Regulation of protein synthesis using Khavinson peptides

Adding peptides to cellular cultures resulted in a tissue-specific stimulation of protein synthesis in the cells of the specific organ, from which these peptides were obtained. This effect of enhancing protein synthesis was diagnosed in young and old animals. It was proven that small peptides exert tissue-specific stimulation on expression of differentiation factors CXCL12, Hoxa3, WEGC1: peptide KEDW – in cells of the pancreas, peptide ADEL - in the bronchial epithelium [66] and peptide AEDG – in fibroblasts. At the same time an induction effect from the peptides on the expression of differentiation factors is most pronounced in the 'old' cell cultures. This established their geroprotective mechanism. Moreover, the KEDW peptide increases expression of metalloproteinases (MMP2, MMP9), serotonin, glycoprotein CD79α, antiapoptotic protein Mcl-1, proliferation factors PCNA and Ki67 and also reduces expression of proapoptotic protein p53 in the 'old' cultures of the pancreas cells. Peptide AEDL regulates synthesis of proteins Ki67, Mcl-1, p53, CD79, NOS-3 in cultures of human bronchial epithelial cells of different passages. This contributes to activation of cell renewal and enhances functional activity of bronchial epithelium cells.

In the cell cultures of human cortical thymocytes, KED peptide enhanced differentiation of thymocytes towards regulatory T-cells, increased their proliferative activity and reduced apoptosis. Moreover, peptide KED stimulated proliferative (Ki67) and anti-apoptotic (Mcl-1) activity of mature regulatory T-cells. In the studies conducted the peptide KED effect on bone marrow stem cells CD34+, was shown to stimulate expression markers of myeloid cells CD14 and B-lymphocytes CD19.

KED stimulating impact on proliferation and its inhibitory effect on apoptosis was multifold in the pineal organotypic cell culture of old rats as compared to that obtained from young animals. This fact evidences the ability of the tripeptide under study to produce a pronounced restorative effect on the cells of the pineal gland within its ageing associated involution. Moreover, the model of maintaining conditioned responses in short-term and long-term memory of melliferous bee helped to reveal KED modulating activity on associative training .

EDR peptide in organotypic cultures of the old rats brain cortex increased expression of markers of the functional activity of cells: Ki67 and serotonin (1,7-fold and 2,2-fold, correspondingly) as compared to control. Thus, EDR possesses pronounced neuroprotective properties.

Adding peptide AEDG to pinealocyte cultures resulted in the stimulation of the synthesis of arylalkylamine - N-acetyltransferase (AANAT) enzyme and transcription factor pCREB, which are involved in the synthesis of melatonin from serotonin. Furthermore, under the effect of peptide AEDG the content of melatonin increased in the culture medium.

Adding peptides AEDG and KE to embryonic retinal cell cultures contributed to the induction of differentiation of various types of neurons in the retina (activation of Brn3, Pax6, Prox1, Vsx1 proteins expression) and pigment epithelium (activation of transthyretin synthesis). Adding extracted peptides of the retina to polypotential cell culture of Xenopus laevis early gastrula ectoderm led to the emergence of retinal and pigment epithelium cells. Adding of other small peptides to pluripotent cells of ectoderm in the same experimental model resulted in emergence of different tissues (nervous, liver, etc.).

The peptide AEDR proved to reinforce expression of cyto- and karyoskeleton proteins in cell cultures of embryonic fibroblasts. The peptide increased expression of cytoskeletal proteins (such as actin, tubulin and vimentin) 2-5-fold and nuclear proteins (lamin A, lamin C) 2-3-fold. Thus, mechanism of action of this peptide is based on its ability to activate synthesis of proteins in cyto- and karyoskeleton and thereby enhance cell proliferation and reduces apoptosis.

These experiments showed that peptides can induce differentiation and proliferation, as well as suppress apoptosis of cells, depending on the structure of the substance added. The results of these studies concludes that there is a possibility of targeted induction of cell differentiation and an employment of a biological cellular reserve, of various organs and tissues. This is the fundamentals for enhancing functions and reserves of human organism, as well as increasing the human lifespan to its maximal capacity.