2 = R | year = 2007 | title = A therapeutic approach for diabetic wound healing using biotinylated GHK incorporated collagen matrices | journal = Life Sciences| volume = 80 | issue = 4| pages = 275–84 | doi = 10.1016/j.lfs.2006.09.018 | pmid = 17049946 }}</ref> Ischemic open wounds in rats treated with GHK-copper healed faster and had decreased concentration of metalloproteinases 2 and 9 as well as of ] (a major inflammatory cytokine) compared with vehicle alone or with untreated wounds.<ref name="Canapp2003" />
	==Current Research==
	===DNA Repair===
	Radioactive anti-cancer treatment slows cell replication by breaking DNA strands. A recent study showed GHK-Cu's ability to restore function of irradiated fibroblasts to that of intact cells. The researchers used cultured human fibroblasts obtained from cervical skin that was either intact or exposed to radioactive treatment (5000 rad). At a very low (1 nanomolar) concentration, GHK-Cu stimulated irradiated fibroblasts growth and increased their production of growth factors bFGF and VGF to the point where it became even higher than that of both the irradiated and intact control cells.<ref>Pollard JD, Quan S, Kang T, Koch RJ. Effects of copper tripeptide on the growth and expression of growth factors by normal and irradiated fibroblasts. Arch Facial Plast Surg. 2005;7(1):27-31</ref>
			==Cosmetic use==
	===Nerve Regeneration===
			Copper peptide GHK-Cu is widely used in ] cosmetics (] name: Copper tripeptide-1).<ref>{{cite journal | last1 = Gorouhi | first1 = F. | last2 = Maibach | first2 = H.I. | year = 2009 | title = Role of topical peptides in preventing and treating aged skin | journal = International Journal of Cosmetic Science| volume = 31 | issue = 5| pages = 327–345 | doi=10.1111/j.1468-2494.2009.00490.x| pmid = 19570099 | s2cid = 205584531 | doi-access = free }}</ref> Several controlled facial studies confirmed ], firming and ] activity of copper peptide GHK-Cu.<ref>{{cite journal | last1 = Pickart-Margolina | year = 2018 | title = Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data | journal =International Journal of Molecular Sciences | volume = 19 | issue = 7| pages = 7| doi = 10.3390/ijms19071987 | pmid = 29986520 | pmc = 6073405 | doi-access = free }}</ref>
	In 2005, Ahmed et al. demonstrated that GHK promotes ]. ] regeneration was studied using collagen tubes with incorporated peptides. GHK increased migration of hematogenous cells into collagen tube, production of nerve growth factors, expression of ] and the rate of regeneration of myelinated nerve fibers. In addition, GHK also increased axon count and proliferation of ] compared to the control.<ref>Ahmed M.R., Basha S.H., Gopinath D., Muthusamy R., Jayakumar R. 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(1):17-30.</ref>
			==Biological chemistry==
	===Effect on Stem Cells===
	In 2009, a group of researchers from the Seoul National University (Republic of Korea) demonstrated that the copper-peptide GHK-Cu stimulated proliferation of ] and increased expression of integrins and ] protein in the ] ]. Since p63 is considered to be an important marker of stem cell and anti-] protein, the authors concluded that GHK-copper is able to revive the proliferative potential of epidermal stem cells and increase their ability to repair tissue.<ref>Kang YA, Choi HR, Na JI, Huh CH, Kim MJ, Youn SW, Kim KH, Park KC. Copper-GHK increases integrin expression and p63 positivity by keratinocytes. Arch Dermatol Res. 2009 Apr;301(4):301-6</ref>
	===Anti-Cancer Effect===		===Copper binding===
			Replacement of ] with other amino acids showed that the ] residue plays major role in copper binding, whereas ] can interact with copper only at alkaline pH. At physiological pH, lysine is able to interact with a ]. The ability of GHK to interact both with copper and with a cellular receptor may allows it to transfer copper into and from cells. The small size of GHK permits speedy traveling in extracellular space and its easy access to cellular receptors.<ref>{{Cite journal |doi = 10.1016/s0304-4165(01)00127-1|pmid = 11325542|title = Copper complexes of glycyl-histidyl-lysine and two of its synthetic analogues: Chemical behaviour and biological activity|journal = Biochimica et Biophysica Acta (BBA) - General Subjects|volume = 1526|issue = 2|pages = 199–210|year = 2001|last1 = Conato|first1 = Chiara|last2 = Gavioli|first2 = Riccardo|last3 = Guerrini|first3 = Remo|last4 = Kozłowski|first4 = Henryk|last5 = Młynarz|first5 = Piotr|last6 = Pasti|first6 = Claudia|last7 = Pulidori|first7 = Fernando|last8 = Remelli|first8 = Maurizio}}</ref>
	In 2010, Hong Y. et al. (Department of Colorectal Surgery, Singapore General Hospital, Singapore) demonstrated that GHK-Cu is able to reverse the expression of certain genes involved in ] spreading of ]. GHK-Cu was effective at a very low concentration - 1mkM.<ref>Hong Y, Downey T, Eu KW, Koh PK, Cheah PY. A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis. 2010 February 9. </ref>
			The molecular structure of the GHK copper complex (GHK-Cu) has been determined by X-ray crystallography, EPR spectroscopy, X-ray absorption spectroscopy, NMR spectroscopy, as well as other methods such as titration. In the GHK-Cu complex, the Cu (II) ion is coordinated by the nitrogen from the imidazole side chain of the histidine, another nitrogen from the alpha-amino group of glycine and the deprotonated amide nitrogen of the glycine–histidine peptide bond.
	===Genomic Studies===
			Since such a structure could not explain a high stability constant of the GHK-Cu complex (log 10 =16.44 vs. 8.68 of the GH copper complex, which is similar to the GHK-Cu structure), it was proposed that another amino group participates in the complex formation. Cu(II) is also coordinated by the oxygen from the carboxyl group of the lysine from the neighboring complex. Another carboxyl group of lysine from a neighboring complex provides the apical oxygen, resulting in the square-planar pyramid configuration.<ref>{{cite journal | last1 = Hureau | first1 = C. | last2 = Eury | first2 = H. | last3 = Guillot | first3 = R. | last4 = Bijani | first4 = C. | last5 = Sayen | first5 = S. | last6 = Solari | first6 = P.L. | last7 = Guillon | first7 = E. | last8 = Faller | first8 = P. | last9 = Dorlet | first9 = P | year = 2011 | title = X-ray and solution structures of Cu(II) GHK and Cu(II) DAHK complexes: influence on their redox properties | journal = Chemistry: A European Journal | volume = 17 | issue = 36| pages = 10151–60 | doi=10.1002/chem.201100751| pmid = 21780203 | doi-access = free }}</ref>
	Recent genomic research suggests that GHK directly modulates gene expression, which may explain the diversity of its biological actions.
			Many researchers proposed that at the physiological pH, GHK-Cu complexes can form binary and ternary structures which may involve amino acid histidine and/or the copper binding region of the albumin molecule. Lau and Sarkar found also that GHK can easily obtain copper 2+ bound to other molecules such as the high affinity copper transport site on plasma albumin (albumin binding constant log 10 =16.2 vs. GHK binding constant 16 log 10 =16.44). It has been established that copper (II) redox activity is silenced when copper ions are complexed with the GHK tripeptide, which allows the delivery of non-toxic copper into the cell.<ref>{{cite journal | last1 = Lau | first1 = S.J. | last2 = Sarkar | first2 = B. | year = 1981 | title = The interaction of copper(II) and glycyl-L-histidyl-L-lysine, a growth-modulating tripeptide from plasma | journal = Biochemical Journal| volume = 199 | issue = 3| pages = 649–56 | doi=10.1042/bj1990649| pmid = 7340824 | pmc = 1163421 }}</ref>
	Iorio et al. used a repository of transcriptional responses to compounds, the Connectivity Map (cMap)<ref>Lamb J. The Connectivity Map: a new tool for biomedical research. Nat. Rev. Cancer. 2007;7(1):54-60.</ref>, and MANTRA software<ref>www.mantra.tigem.it</ref> to explore networks of compounds producing similar transcriptional responses. GHK, as one of the compounds studied, increased mRNA production in 268 genes while suppressing 167.<ref>Iorio F., Bosotti R., Scacheri E. et al. Discovery of drug mode of action and drug repositioning from transcriptional responses. Proc. Natl. Acad. Sci. USA, 2010;17 (107):14621-14626.</ref>
			===Biological significance===
			Copper is vital for all ] organisms from microbes to humans. A dozen enzymes (cuproenzymes) use changes in copper oxidation state to catalyze important biochemical reactions including ] (]), antioxidant defense (ceruloplasmin, superoxide dismutase (SOD), detoxification (metallothioneins), blood clotting (blood clotting factors V and VIII), melanin production (tyrosinase) and the connective tissue formation (lysyl peroxidase). Copper is required for iron metabolism, oxygenation, ], embryonic development and many other essential biological processes. Another function of copper is signaling – for example, stem cells require a certain level of copper in the media to start their ] into cells needed for repair. Thus, GHK-Cu's ability to bind copper and to modulate its tissue level is a key factor determining its biological activity.<ref>Pickart L. The human tripeptide GHK (Glycyl-L-histidyl-L-Lysine), the copper switch and the treatment of the degenerative conditions of aging. In Anti-Aging Therapeutics Volume XI, 301-3012. Ed. By Klatz R. and Goldman R. Chicago, IL, USA: American Academy of Medicine, 2009</ref>
	==Cosmetic Use==		==See also==
			* ] unknown but heavier molecule
	===Facial Studies===
	Copper peptide GHK-Cu is widely used in ] cosmetics (] name: Copper tripeptide-1).<ref>Gorouhi F., Maibach H.I. Role of topical peptides in preventing and treating aged skin. Int. J. Cosm. Sci., 2009;31:327-345</ref> Several controlled facial studies confirmed ], firming and ] activity of copper peptide GHK-Cu.<br>
	Abdulghani et al. established that facial cream containing GHK-Cu increased collagen in photoaged skin of 20 female volunteers, performing better than ] and ].<ref>Abdulghani, AA, Sherr S, Shirin S, Solodkina G, Tapia EM,Gottlieb AB. Effects of topical creams containing vitamin C, a copper-binding peptide cream and melatonin compared with tretinoin on the ultrastructure of normal skin - A pilot clinical, histologic, and ultrastructural study. Disease Manag Clin Outcomes. 1998;1:136-141</ref><br>
	Leyden et al. conducted 12 weeks facial study of GHK-Cu containing face and eye cream, reporting significant improvement of skin laxity, clarity and appearance, reduced fine lines and the depths of ] and increased skin density and thickness comparing to ]. GHK-Cu eye cream performed better than vitamin K cream.<ref>Leyden J, Stephens T, Finkey MB, Appa, Y, Barkovic S, Skin Care Benefits of Copper Peptide Containing Facial Cream. Amer Academy Dermat Meeting, February 2002, Abstract P68, P69</ref><br>
	Finkley et al. conducted 12 week facial study on 67 women and reported that GHK-Cu cream applied twice daily improved aged skin appearance, increased thickness, reduced wrinkles and strongly stimulated dermal keratinocyte proliferation as determined by histological analysis of biopsies. The same study found copper peptide GHK-Cu to be non-toxic and non-irritating.<ref>Finkley MB, Appa Y, Bhandarkar S. Copper Peptide and Skin. Cosmeceuticals and Active Cosmetic, 2nd Edition, P. Eisner and H.I. Maibach (Eds.) Marcel Dekker, New York. 2005:549-563</ref>
	===Hair Growth===
	Copper peptide GHK-Cu and its analogues were found to strongly stimulate ]. The efficiency of synthetic analog of GHK-Cu was similar to that of 5% ].<ref>Uno H, Kurata S Chemical agents and peptides affect hair growth. J Invest Dermatol. 1993 Jul;101(1 Suppl):143S-147S</ref> A commercial product GraftCyte was clinically proven to improve ] outcome. Another hair product that contains copper-peptide GHK-Cu is ].<ref>Perez-Meza D, Leavitt M, Trachy R. Clinical evaluation of GraftCyte moist dressings on hair graft viability and quality of healing. Inter. J. Cos. Surg. 1988;6:80-84</ref>
	==Biological Chemistry==
	===Copper Binding===
	Research of the copper binding properties of GHK and two synthetic peptides, in which ] was replaced with a synthetic amino acid, established that the amino acid ] plays major role in copper binding, while ] can interact with copper only at alkaline pH. At physiological pH, lysine is able to interact with a ]. The ability of GHK to interact both with copper and with a cellular receptor allows it to transfer copper into and from cells. The small size of GHK permits speedy traveling in extracellular space and its easy access to cellular receptors.<ref>Conato at al. Copper complexes of glycyl-histidyl-lysine and two of its synthetic analogues: chemical behaviour and biological activity. Biochim Biophys Acta. 2001; 3;1526(2):199-210</ref>
	===Biological Significance===
	Copper is a transitional metal that is vital for all ] organisms from microbes to humans. A dozen enzymes (cuproenzymes) use changes in copper oxidation state to catalyze important biochemical reactions including ] (]), antioxidant defense (ceruloplasmin, superoxide dismutase (SOD), detoxification (metallothioneins), blood clotting (blood clotting factors V and VIII), melanin production (tyrosinase) and the connective tissue formation (lysyl peroxidase). Copper is required for iron metabolism, oxygenation, ], embryonic development and many other essential biological processes. Another function of copper is signaling – for example, stem cells require a certain level of copper in the media to start their ] into cells needed for repair. Thus, GHK-Cu’s ability to bind copper and to modulate its tissue level is a key factor determining its biological activity.<ref>Pickart L. The human tripeptide GHK (Glycyl-L-histidyl-L-Lysine), the copper switch and the treatment of the degenerative conditions of aging. In Anti-Aging Therapeutics Volume XI, 301-3012. Ed. By Klatz R. and Goldman R. Chicago, IL, USA: American Academy of Medicine, 2009</ref>
	==References==		==References==
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