New Data of the Cosmeceutical and TriPeptide GHK
SOFW Journal (2015)
GHK-Cu May Prevent Oxidative Stress in Skin
by Regulating Copper and Modifying Expression of
Numerous Antioxidant Genes Cosmetics (2015)
GHK Peptide as a Natural Modulator of
Multiple Cellular Pathways in Skin Regeneration (2015)
GHK, the Human Skin Remodeling Peptide Induces Anti-Cancer
Expression and DNA Repair Analytical Oncology (2014)
GHK and DNA: Resetting the Human Genome to Health
BioMed Research International (2014)
Avoid Buying Fake Copper Peptides Dangerous

Anti-Inflammatory Actions: Damaged Tissue   

The anti-oxidant actions of GHK and GHK-Cu that help to protect injured tissue appear to have multiple actions. These are (1) a direct anti-inflammatory of the copper-peptide complex, (2) an activity that blocks the release of free iron from ferritin molecules, (3) an ability to block tissue damage caused by interleukin-1 at a GHK-Cu concentration of about 10exp(-10) M, and (4) an ability to block the oxidation of low density lipoproteins (LDL) by free copper.

Anti-Oxidant Actions 
Development of tissue protective analogs of GHK-Cu 
GHK-Cu and analogs were tested for anti-oxidant and tissue protective properties GHK-Cu and analogs were found to enhance or restore resistance to oxidative or inflammatory damage. Certain analogs were 100-fold more effective than GHK-Cu.
US Patent 5,118,665   New anti oxidative and anti-inflammatory metal peptide complexes - containing glycine, histidine and lysine residues used to enhance or restore resistance to oxidative or inflammatory damage.  Pickart
Blocking of iron oxidation
A study of whether some of the wound healing properties of GHK-Cu are due to an affect on iron metabolism. The presence of iron complexes in damaged tissues is detrimental to wound healing, due to local inflammation, as well as microbial infection mediated by iron. The effects of GHK:Cu(II) on iron catalyzed lipid peroxidation. GHK:Cu(II) inhibited lipid peroxidation if the iron source was ferritin. Whereas GHK:Cu(II) inhibited ferritin iron release it did not exhibit significant superoxide dismutase-like or ceruloplasmin activity. It appears that  GHK-Cu binds to the channels of ferritin involved in iron release and physically prevents the release of fee). Thus, a biological effect of GHK:Cu(II), related to wound healing, may be the inhibition of ferritin iron release in damaged tissues, preventing inflammation and microbial infections. 
Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation.  Miller, DeSilva, Pickart, Aust. Pickart and Aust  (Biotechnology Center, Utah State University, Logan, UT, USA)  Adv. Exp Med Biol 1990;264:79-84 
Finding of superoxide dismutase and catalase-like activities in GHK Nickel complexes

The reactions between nickel ions and GHK and similar oligopeptides were characterized by spin trapping  experiments.

GHK-Cu possessed superoxide dismutase and catalase-like activities.

Redox chemistry of complexes of nickel) with some biologically important peptides in the presence of reduced oxygen species.  Coterie N; Tremolieres E; Berliner JCL; Cattier JP; Henichart JP  (INSERM, Ill, France)  J Internat BioPharm 1992 Apr;46(1):7-15
Cytoprotective actions against oxygen free radicals
GHK-Cu markedly inhibited intestinal mucosal tissue from lipid peroxidation by oxygen-derived free radicals.
Alberghina M, Lupo G, La Spina G, Mangiameli A, Gulisano M, Sciotto D, Rizzarelli E, Cytoprotective effect of copper(II) complexes against ethanol-induced damage to rat gastric mucosa, J Inorg Biochem. 1992 Mar;45(4):245-59.
Anti-oxidant protection of insulin secreting cells after injury. Interleukin beta (IL-1 beta) is released during injuries and after tissue damage. IL-1 inhibits insulin release by pancreatic cells.
The study tested whether GHK-Cu would block the IL-1 damage to insulin secreting pancreatic cells. Rat pancreatic islet cells  were incubated with or without 50 U/ml IL-1 beta, in the presence or absence of various  concentrations of Cu(II)-GHK or CuSO4 (1-1000 ng/ml). After  incubation, insulin secretion was evaluated in the presence of either 2.8 mmol/l (basal insulin secretion) or 16.7 mmol/l glucose (glucose-induced release). In control islets, basal insulin secretion was 92 +/- 11 ( pg/islet) and glucose-induced release was 2824 +/- 249. In islets pre-exposed to 50 U/ml IL-1 beta, basal insulin release was not significantly affected but glucose- induced insulin release was greatly reduced (841 +/-  76 ). In islets incubated with IL-1 beta and Cu-GHK (0.4 mumol/l, maximal effect) basal secretion was 119.0 +/- 13 and  glucose-induced release was 2797 +/- 242. CuSO4 was without protective actions.
Copper addition prevents the inhibitory effects of interleukin 1-beta on rat pancreatic islets,  Vinci, Caltabiano, Santoro, Rabuazzo, Buscema, Purrello, Rizzarelli, Vigneri and Purrello  (University of Catania Medical  Endocrinology, University of Catania Medical School, Italy)  Diabetologia 1995 38(1):39-45 
Increase superoxide dismutase in wounds
Biotin was attached to GHK then bound to collagen films. This gave increased wound contraction, increased cell proliferation, and produced a high expression of the antioxidant superoxide dismutase. Tissue copper levels were increased 9-fold.
Arul V, Gopinath D, Gomathi K, Jayakumar R. Biotinylated GHK peptide incorporated collagenous matrix: A novel biomaterial for dermal wound healing in rats. Biomed Mater Res B Appl Biomater. 2005 May;73(2):383-91
GHK detoxifies 4-hydroxy-2-nonenal, a toxic mlecule
GHK blocks the toxic actions of 4-hydroxy-2-nonenal (HNE), a fatty acid decomposition product felt to be causative in the development of diabetes, nephropathy, retinopathy, and neurodegenaerative diseases.

Beretta G, Artali R, Regazzoni L, Panigati M, Facino RM, Glycyl-histidyl-lysine (GHK) is a quencher of alpha,beta-4-hydroxy-trans-2-nonenal: a comparison with carnosine. insights into the mechanism of reaction by electrospray ionization mass spectrometry, 1H NMR, and computational techniques.
Chem Res Toxicol. 2007 Sep;20(9):1309-14.

GHK blocks block acrolein production
Acrolein is a toxin created by carbonyl radicals from polyunsaturated fatty acids. GHK detoxifies acrolein. The authors suggest that GHK may be of value in prevention of atherosclerosis, diabetes, neuropathy, and Alzheimer disease.

Beretta G, Arlandini E, Artali R, Anton JM, Maffei Facino R.

Acrolein sequestering ability of the endogenous tripeptide glycyl-histidyl-lysine (GHK): Characterization of conjugation products by ESI-MS(n) and theoretical calculations.
J Pharm Biomed Anal. 2008 Jul 15;47(3):596-602.

Anti-Inflammatory Actions: General  

Blocking the oxidation of low density lipoproteins GHK tested on effecting the extent of in vitro Cu(2+)-dependent oxidation of low density lipoproteins (LDL)
GHK blocked the extent of in vitro Cu(2+)-dependent oxidation of low density lipoproteins (LDL).  Treatment of LDL with 5 microM of copper (+2) for 18 h in either phosphate buffered saline (PBS) or Ham's F-10 medium resulted in extensive oxidation as determined by the content of  thiobarbituric acid reactive substances (TABORS). In PBS, oxidation was entirely blocked by gly-his-lys (GHK). In comparison , superoxide dismutase (SOD) provided only 20% protection. 
The influence of medium components on Cu(2+) dependent oxidation of low- density lipoproteins and its sensitivity to superoxide  dismutase.  Thomas  (Marion Merle Dow Research Institute, Cincinnati, Ohio, USA)  Biochem Biophys Acta 1992 1128(1):50-7 
Angiotensin II appears to incite inflammatory processes that accelerated atheroma development.  GHK  interacts with the angiotensin II AT1 receptor.

The effect of GHK on phosphorylase A was determined. Binding competition experiments using the radioligand [125I][Sar1-Ile8] angiotensin II measured the interaction of GHK  with AT1 receptors.
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 GHK 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 GHK 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
GHK-Cu inhibits platelet aggregation
GHK-Cu inhibits platelet aggregation at 10exp (-7) M
Unpublished studies.  Savage, Pickart, et al,  Hope Heart Institute, Seattle, Washington, USA
GHK-Cu inhibits thromboxane production
Significant inhibition at 10exp (-7) M
Unpublished studies.  Savage, Pickart, et al,  Hope Heart Institute, Seattle, Washington, USA

Gene Expression that Suggests Antioxidant Activity


Percent Change in Gene Expression




Inhibits the oxidative/inflammatory gene NF-κB.



This proline-rich, antioxidant protein protects outer skin cells from oxidative damage from ROS. When the ROS level is low, the protein remains in the outer cell membrane but when the ROS level is high, the protein clusters around the cell's DNA to protect it.



Upregulation of ITGB4 promotes wound repair ability and antioxidative ability.



Binds oxidized phospholipids and increases the antioxidant effect of HDL.



Absence of PON3 (paraoxonase 3) in mice resulted in increased rates of early fetal and neonatal death. Knockdown of PON3 in human cells reduced cell proliferation and total antioxidant capacity.



The protein encoded by this gene is an inhibitor of the pro-inflammatory cytokine IL18. IL18BP abolished IL18 induction of interferon-gamma (IFNgamma), IL8, and activation of NF-κB in vitro. Blocks neutrophil oxidase activity.



Inhibits the conversion of Fe(2+) to Fe(3+). HEPH increases iron efflux, lowers cellular iron levels, suppresses reactive oxygen species production, and restores mitochondrial transmembrane potential.



Acts as a direct negative regulator of NLRP3. NLRP3 triggers the maturation of the pro-inflammatory cytokines IL-1β and IL-18.



Reduces intracellular ROS level. Plays a significant role in reduction of oxidative stress.



PON1 (paraoxonase 1) is a potent antioxidant and a major anti-atherosclerotic component of high-density lipoprotein.



Metallothioneins (MTs) display in vitro free radical scavenging capacity, suggesting that they may specifically neutralize hydroxyl radicals. Metallothioneins and metallothionein-like proteins isolated from mouse brain act as neuroprotective agents by scavenging superoxide radicals.



Produces cyclooxygenase-II (COX-II) which has antioxidant activities.



The p53-SLC2A9 pathway is a novel antioxidant mechanism. During oxidative stress, SLC2A9 undergoes p53-dependent induction, and functions as an antioxidant by suppressing ROS, DNA damage and cell death.



Nuclear respiratory factor 2 helps activate antioxidant responsive element regulated genes which contribute to the regulation of the cellular antioxidant defense systems.



Produces cyclooxygenase-I (COX-I) which has antioxidant activity.



GHK suppresses this pro-oxidant TNF gene.



This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO). High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis (From NCBI GENE entry).


Anti-Oxidant and Anti-Inflammatory Actions of GHK and GHK-Cu

Human NSAIDs       

GHK and GHK-Cu may function as the circulating human non-steroidal anti-inflammatories (NSAIDs). In human plasma there is about 200 nanograms per milliliters of GHK and GHK-Cu at age 20. This declines to about 80 nanograms per milliliter at age 60 but these levels are highly variable. Given the respective binding constants for copper(+2) between GHK and albumin in human plasma, it is likely that only about 10% of circulating GHK is chelated with copper(+2). In areas of tissue damage, this ratio could be higher because of lowered albumin concentrations. There are very close similarities between the three dimensional chemical structures of GHK-Cu and H2-Receptor antagonists used as anti-ulcer medicines such as cimetidine, ranitidine, famotidine and nizatidine. Since GHK-Cu is a normal component of saliva present at about 40 nanograms/milliliter, it may function a natural protector of gastrointestinal linings.  Also, most common anti-ulcer drugs are potent binders of ionic copper (II).There are also similarities, though less obvious, between most Non-Steroidal Anti-Inflammatory Drugs (NAISDs) and GHK. Virtually all NSAIDs avidly bind copper(+2).

Similarities between GHK and Anti- Ulcers Pharmaceutics 
Note the 3 main components - 
(1) an N-terminal side change, 
(2) and central imidazole ring, 
(3) a C-terminal - lysine-like - very basic group 


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