Tissue remodeling follows the initial phase of wound healing and stops inflammatory and scar-forming processes, then restores the normal tissue morphology. The human peptide Gly-(L-His)-(L-Lys) or GHK, has a copper 2+ (Cu(2+)) affinity similar to the copper transport site on albumin and forms GHK-Cu, a complex with Cu(2+). These two molecules activate a plethora of remodeling related processes: (1) chemoattraction of repair cells such as macrophages, mast cells, capillary cells; (2) anti-inflammatory actions (suppression of free radicals, thromboxane formation, release of oxidizing iron, transforming growth factor beta-1, tumor necrosis factor alpha and protein glycation while increasing superoxide dismutase, vessel vasodilation, blocking ultraviolet damage to skin keratinocytes and improving fibroblast recovery after X-ray treatments); (3) increases protein synthesis of collagen, elastin, metalloproteinases, anti-proteases, vascular endothelial growth factor, fibroblast growth factor 2, nerve growth factor, neutrotropins 3 and 4, and erythropoietin; (4) increases the proliferation of fibroblasts and keratinocytes; nerve outgrowth, angiogenesis, and hair follicle size. GHK-Cu stimulates wound healing in numerous models and in humans. Controlled studies on aged skin demonstrated that it tightens skin, improves elasticity and firmness, reduces fine lines, wrinkles, photodamage and hyperpigmentation. GHK-Cu also improves hair transplant success, protects hepatic tissue from tetrachloromethane poisoning, blocks stomach ulcer development, and heals intestinal ulcers and bone tissue. These results are beginning to define the complex biochemical processes that regulate tissue remodeling.

Glycyl-L-histidyl-L-lysine (GHK) is a tripeptide with affinity for copper(H) ions and was isolated from human plasma.This peptide appears to play a physiological role in wound healing. We report the stimulating effect of GHK-Cu on collagen synthesis by fibroblasts. The stimulation began between IO-'2 and IO-" M, maximized at 10e9 M, and was independent of any change in cell number. The presence of a GHK triplet in the a;(I) chain of type I collagen suggests that the tripcptide might be liberated by proteases at the site of a wound and exert in situ healing effects.

GHK (glycyl-L-histidyl-L-lysine) is present in human plasma, saliva, and urine but declines with age. It is proposed that GHK functions as a complex with copper 2+ which accelerates wound healing and skin repair. GHK stimulates both synthesis and breakdown of collagen and glycosaminoglycans and modulates the activity of both metalloproteinases and their inhibitors. It stimulates collagen, dermatan sulfate, chondroitin sulfate, and the small proteoglycan, decorin. It also restores replicative vitality to fibroblasts after radiation therapy. The molecule attracts immune and endothelial cells to the site of an injury. It accelerates wound-healing of the skin, hair follicles, gastrointestinal tract, boney tissue, and foot pads of dogs. It also induces systemic wound healing in rats, mice, and pigs. In cosmetic products, it has been found to tighten loose skin and improve elasticity, skin density, and firmness, reduce fine lines and wrinkles, reduce photodamage, and hyperpigmentation, and increase keratinocyte proliferation. GHK has been proposed as a therapeutic agent for skin inflammation, chronic obstructive pulmonary disease, and metastatic colon cancer. It is capable of up- and downregulating at least 4,000 human genes, essentially resetting DNA to a healthier state. The present review revisits GHK's role in skin regeneration in the light of recent discoveries.

The plasma tripeptide glycyl-L-lysine (GHL), when added at nanomolar concentrations to a wide group of cultured systems, produces a disparate set of responses ranging from the stimulation of growth and differentiation to outright toxicity. Such diverse actions imply that this tripeptide mediates some basic biochemical function common to many types of cells and organisms. During the isolation of GHL we found the compound to co-isolate through a number of steps with approximately equimolar copper and about 1/5 molar iron. Maximal effects on hepatoma cells (HTC4) were seen when the peptide was added with copper and iron to the growth medium. Structure-function studies revealed that several tripeptides with a histidyl-lysyl linkage were nearly as active as GHL. The association of GHL with copper and a homology similarity between the tripeptide and the copper transport sites on albumin and alpha-fetoprotein, where the cupric atom is bound to a histidyl residue adjacent to a basic residue, suggested that GHL may act as a copper transport factor. We report here that the tripeptide readily forms complexes with copper(II) and enhances the uptake of the metal into cultured hepatoma cells.

Oxidative stress, disrupted copper homeostasis, and neuroinflammation due to overproduction of proinflammatory cytokines are considered leading causative factors in development of age-associated neurodegenerative conditions. Recently, a new mechanism of aging—detrimental epigenetic modifications—has emerged. Thus, compounds that possess antioxidant, anti-inflammatory activity as well as compounds capable of restoring copper balance and proper gene functioning may be able to prevent age-associated cognitive decline and ward off many common neurodegenerative conditions. The aim of this paper is to bring attention to a compound with a long history of safe use in wound healing and antiaging skin care. The human tripeptide GHK was discovered in 1973 as an activity in human albumin that caused old human liver tissue to synthesize proteins like younger tissue. It has high affinity for copper ions and easily forms a copper complex or GHK-Cu. In addition, GHK possesses a plethora of other regenerative and protective actions including antioxidant, anti-inflammatory, and wound healing properties. Recent studies revealed its ability to up- and downregulate a large number of human genes including those that are critical for neuronal development and maintenance. We propose GHK tripeptide as a possible therapeutic agent against age-associated neurodegeneration and cognitive decline.