Copper peptide GHK-Cu is a naturally occurring copper complex of a glycyl-L-histidyl-L-lysine peptide. Since it has three amino acids it is called tripeptide. The GHK-Cu tripeptide has strong affinity for copper(II) and was first isolated from human plasma. It can be found also in saliva and urine.
Overview[edit]
Copper peptides are naturally occurring small protein fragments that have high affinity to copper ions.[2] In human plasma, the level of GHK-Cu is about 200 µg/ml at age 20. By the age of 60, the level drops to 80 µg/ml. In humans, tripeptide GHK-Cu can promote activation of wound healing, attraction of immune cells, antioxidant and anti-inflammatory effects, stimulation of collagen and glycosaminoglycan synthesis in skin fibroblasts and promotion of blood vessels growth. Recent studies revealed its ability to modulate rmStringexpression of a large number of human genes, generally reversing gene rmStringexpression to a healthier state. Synthetic GHK-Cu is used in cosmetics as a reparative and anti-aging ingredient.[3]
History[edit]
Loren Pickart isolated the copper peptide GHK-Cu from human plasma albumin in 1973.[4] Pickart noticed that liver tissue obtained from patients aged 60 to 80 years had an increased level of fibrinogen. 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.[5][6] 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 chelating metal ions.[7]
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.[8]
Further research established that GHK peptide has a strong affinity for copper and exists in two forms – GHK and GHK-Cu. On the basis of the available data, it was proposed that GHK-Cu functions by modulating copper intake into cells.[9]
Wound healing[edit]
Biochemical studies[edit]
In the late 1980s, copper peptide GHK-Cu started attracting attention as a promising wound healing agent. Pioneers in this field were J.P Borel and F. Maquart from Université de Reims Champagne-Ardenne (France). At optimal, picomolar to nanomolar concentrations, GHK-Cu stimulated the synthesis of collagen in skin fibroblasts, increased accumulation of total proteins, glycosaminoglycans (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.[10][11] They proposed a class of emergency response molecules which are released from the extracellular matrix at the site of an injury.[12] GHK-Cu also increased synthesis of decorin – a small proteoglycan involved in the regulation of collagen synthesis, wound healing regulation and anti-tumor defense.[13]
The same group established that GHK-Cu stimulated both the synthesis of metalloproteinases, 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.[14]
Wound healing in animals[edit]
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 angiogenesis. It also elevated the level of antioxidant enzymes.[15][16]
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.[17]
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 cell proliferation, as well as increased rmStringexpression 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 glutathione and ascorbic acid, increased synthesis of collagen, and activation of fibroblasts and mast cells.[18] 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.[19]
Human trials[edit]
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.[20] However, a 0.4% GHK-Cu cream failed to reach therapeutic goal in treatment of venous ulcers.[21]
Current research[edit]
Anti-inflammatory activity[edit]
GHK peptide has anti-inflammatory properties. Even though an exact mechanism remains unclear, in a recent study GHK and its copper complexes decreased TNF-alpha-dependent IL-6 secretion in normal human dermal fibroblasts. Because of the anti-inflammatory properties, copper-peptides could replace corticosteroids or non-steroidal anti-inflammatory drugs in treatment of inflammatory skin conditions. They also can reduce UV-induced erythema.[22]
DNA repair[edit]
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.[23]
Nerve regeneration[edit]
In 2005, Ahmed et al. demonstrated that GHK promotes nerve regeneration. Axon regeneration was studied using collagen tubes with incorporated peptides. GHK increased migration of hematogenous cells into collagen tube, production of nerve growth factors, rmStringexpression of integrins and the rate of regeneration of myelinated nerve fibers. In addition, GHK also increased axon count and proliferation of Schwann cells compared to the control.[24]
Effect on stem cells[edit]
In 2009, a group of researchers from the Seoul National University (Republic of Korea) demonstrated that the copper-peptide GHK-Cu stimulated proliferation of keratinocytes and increased rmStringexpression of integrins and p63 protein in the epidermal stem cells. Since p63 is considered to be an important marker of stem cell and anti-senescence protein, the authors concluded that GHK-copper is able to recover epidermal stem cells and increase their ability to repair tissue. [25] In 2012, the same group reported that similar activity was observed for copper-free GHK.[26]
Anti-cancer effect[edit]
In 2010, Hong Y. et al. demonstrated that GHK-Cu is able to reverse the rmStringexpression of certain genes involved in metastatic spreading of colon cancer. GHK-Cu was effective at a very low concentration - 1mkM.[27] A 2012 paper reports that GHK, at a very low concentration, does not harm normal fibroblasts (a major repair cell) but did induce programmed cell death two cancer cell lines. Thus, GHK reversed this effect of the cancer cells on the genes.[28]
Genomic studies[edit]
Recent genomic research suggests that GHK directly modulates gene rmStringexpression, which may explain the diversity of its biological actions. Iorio et al. used a repository of transcriptional responses to compounds, the Connectivity Map (cMap),[29] and MANTRA software 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.[30] GHK was found to reverse the gene-rmStringexpression signature of emphysematous destruction found in lung tissue obtained from smokers with COPD (Chronic Obstructive Pulmonary Disease). The gene rmStringexpression signature associated with emphysema severity included 127 genes, involved in inflammation and repair. Using the Connectivity Map, researchers established that the peptide GHK downregulated genes involved in lung destruction and inflammation, while upregulating genes involved in tissue repair. Addition of 10 nanomolar GHK to lung fibroblasts from emphysema lungs restored their ability to remodel collagen and assemble it into properly organized fibrils.[31]
Cosmetic use[edit]
Facial studies[edit]
Copper peptide GHK-Cu is widely used in anti-aging cosmetics (INCI name: Copper tripeptide-1).[32] Several controlled facial studies confirmed anti-aging, firming and anti-wrinkle activity of copper peptide GHK-Cu.
Abdulghani et al. established that facial cream containing GHK-Cu increased collagen in photoaged skin of 20 female volunteers, performing better than vitamin C and retinoic acid.[33]
Leyden et al. conducted a 12-week 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 wrinkles and increased skin density and thickness comparing to placebo. GHK-Cu eye cream performed better than vitamin K cream.[34]
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.[35]
Hair growth[edit]
Copper peptide GHK-Cu and its analogues were found to stimulate hair growth. In some circumstances, the efficiency of synthetic analog of GHK-Cu was similar to that of 5% minoxidil.[36] A commercial product GraftCyte was clinically proven to improve hair transplantation outcome.[37]
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