| Reference | [1]. Int J Mol Sci. 2018 Jul 7;19(7):1987. doi: 10.3390/ijms19071987.<br />
Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data.<br />
Pickart L(1), Margolina A(2).<br />
Author information: (1)R&D Skin Biology; 4122 Factoria Boulevard SE, Suite Number 200, Bellevue, WA 98006, USA. [email protected]. (2)R&D Skin Biology; 4122 Factoria Boulevard SE, Suite Number 200, Bellevue, WA 98006, USA. [email protected].<br />
The human peptide GHK (glycyl-l-histidyl-l-lysine) has multiple biological actions, all of which, according to our current knowledge, appear to be health positive. It stimulates blood vessel and nerve outgrowth, increases collagen, elastin, and glycosaminoglycan synthesis, as well as supports the function of dermal fibroblasts. GHK’s ability to improve tissue repair has been demonstrated for skin, lung connective tissue, boney tissue, liver, and stomach lining. GHK has also been found to possess powerful cell protective actions, such as multiple anti-cancer activities and anti-inflammatory actions, lung protection and restoration of chronic obstructive pulmonary disease (COPD) fibroblasts, suppression of molecules thought to accelerate the diseases of aging such as NFκB, anti-anxiety, anti-pain and anti-aggression activities, DNA repair, and activation of cell cleansing via the proteasome system. Recent genetic data may explain such diverse protective and healing actions of one molecule, revealing multiple biochemical pathways regulated by GHK.<br />
DOI: 10.3390/ijms19071987 PMCID: PMC6073405 PMID: 29986520 [<br />
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[2]. Life Sci. 2020 Jan 15;241:117139. doi: 10.1016/j.lfs.2019.117139. Epub 2019 Dec 4.<br />
Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways.<br />
Ma WH(1), Li M(2), Ma HF(1), Li W(1), Liu L(1), Yin Y(1), Zhou XM(3), Hou G(4).<br />
Author information: (1)Department of Respiratory and Critical Care Medicine, First Hospital of China Medical University, No.155, Nanjing North Street, Shenyang, China. (2)Department of Respiratory Medicine, Qingdao Municipal Hospital, No.1, Jiaozhou Road, Qingdao, China. (3)Department of Respiratory Medicine, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Shenyang, China. Electronic address: [email protected]. (4)Department of Respiratory and Critical Care Medicine, First Hospital of China Medical University, No.155, Nanjing North Street, Shenyang, China. Electronic address: [email protected].<br />
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious lung problem with advancing and diffusive pulmonary fibrosis as the pathologic basis, and with oxidative stress and inflammation as the key pathogenesis. Glycyl-L-histidyl-l-lysine (GHK) is a tripeptide participating into wound healing and regeneration. GHK-Cu complexes improve GHK bioavailability. Thus, the current study aimed to explore the therapeutic role of GHK-Cu on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. METHODS: BLM (3 mg/kg) was administered via tracheal instillation (TI) to induce a pulmonary fibrosis model in C57BL/6j mice 21 days after the challenge of BLM. GHK-Cu was injected intraperitoneally (i.p.) at different dosage of 0.2, 2 and 20 μg/g/day in 0.5 ml PBS on alternate day. The histological changes, inflammation response, the collagen deposition and epithelial-mesenchymal transition (EMT) was evaluated in the lung tissue. EMT was evaluated by ɑ-SMA and fibronectin expression in the lung tissue. NF-κB p65, Nrf2 and TGFβ1/Smad2/3 signalling pathways were detected by immunoblotting analysis. RESULTS: GHK-Cu complex inhibited BLM-induced inflammatory and fibrotic pathological changes, alleviated the inflammatory response in the BALF by reducing the levels of the inflammatory cytokines, TNF-ɑ and IL-6 and the activity of MPO as well as reduced collagen deposition. In addition, the GHK-Cu treatment significantly reversed the MMP-9/TIMP-1 imbalance and partially prevented EMT via Nrf2, NF-κB and TGFβ1 pathways, as well as Smad2/3 phosphorylation. CONCLUSIONS: GHK-Cu presented a protective effect in BLM-induced inflammation and oxidative stress by inhibiting EMT progression and suppressing TGFβ1/Smad2/3 signalling in pulmonary fibrosis.<br />
DOI: 10.1016/j.lfs.2019.117139 PMID: 31809714<br />
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[3]. Int J Mol Sci. 2020 Aug 27;21(17):6190. doi: 10.3390/ijms21176190.<br />
Ternary Cu(II) Complex with GHK Peptide and Cis-Urocanic Acid as a Potential Physiologically Functional Copper Chelate.<br />
Bossak-Ahmad K(1), Wiśniewska MD(1), Bal W(1), Drew SC(1)(2), Frączyk T(1).<br />
Author information: (1)Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland. (2)Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Melbourne 3010, Australia.<br />
The tripeptide NH2-Gly-His-Lys-COOH (GHK), cis-urocanic acid (cis-UCA) and Cu(II) ions are physiological constituents of the human body and they co-occur (e.g., in the skin and the plasma). While GHK is known as Cu(II)-binding molecule, we found that urocanic acid also coordinates Cu(II) ions. Furthermore, both ligands create ternary Cu(II) complex being probably physiologically functional species. Regarding the natural concentrations of the studied molecules in some human tissues, together with the affinities reported here, we conclude that the ternary complex [GHK][Cu(II)][cis-urocanic acid] may be partly responsible for biological effects of GHK and urocanic acid described in the literature.<br />
DOI: 10.3390/ijms21176190 PMCID: PMC7503498 PMID: 32867146<br />
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[4]. Wound Repair Regen. 2017 Apr;25(2):270-278. doi: 10.1111/wrr.12520. Epub 2017 Apr 27.<br />
GHK-Cu-liposomes accelerate scald wound healing in mice by promoting cell proliferation and angiogenesis.<br />
Wang X(1), Liu B(2), Xu Q(3), Sun H(1), Shi M(1), Wang D(1), Guo M(1), Yu J(1), Zhao C(4), Feng B(1).<br />
Author information: (1)Department of Biotechnology, Dalian Medical University, Dalian, China. (2)Key Laboratory of Biotechnology and Bioresources Utilization, (Dalian Minzu University), Ministry of Education, Dalian, China. (3)Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China. (4)College of Life Sciences, Liaoning Normal University, Dalian, China.<br />
Glycyl-l-histidyl-l-lysine (GHK)-Cu is considered to be an activator of tissue remodeling, and has been used in cosmetic products. In this study, we prepared liposomes encapsulating GHK-Cu and analyzed their effect on human umbilical vein endothelial cells (HUVECs) proliferation and scald wound healing in mice. The nanoscaled GHK-Cu-liposomes promoted HUVECs proliferation, with a 33.1% increased rate. Flow cytometry analysis showed increased cell number at G1 stage and decreased cell number at G2 stage after GHK-Cu-liposomes treatment. Western blotting indicated that the expression of vascular endothelial growth factor and fibroblast grow factors-2 were both enhanced, as well as cell cycle-related proteins CDK4 and CyclinD1. In a mice scald model, angiogenesis in burned skin treated with GHK-Cu-liposomes was better compared with free GHK-Cu, and immunofluorescence analysis showed enhanced signal of CD31 and Ki67 in GHK-Cu-liposomes treated mice. Moreover, the wound healing time was shortened to 14 days post injury. Our results provide the evidence that GHK-Cu-liposomes could be utilized as a treatment for skin wounds.<br />
DOI: 10.1111/wrr.12520 PMID: 28370978<br />
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[5]. Oxid Med Cell Longev. 2012;2012:324832. doi: 10.1155/2012/324832. Epub 2012 May 10.<br />
The human tripeptide GHK-Cu in prevention of oxidative stress and degenerative conditions of aging: implications for cognitive health.<br />
Pickart L(1), Vasquez-Soltero JM, Margolina A.<br />
Author information: (1)Skin Biology, Research & Development Department, Bellevue, WA 98006, USA. [email protected]<br />
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.<br />
DOI: 10.1155/2012/324832 PMCID: PMC3359723 PMID: 22666519<br />
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[6]. Biomed Res Int. 2015;2015:648108. doi: 10.1155/2015/648108. Epub 2015 Jul 7.<br />
GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration.<br />
Pickart L(1), Vasquez-Soltero JM(1), Margolina A(1).<br />
Author information: (1)Skin Biology, Research & Development Department, 4122 Factoria Boulevard, SE Suite No. 200 Bellevue, WA 98006, USA.<br />
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.<br />
DOI: 10.1155/2015/648108 PMCID: PMC4508379 PMID: 26236730
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