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GHK and DNA: Resetting the Human Genome to Health
BioMed Research International (2014)
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GHK-Cu - Function in Human Body     

A number of names have been used in the scientific literature for GHK.

  Names and identifications used for GHK
Systematic name  N(2)-(N-Glycyl-L-histidyl)-L-lysine 
CAS Registration number  49557-75-7 
Molecular Formula C14-H24-N6-O4
General name  Glycyl-histidyl-lysine 
Synonyms

Copper glycyl-histidyl-lysine 
Copper(II)ghk

GHK Copper 2+
Glycylhistidyllysine 
Gly-his-lys 
Iamin 
NSC 379527
Prezatide (or Prezatide Copper as a complex)

 

What is the function of GHK in the human body?

GHK appears to be a molecule that resets gene expression to that of a young adult age of about age 20 to 25.

During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, boney tissue) , increases collagen, decorin, angiogenesis, and nerve outgrowth, possesses anti-oxidant and anti-inflammatory effects, increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Recently, GHK has been found the reset genes of diseased cells from patients with cancer patients or COPD to a more healthy state. Cancer cells reset their programmed cell death system while COPD patients cells shut down tissue distructive genes and activated repair and remodeling activities. GHK also affect on genes that suppress fibrinogen synthesis and the insulin/insulin-like system, and inhibits cancer growth. It activates genes of that increase the ubiquitin-proteasome system, DNA repair, anti-oxidant systems, and healing by the TGF-beta Superfamily.

GHK is present blood plasma, saliva, and urine in physiologically active quantities. Evidence suggests that it is a biochemical feedback signal that is generated after tissue injury. It appears to have two main functions: (1) first as a potent tissue protective, anti-inflammatory agent that limits oxidative damage after tissue injury, and (2) as a signal that activates tissue remodeling, that is, the processes for removal of damaged protein and scar tissue and their replacement by normal tissue. Thus, GHK-Cu links the processes of removal of damaged scar tissue and deposition of new tissue.       

GHK, which is generated in damaged tissues and during normal tissue turnover, directly accelerates many healing associated properties at concentration of around 10exp(-10)M. Some of the GHK stimulated effects seem to be directly mediated by GHK or GHK-Cu after it obtains copper (II) from albumin. Other actions of GHK and GHK-Cu are likely to arise from GHK-Cu's attraction of wound macrophages and other healing-associated immune cells which, in turn, release families of growth factor proteins appropriate to the repair of the damaged tissue.       

Francois Maquart and colleagues at Reims have argued that GHK-Cu acts on the second phase of healing as an inducer of tissue remodeling processes. Further support for this concept is that the molecular weight of collagen fragments induced by GHK-Cu are much smaller than those produced in the early phase of wound repair. This suggests that, with the copper complex, collagen synthesis and degradation are simultaneously occurring. Also, in cell culture, GHK-Cu reduces the secretion of the scar producing protein, TGF-beta-1 by normal fibroblasts and keloid-producing fibroblasts. This, combined with GHK-Cu's healing activities, suggests that scar-free healing needs both, an activation of metalloproteinases, and a reduction in TGF-beta-1 production.



In brief, the biochemical actions that suggest that GHK-Cu functions a a feedback signal for tissue protection and repair/remodeling after tissue injury are:

1. GHK is a very rare sequence in human proteins and exists mainly in inflammation associated proteins such as collagen, thrombospondin, fibrin a-chain, prokininogen, complement C1q, interleukin 4, skin collagenase, coagulation factor XI, and SPARC. Biologically effective levels of (10exp (-10) M) of GHK and GHK-Cu are generated by proteolysis after tissue damage.

2. Human plasma levels are significant but highly variable - averaging about 200 nanograms/milliliter at age 20 (10exp (-7) M) but dropping to about 80 nanograms/milliliter at age 70. Tissue regeneration also drops similarly with age. GHK-Cu appears to be bound to the plasma protein albumin. There are relatively few other small peptides in human plasma. GHK is found in lower levels in saliva and urine.

3. In human plasma and damaged tissues, GHK is likely to exist as a mixture of GHK and GHK-Cu. GHK has high binding affinity for copper (II) - pK=16.2 - very close to the affinity for copper (II) of albumin. GHK effectively competes with albumin for copper. However, under physiological conditions only about 5% to 20% of GHK molecules would be expected to exist as GHK-Cu complexes with copper (II).

4.  GHK is a extremely potent chemoattractant (active at 10exp (-12) M) for mast cells, wound macrophages and polymorphonuclear cells, all of which release protein growth factor proteins that stimulate tissue repair.

5. GHK-Cu links the processes of removal of damaged scar tissue and deposition of new tissue. In cell culture systems, and in vivo in rats and mice, GHK-Cu, acts directly, in a dose dependent manner, at approximately (10exp (-9) M), on fibroblasts by increasing the production of m-RNA for, and protein synthesis of, collagen, elastin, proteoglycans, glycosaminoglycans and decorin. In addition, GHK-Cu simultaneously stimulates the m-RNA production of, and synthesis of, certain metalloproteases and protease inhibitors (TIMP-1 and TIMP-2) felt to function in the removal of damaged protein.

6. Interestingly, the molecular weight of collagen induced by GHK-Cu is lower than that produced during healing after injury. H. Paul Ehrlich observed that GHK-Cu appears to simultaneously stimulate both collagen synthesis and breakdown.

7. GHK-Cu, at concentrations of 10exp (-9) M, also reduces fibroblast secretion of TGF-beta (transforming growth factor beta-1). This effect occurs with normal fibroblasts and keloid-producing fibroblasts. TGF-beta1 is a growth factor that increases wound healing but also induces scar formation. This, combined with GHK-Cu's healing activities, suggests that scar-free physiological healing needs a both an activation of metalloproteinases (Item 5 above) plus a reduction in TGF-beta1 production.

8. GHK-Cu increases collagen synthesis by bone chondrocytes (chick). GHK-Cu Increases growth of human marrow stromal cells and promotes the attachment of human osteoblastic cells.

9. GHK-Cu induces angiogenesis and a family of 6 proteins from 35K to 66K. Tissue areas deficient in copper (II) will not support the ingrowth of new blood vessels or angiogenesis. 10. GHK increases differentiation, viability and axon outgrowth in cultured chick and rat neurons at 10exp (-7) M to 10exp (-8) M.

10 GHK-Cu blocks ferritin channels and the release of tissue damaging free (oxidative) iron after tissue injury, thus blocking iron catalyzed lipid peroxidation that occurs after injury.

11. GHK-Cu blocks interleukin-1 damage to pancreatic islet cells at 10exp (-10) M.

12. GHK-Cu blocks low density lipoproteins (LDL) oxidation by copper.

13. The three dimensional structure of GHK-Cu is striking similar to many pharmaceutical anti-ulcer (stomach) medicines. Also virtually all pharmaceutical  non steroidal anti-inflammatories (NSAIDs)s have a high affinity for copper (II).



Proposed Simple Mechanism of GHK-Cu Actions After Tissue Injury

Information from a variety of sources allows us to propose a mechanism for GHK-Cu effects.The sequence of events of GHK-Cu induced effects appear to be as follows:

1. Initially after tissue damage, the first stage of wound healing processes is activated. These include localized blood coagulation, an early neutrophil invasion that secretes sterilizing oxygen radicals, and later an induction by growth factors, such as TGF-beta-1, of copious amounts of scar-forming collagen to form a protective covering over the injury.

2. A second stage of healing begins to be activated as disrupted cells release proteases that generate a population of peptides that include Gly-His-Lys and His-Gly-His-Lys, both of which have a very high affinity for copper (+2) ion.

3. The Gly-His-Lys and His-Gly-His-Lys begin to accumulate copper (+2) ion from albumin and form GHK-Cu and HGHK-Cu.

4. The accumulation of peptide-bound copper ion produces multiple anti-inflammatory effects that help to stop the actions of sterilizing oxygen radicals and permit the initiation of healing events. GHK-Cu blocks ferritin channels and the release of free (oxidative) iron, thus blocking iron catalyzed lipid peroxidation that occurs after injury. GHK-Cu blocks also interleukin-1 damage to tissue cells.

5. GHK-Cu released into the blood stream raises the body's production of, and circulating blood concentration of, wound macrophages that enhance repair.

6. GHK-Cu suppresses the synthesis of scar development by repressing fibroblast production of TGF-beta-1.

7. GHK-Cu also chemoattracts wound macrophages to the wound area. These macrophages act directly to stimulate healing by removing cellular debris and secreting a family of approximately 20 growth factor proteins.

8. GHK-Cu acts directly on fibroblasts to stimulate m-RNAs for collagen, elastin, proteoglycans, metalloproteinases, and TIMP-1 and TIMP-2. This in turn raises the levels of these proteins. This results in a condition whereby protein synthesis and deposition is occurring concomitant with protein breakdown that removes scar tissue and cellular debris remaining from the tissue disruption. Thus, GHK-Cu links scar reduction and the rebuilding of tissues.

9. GHK-Cu induces angiogenesis by serving as a chemoattractant to direct new blood capillaries to the wound area and by inducing the production of several protein essential for angiogenesis.

10. GHK-Cu induces neuronal outgrowth and re-innervation of the damaged tissues.

11. This mechanism of copper-peptide induced tissue repair appears to function for skin, hair follicles, the stomach lining, the intestinal lining, bone tissue, and hooves and fingernails.

12. This copper-peptide regeneration mechanism is different from most known biochemical hormonal response patterns such as the insulin-glucose system or the erythropoetin-red blood cell system. With these systems, a small change in the concentrations of glucose or red blood cells results in a precisely controlled release of the hormones to re-establish normal glucose or red blood cell levels.

13. The copper-peptide tissue remodeling is a much looser stimulus-response system - somewhat like a "fuzzy logic" response. Traumatic tissue damage is an inherently messy business - damage many be slight or massive. The bodily repair systems do not always receive rapid and clear information as to the extent of tissue damage - damages may be sudden and acute - or the result of a slow degenerative disease. This may explain why dermal scars and lesions last so long in adults; the body just does not recognize the need to remove the imperfections.

Proposed Complex Mechanism of GHK-Cu Actions Based On Gene Expression

The Broad Institute's Connectivity Map was used to acquire our gene expression data (retrieved March 5, 2013). The Connectivity Map is a large database that contains more than 7,000 gene expression profiles of 5 human cell lines treated with 1,309 distinct small molecules. Three GHK profiles are contained in this repository. These profiles were created using the GeneChip HT Human Genome U133A Array. Among the 5 cell lines used by the Connectivity Map only 2 were treated with GHK. Two of the profiles were created using the PC3 cell line while the third used the MCF7 cell line. Our studies utilized all three gene expression profiles.

In order to analyze the gene data obtained from the Connectivity Map, we used GenePattern. GenePattern is a publicly available computational biology open-source software package developed for the analysis of genomic data. The CEL files were processed with MAS5 and background correction. Files were then uploaded to the ComparativeMarkerSelectionViewer module in order to view fold changes for each probe set.

Due to multiple probe sets mapping to the same gene, we converted the fold changes in m-RNA production produced by GenePattern to percentages, then averaged all probe sets representing the same gene. It was determined that the 22,277 probe sets in the Broad data represent 13,424 genes. This ratio (1.66) was used to calculate the overall number of genes that affect GHK at various cutoff points (rather than probe sets).

Our estimate of the number of genes affected by GHK at various cutoff points (number of probe sets mapping to the same gene divided by 1.66). The number of genes stimulated or suppressed by GHK with a change greater than or equal to 50% is 31.2%.

GHK appears to be a molecule that resets gene expression to that of a young adult age of about age 20 to 25.

During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, boney tissue) , increases collagen, decorin, angiogenesis, and nerve outgrowth, possesses anti-oxidant and anti-inflammatory effects, increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Recently, GHK has been found the reset genes of diseased cells from patients with cancer patients or COPD to a more healthy state. Cancer cells reset their programmed cell death system while COPD patients cells shut down tissue distructive genes and activated repair and remodeling activities. GHK also affect on genes that suppress fibrinogen synthesis and the insulin/insulin-like system, and inhibits cancer growth. It activates genes of that increase the ubiquitin-proteasome system, DNA repair, anti-oxidant systems, and healing by the TGF-beta Superfamily.


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