PEPTIDES — AGE-REGRESSION.COM

BIOACTIVE PEPTIDES

Short chain Amino Acids / Transcription Factors

(WikiLink: Peptides) - (05/24/2022)

Peptides are simply a sequence of two or more amino acids covalently linked via peptide bonds.

Peptides are molecules that contain 2–100 amino acid residues bonded by amide(peptide) bonds. Peptides support many key processes in the body due to their antioxidant, antimicrobial, antibacterial, anti-inflammatory, anticarcinogenic, antitumor, and immunoregulatory characteristics. [16]

Peptides are characterized by their wide range of biological activity: they regulate functions of the endocrine, nervous, and immune systems. The mechanism of such action of peptides involves their ability to regulate gene expression and protein synthesis in plants, microorganisms, insects, birds, rodents, primates, and humans.

Short peptides are able to penetrate the cell membrane and activate signalling pathways regulating differentiation of gene expression through various ways such as, interacting with proteins of histone, changing gene accessibility for transcription, regulating gene methylation status and activating/inhibiting their expression or directly interacting with the DNA” [20,23-26].

Peptides and proteins are composed of 20 kinds of amino acids (chart on right), which are at once alike and dissimilar. They share common features that allow them to form peptide bonds with each other while also exhibiting distinctive chemical features. This diversity of amino acids and the sheer number of possible combinations in their linear order allow for tremendous dissimilarity in the chemical and physical properties of proteins. Furthermore, proteins do not exist as unstructured chains. Rather, they fold in on themselves to form three-dimensional architectures with unique features. [1]

⫸ Peptides play a role of signalling molecules and regulatory factors via interaction with DNA and histone proteins [17]. They have importance not only in the transmission of bio-information (as autocrine hormones and neuropeptides) but also in modulation of transcription, restoring genetically conditioned alterations”, which occurr with age.

Short peptides, simple biomolecules constituting proteins, provide a valuable support for stem cell-based regenerative bio-medicine due to their unique advantages. They have small molecular weight, are stable, versatile, easily synthesized, cheap, easy to manufacture, noncytotoxic, biodegradable, biocompatible, thermoreversible, thixotropic, can cross the cell membrane and may be modi"ed in a wide variety of ways to perform speci"c functions [12-16]. Peptides play a role of signalling molecules and regulatory factors via interaction with DNA and histone proteins [17]. #ey have importance not only in the transmission of bio-information (as autocrine hormones and neuropeptides) but also in modulation of transcription, „restoring genetically conditioned alterations”, which occurr with age. Cyclic short peptides have additional extra features such as high specificaffinity, selectivity or stability to protein targets [18]. Short peptides have geroprotetive, neuroprotective, vasoprotective, skin protective, reparative, immunomodulatory, retinoprotective or anticancer effects [19,20]. ⫷[3]

Background and Biological Directives of Small Peptides

⫸The use of extracts obtained from animal tissues for terapeutic purposes originates deep in the past. For many centuries and millennia, representatives of all known civilizations have used them as medicines. In traditional Chinese medicine, more than 1,500 of the medicines used are of animal origin, and many of them are described in ancient Indian treatises on Ayurvedic medicine. Various extracts and humors of biological origin were used by the healers in Ancient Egypt and pre-Columbian America. Among the early Slavs, medicines based on animal tissues also had an important role among healers. In 1778, the first Russian pharmaceutical register, Pharmacopoea Rossica, was created, and a significant part of the register described medicines of animal origin. This can be considered as their recognition by the official national medicine [1]. The first scientific studies of the effectiveness of animal tissue extracts were conducted in the XIX century and were related to the French physiologist Ch. Brown-Sequard, and the famous Russian scientist I.I. Mechnikov, who studied the biological properties of spermine. This term denoted substrates obtained from the tissues of the testes, ovaries, spleen,and other organs.

They were first (modern) studied in 1970s, when Russian researchers V.Kh. Khavinson and V.G. Morozov developed a method to obtain special biologically active substances of peptide nature, cytomedins, from animal tissues [3]. Subsequently, it was revealed that such substances are present in almost all organs and tissues, that they belong functionally to the mediator link of the bioregulation systems their biological activity is determined by specific oligomeric molecules consisting of amino acids, namely low molecular weight peptides [4]. Further studies demonstrated the regulatory effect of cytomedines on various physiological functions; therefore, they were attributed to the class of regulatory peptides.

The theory of regulatory peptides is based on the concept of peptide regulation of physiological processes proposed by the outstanding Russian physiopeptide regulation is considered the most important and ancient mechanism for cooridinating vital activity, and is part of the process of evolution of multicellular organisms, where the peptides themselves are carriers and transmitters of inrcellular information [5]. Regulatory peptides are polyfunctional, while each type of molecule has its own special unique program that determines both their direct action as activators or inhibitors of physiological processes, and the ability to induce the release of other substances with similar properties.

After the synthesis of endogenous regulatory peptides or the administration of exogenous regulatory peptides, new portions of biologically active substances are released, which in turn initiate the release of the next group of peptide regulators. Thus, a process is formed, designated as “peptide cascade.” As a result, peptide bioregulation has exceptional flexibility and enables the formation of the required amount of the necessary regulatory substances in a short time in the proper place [6].

The use of bioregulatory peptides in clinical practice has an essential scientific substantiation. The most important aim of the therapeutic effect is correction of the functional activity of cells in the desired direction.

The function of intercellular mediators is performed by both secretory proteins, cytokines, and peptide bioregulators that maintain the structural and functional homeostasis of cell populations [7].

The mechanism of biological activity of bioregulatory peptides at the molecular level can be represented as follows: Oligomeric peptides enter the cell nucleus through the cytoplasm and the nuclear membrane. The complementary interaction of these peptides with the promoter zones of genes signals for transcription, translation, and synthesis of proteins on ribosomes. These processes contribute to a change in the function of various organs and tissues, thereby providing the necessary therapeutic effect [8].⫷[15]

A review article: “Short Peptides: On the Trail of Future Stem Cell-Based Regenerative Therapies,” from the of Int journal of Nutr Sci. 2021, provides an excellent overview of this field and the relevance of the specific peptides described below. [3]

◉ It was shown that long-term application of peptides, both isolated from the organs and synthesized from the amino acids, in animals (as a rule starting from the period after maturity) leads to a reliable increase in their mean lifespan by 20–40% and reaching a species limit.[2]

◉ Peptides, like chromokines are powerful bioregulators, controlling the status of cellular protein production and cell and organ health. Simple biomolecules can have dramatic impact on future regenerative biomedicine and tissue engineering. [3]

◉ The peptides formed via limited proteolysis are endocrine and autocrine carriers of information about the local state of the functions of an organ or tissue.[8]

◉ There are a large number of peptides that are known regulators of the differentiation, proliferation, and apoptosis of cells in normal conditions with pathology and aging of the body. [8]

◉ Multiple Human clinical trials have demonstrated improvements in organ function, systemic health and biological age. [2]

◉ It was revealed that small peptides (di-, tri- andtetrapeptides) are capable of complementary interactions with the DNA specific binding site on the promoter segment of genes, inducing disjoining of double helix strands and RNA polymerase activation. [2]

◉ Discovery of the phenomenon of peptide activation of gene transcription points out the natural mechanism of organism to maintain physiologic functions, which is based on the complementary interaction of the DNA and regulatory peptides. [2]

◉ Peptide bioregulators in humans for preventive purposes led to a significant rehabilitation of the main physiological functions and a reliable mortality decrease in different age groups during theperiod of 6–12 years. [2] (See table 3 below.)

◉ An accurate biological clock has been produced utilizing a biological age model correlated upon plasma peptides in adults. [11]

A number of small peptides (Khavinson Peptides) have been isolated from different organs and tissues and their analogues (di-, tri-,tetrapeptides) were synthesized from the amino acids. It was shown that long-term treatment with some peptide preparations increased mean life span by 20–40%, slow down the age-related changes in the biomarkers of aging and suppressed development of spontaneous and induced by chemical or radiation carcinogens tumorigenesis in rodents. [2] It was also demonstrated that these peptides have the ability to bind DNA/RNA and facilitate the methylation and demethylation CGC motifs of DNA. [13]

Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocytes, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity.[24]

The table below provides a very brief description. Some of these proteins also have a large body of human clinical experience.

By clicking on the peptides (Name) you are taken to the National Center for Biotechnology Information and the dedicated page for that specific compound. Clicking on the amino acid (sequence) takes you to the PubChem page for that specific sequence.

These regulatory peptides all initiate peptide cascades. Those cascades are self regulatory and limiting. This instills a relative safe therapeutic profile to them.

Name (Sequence) ~ No of Amino Acids ~ Organ Source ◉ Primary Biological Activity(s) _______ _____________ ____________________ ________________ _________________________________

Epitalon* (Ala-Glu-Asp-Gly) (AEDG) Tetrapeptide Epitalon synthetic sequence isolated from pineal gland protein; Epiphysis preparation "Epitalamin." {P1 - [24]}

◉ ⫸ Ala-Glu-Asp-Gly, also know as epitalon. Epitalon regulates the function of the brain in the special way. ◉ It stimulates gene expression and protein synthesis during neurogenesis [39]. ◉ In consequence, either delay the progression of neurodegenerative diseases or elimination of the source of them is possible [4]. ⫷[31]

◉ Induces pluripotent cell diferentiation into epidermis, mesenchyme and nervous tissue. ◉ Stimulates gene expression and protein synthesis during neurogenesis. ◉ Induction of activity of telomerase and its elongation in fibroblast culture in relation to reactivation of the telomerase gene and indication of prolonging the life span of a cells. [3] ◉ Demonstrates potent anti-tumorigenesis. [2] ◉ Prolonged life of animals, increased telomere length. [12] ◉ Increased melatonin synthesis in pineal gland during aging. [12] ◉ Induced retinal cells differentiation, retinaprotector. [12] ◉ Normalized renal function in pathology model in rats. [12] ◉ Results of two human clinical studies are described below.

◉ Another interesting issue of epitalon is, induction of activity of telomerase and its elongation in fibroblast culture in relation to reactivation of the telomerase gene and indication of prolonging the life span of a cells” [21].

◉ Regulation of neuro-immuno-endocrine function, circadian rhythm regulation, retina-protective effect, antioxidant effect, stress-protective effect, geroprotection, activation of skin fibroblasts’ function, differentiation of plant cells, DNA binder. [16]

➲ Chonluten (EDG) is derived from the Epitalon sequence.

➲ Pinealon has some sequence homology “ED”

◉ Medical Professional Monograph Epithalon

Bronchogen (Ala-Glu-Asp-Leu) (AEDL) Tetrapeptide

◉ Bronchogen restores the lung function in various pathologies. It is efficient in models of acute bacterial lunginflammation, chronicle fibrosis, and sublethal toxic lung damage (Khavinsonet al. 2009). These pathologies are characterized by significant changes in lungmorphology as well as in cell composition of bronchoalveolar fluid (BAL fluid)with increased neutrophil and lymphocyte quantity, as well as a reduced number ofalveolar macrophages. AEDL has an ability to regulate a wide variety of proteins in humanbronchial epithelium, and, therefore, it may influence the treatment of acute andchronic lung inflammations. It was found earlier that AEDL increased the expresion of the HOXA3 gene transcription factor in cell cultures of human bronchialepithelium during aging (Khavinson et al. 2012). AEDL specifically showed toregulate the cell renewal processes for the bronchial epithelium. AEDL alsochanged the functional cell state by acting on the content of CD79 and NOS-3proteins. The increased expression of the glycoprotein CD79, observed in bronchialepithelium by the influence of AEDL, may indicate an increased local immunity ofthe bronchopulmonary system. [30]

Chonluten (Glu-Asp-Gly) (EDG) Tripeptide pineal gland ➲ Contained within Epitalon. {P5 - [24]}

◉ Reduces apoptosis

Pinealon (Glu-Asp-Arg) (EDR) Tripeptide Isolated from brain ➲ Subunit (ED) contained within epilation

◉ This work has demonstrated that the EDR normalized spines morphology of neurons in a mouse model of HD and interacted with DNA in a solution. This effect points to the ability of EDR peptide to regulate homeostasis in neurons. According to the previous data and present study we propose that EDR peptide penetrates into neurons and regulates a number of dendritic spines through binding with nucleotides.Thus, the peptide EDR as a representative of a pool of regulatory biologically active peptides, holds promise as one of neuroprotective agents that are encouraging for further study as a compound effective for the treatment of HD. EDR peptide, Pinealon [26–28], is found in Cortexin and exhibits neuroprotective activity similar to this drug. [19]

◉ Neuroprotection, activation of stem cells’ neuronal differentiation, antioxidant effect, DNA binding.[16]

Thymalin (Pyo-Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn) metallopeptide, zinc/peptide complex, Calf thymus {P4 - [24]}

◉ This drug normalizes the functions of the immune system and stimulates the processes of regeneration and hematopoiesis if they are suppressed.

◉ Fully restored the number and functional activity of Tlymphocytes and contributed to the reduction of B lymphocytes to the normal range. tion of reparative processes [6] This drug normalizes the functions of the immune system and stimulates the processes of regeneration and hematopoiesis if they are suppressed. Timalin was used in more than 550 patients with a variety of acute and chronic diseases of bones and soft tissues. Pronounced clinical and immune effects characterized by the recovery of cellu!lar and humoral immunity to the norm, as well as the processes of regeneration, were observed in 79% of patients. [8]

The injection of thymalin in guinea pigs stimulated both lymphoid and epithelial components of thymus. Furthermore, the structure of the thymus changed due to the proliferation and differentiation of lymphoid elements and an increase in the number of mature lymphocytes in it [62, 63].

The peptide sequence is also referred to by brand name of: “Timalin,” in the literature.

➲ Many smaller bioactive peptides are derived from the Thymalin sequence, including Thymogen; (EW), Vilon; (KE) and Crystagen; (EDP).

➲ Thymogen (Glu-Trp) (EW) Dipeptide Calf thymus {P3 - [24]}

◉ Immunostimulatory drug [6,8] For example, Glu-Trp dipeptide stimulated immunity [37, 98, 125, 126]. [?]

◉ Drug, regulation of immune system function, antioxidant effect, stress-protective effect, geroprotection, DNA binding.[16]

From Fight Aging’s Website:

How to Plan and Carry Out a Simple Self-Experiment, a Single Person Trial of Khavinson Peptides for Thymic Regrowth

Vesugen ([Lys-Glu]-Asp) (KED) Tripeptide Isolated from Vessels = [T-38] ➲ Contains [Vilon]

◉ ⫸ The capacity of the studied tripeptides to promote cell proliferation in the skin tissues of young and old animals provides the basis for further study of these substances as preparations boosting the regenerative processes in the skin, including those at age-associated pathology. T-38 produced a marked stimulatory effect on proliferation. It was previously shown that the KED peptide regulated the expression of cell aging and apoptosis of genes [53] and proteins (nestin, GAP-43) of neuronal differentiation [35]. In this study, additional molecular epigenetic points of peptides neuroprotective properties were discovered. Low-energy complexes of EDR and KED peptides with a 6-nucleotide dsDNA sequence were calculated using the molecular modeling method. These complexes are often found in the promoters of the CASP3, NES, GAP43, APOE, SOD2, PPARA, PPARG, GDX1 genes. The regulation of the expression of these genes by tripeptides may reflect the molecular mechanism of their neuroprotective activity. Interestingly, protein products of these genes are involved in neuroplasticity, synaptic pathology and cognitive impairments in AD. ⫷[19]

◉ Regulation of cardiovascular system function, neuroprotector, activation of stem cells’ neuronal differentiation, activation of skin fibroblasts’ function, geroprotection, DNA binding.[16]

◉ Activates neuronal differentiation. [32]

➲ Vilon (Lys-Glu) (KE) Dipeptide Synthetic immunomodulatory {P2 - [24]}

◉ Activate neuronal and immune cell diferentiation. [3] It was also demonstrated that dipeptide showing immunomodulating activity, regulates gene interleukin-2 (T-cell growth factor) expression in blood lymphocytes and demonstrates anti-tumorigenesis. [2] Simultaneously, the number of lymphocytes bearing markers CD4+ increased in the peripheral blood and that of CD8+ decreased. It was found that the use of the KE peptide stimulates cellular immunity and nonspecific resistance of the organism and has an activating effect on macrophages, blood lymphocytes, thymocytes, and neutrophils [8] Inclusion of Vilon in the complex treatment of patients with inoperable cancer of the stomach, esophagus, and the lung allowed not only improving the quality of life of patients, but also significantly extended the period of their lives. It was found in the experiment the KE peptide demonstrates pronounced selective binding to the TCGA DNA sequence, which is part of these genes. It is assumed that the KE peptide can regulate gene expression and the synthesis of heat-shock proteins (HSPs), cytokines (IL-3, IL-4, IL-5, IL-6, IL-10, IL-17A, TNFα), tissue factor, proteins of the fibrinolysis system (plasminogen, tissue and urokinase plasminogen) activators, antithrombin III), and proteins of “youth” and “old age” (GDF11, FNDC5, betatrophin, FGF19, FGF21, FGF23, HMGB1, MIC1/GDF15, JAM-A) (Khavinson et al., 2011a, 2014b, 2015a, 2015b, 2018; Kuznik et al., 2014, 2017). It was found that the KE motif is found in the amino-acid sequences of some cytokines and peptide hormones that are similar in function to the KE peptide. In the human proteome, nuclear proteins contain the largest number of KE motifs, while cytoplasmic and all other proteins have the minimal KE content. During limited proteolysis, the KE-peptide molecules released from nuclear proteins can bind to DNA and regulate gene expression (Terekhov et al., 2019). [8]

⫸ KE peptide has the highest affinity to dsDNA among the selective charged dipeptides and different biological activities. In particular, the administration ofthe KE peptide causes a 2-fold suppression of HER-2/neu(human breast cancer) gene expression in transgenic mice.This suppression is accompanied by a reliable reduction ofthe tumour diameter (32). It also contributes to a reducedincidence of tumours and a general increase of mean lifespan in animals (33). The effect of the KE peptide on theexpression of 15 247 murine heart and brain genes beforeand after peptide administration was studied with DNA microarray techchnology. It was shown that the KE peptideupregulates the expression of 157 genes and downregulatesthe expression of 23 genes (34). Also, it has been observedthat the KE peptide is capable of regulating gene expression of Interleukin-2 in blood lymphocytes, indicating itsimmunomodulating activity (35). The KE peptide also regulates expression of SD4, CD5 and CD8 glycoproteins in thymic cell culture and induces immune cell differentiation(36). In addition, the KE peptide was found to be capable to activate heterochromatin in the cell nuclei in senile patientsand facilitate the “release” of genes suppressed as a resultof heterochromatinization of chromosome euchromatin areas (14). Thus, the KE peptide has geroprotective effectin immune cells. Therefore, the KE peptide is a promising immunoprotector, geroprotector and antitumour substance and the molecular mechanism of its biological activity is very important. ⫷[17]

◉ Regulation of immune system function, antioxidant effect,stress-protective effect, geroprotection, activation of stemcells’ neuronal differentiation, activation of plant cells’differentiation, DNA binding.[16]

◉ Activates neuronal differentiation. [32]

➲ Crystagen (Glu-Asp-Pro) (EDP) Tripeptide Isolated from thymus = Т-36

◉ Crystagen had a greater effect on the T-cell element of immunity (an increase in the number of CD3+-, CD4+-cells, normalization of the CD4+/CD8+ ratio) and had a less pronounced effect on B lymphocytes. [8]

◉ EDP peptide activates the proliferation of VTEC2.H/S human thymic epithelial cells (Khavinson et al., 2006). The EDP peptide inhibits the proliferation of human erythro myelosis tumor K-562 cells. The inhibition of proliferation under the action of crystagen, which is directed at immortalized cells, may indicate its antitumor activity. The EDP peptide enhances the spontaneous proliferative activity of normal lymphocytes; (Khavinson et al., 2011b)[8]

Pancragen ([Lys-Glu-Asp]-Trp) (KEDW) Tetrapeptide Isolated from Pancreas ➲ Contains [T-38]

◉ ➲ ◉ KEDWa led to a 53% drop of TNF- level in 3-month-old rats and a 46% elevation of Insulin, IGF-I in 9-month-old rats, Note: Reverses Diabetes [4] Decreases blood glucose level in animals with experimental diabetes mellitus. [2]

GHK-Cu** (Glu-His-Lys) (EHK) Tripeptide metallopeptide, copper/ peptide complex, Albumin

◉ Naturally occurring copper peptide with anticancer and immune modulation properties.

See: Copper TriPeptide GHK-Cu

Semax (Met–Glu–His–Phe–Pro–Gly–Pro) () 7 mer peptide ACTH(4−7)-PGP (Semax)

◉ Nootropic drug [6].

◉ ⫸Semax (H-Met-Glu-His-Phe-Pro-Gly-Pro-OH) is a synthetic analog of the adrenocorticotropic hormone 4 - 10 fragment (ACTH4-10). It exhibits distinct neuroprotective and nootropic properties and is the basis for a number of drugs that are used in clinical practice for the treatment of CNS diseases (ischemic brain stroke, dysulatory encephalopathy, optic nerve atrophy, etc.) and to enhance adaptability under extreme conditions in healthy persons.

ACTH is one of the main regulatory components of the pituitary-hypothalamic axis, and interacts with other peptide hormones (prolactin, vasopressin, thyroliberin, the vasointestinal peptide, opioid peptides, etc.) and with the mediatory systems of the hypothalamus [7]. Semax in the body showed that this peptide has pronounced neuroprotective properties. Semax appears to stimulate the proliferation of repopulating elements of the nervous tissue [73]. Semax significantly increased the attention and short-term memory of the subjects during testing, both at the beginning and at the end of the day. Semax can be administered to healthy individuals to prevent the negative impact of the environment, in particular the impact of long-term psychoemotional stress (increased information load, the effect of intense muscular workload, professional work in difficult conditions, a high degree of responsibility, conflict, financial problems, etc.). The half-life of Semax in the serum is >1 h. Its prolonged effect is associated with the cytoprotective activity of its fragments [90]. ⫷[21]

◉ Semax forms stable complexes with Cu2+ ions, with a conditional dissociation constant (cβ Kd) of 1.3·10−15 M at ph 7.4.55. This evidence confirms that Semax strongly interacts with the Cu2+ ion, preventing the formation of Aβ1−40:metal complexes. [20]

◉ Drug, neuroprotection.[16]

Selank (H-[Thr-Lys-Pro-Arg]-Pro-Gly-Pro-OH) ➲ Contains [Tuftsin]

◉ A synthetic analog of the short fragment of the human immunoglobulin G heavy chain (tuftsin). It exhibits antianxiety and nootropic effects. A drug based on Selank is used in therapy for generalized anxiety disorders and neurasthenia and to enhance adaptability under extreme conditions in healthy persons. Sollertinskaya et al. showed that Selank has pronounced neuropsychotropic, antidepressant, and antistress effects and abolishes the reaction of aggression and fear in primates with neurosis. It has been established that Selank has a significant positive action on learning processes. There is a relationship between stressors and diseases of the CNS, such as anxiety and depression [165]. Compared with the original tuftsin molecule, the effect of the final product, Selank, on the immune system is weaker; however, this peptide has a strong and long-lasting impact on the CNS [148,177]. The administration of Selank and all of its fragagents has a significant influence on the levels of expression of the mRNAs of genes encoding chemokines, cytotokines and their rceptors. Moreover, the activation of some of them occurs even at 1 day after a single injection of the peptides. As is well known, the adequacy of the immune response to an antigenic stimulus is determined by the balance of cell-mediated (Th1) and humoral (Th2) responses. Moreover, Selank and tuftsin increasingly led to changes in the expression of cytokines that are characteristic of the immune response to specific cell type, whereas the introduction of Gly-Pro altered the expression of genes involved in the humoral immune response. Thus, we can assume that the mechanism underlying the antiviral action of Selank is based on its ability to modulate the balance between Th1 and Th2 cytokines [197]. [21]

Tuftsin (Thr-Lys-Pro-Arg) () tetrapeptide leucophilic fraction of the IgG protein ➲ Contained within Selank

◉ ⫸ Is one of the first peptides of the immune system for which a distinct influence on the functions of the CNS was described. The principal biologic activity of tuftsin consists of the activation of phagocytosis by granulocytes and macrophages. It also activates pinocytosis, increases the respiratory burst of phagocytic cells (thus stimulating their bactericidal activity), destroys neoplastic cells, and affects the formation of antibodies. Tuftsin stimulates the formation of superoxide and nitroxide radicals by macrophages, which leads to an increase in their digestive capacity [124,130,131]. In vivo experiments showed that tuftsin induces strong antibacterial activity without apparent toxicity. It increases the cytotoxic action of T lymphocytes and stimulates the synthesis of antibodies [132-134]. Tuftsin normalizes the levels of dopamine, norepinephrine, and serotonin [144]. Russian scientists conducted a detailed study of the synthesis and long-acting effect of tuftsin analogs. The result was ɚ heptapeptide containing the sequence Thr-Lys-Pro-Arg elongated with the C-terminal part of the tripeptide Pro-Gly-Pro, which proved to be most suitable for the stabilization of the molecule and enhanced its resistance to proteases. The resulting peptide, H-Thr-Lys-Pro-Arg-Pro-Gly-Pro-OH, which was named Selank, (See entry above this one) had a pronounced anxiolytic activity. ⫷ [21, 22]

◉ WE have shown in this laboratory that a specific cell bound leucophilic γ-globulin fraction, leucokinin, is essential for maximal stimulation of the phagocytic activity of the blood neutrophilic leucocyte1,2. We now report that the whole stimulatory effect of leucokinin can be ascribed to a single peptide fragment liberated by a specific enzyme in the outer membrane of the neutrophile. We shall refer to this peptide as `tuftsin' (after Tufts University) and to the enzyme as leucokininase. The peptide `tuftsin' has been produced in vitro from a γ-globulin fraction, PC IV, by treatment with leucokininase. PC IV is prepared by chromatography on phosphocellulose columns3 and contains all the leucokinin activity of serum γ-globulin2. [27]

Prostatilen (Polypeptide Complex) Isolated from Prostrate

◉ ⫸ The administration of prostatilen for 5–10 days not only improved the pattern of the disease, but normalized the prostatic function more quickly than the Swiss raveron preparation. In the case of prostatilen, the decrease in the infiltration of inter stitial tissue was more pronounced; the signs of improvement in the functional activity of acinic epi thelium were clearly seen; venule thrombosis decreased; and the ratio between leukocytes and lipoid bodies was restored in acinic secretion [1]. Further more, the action of prostatilen increased the weight of the testes, prostate, and seminal vesicle and improved spermatogenesis parameters in rats with chronic pros tatitis. The action of prostatilen resulted in a decrease in the number of tubules with impaired sperm matura tion and an increase in the quantity of spermatoblasts in the basal membrane in experimental animals [1].

Prostatilen caused a decrease in bladder capacity and intravesical pressure 5 min after intramuscular administration in rats. This effect eased urination, which started with lesser filling and pressure in the bladder [28]. ⫷[25]

Cortexin (82 aa-seq) Isolated from Brain ➲ Contains Pinealon AA 26-28 “EDR

◉ Patients with symptoms of neurosis were able to achieve full recovery of productive mental activity, and in patients with more severe disorders. Cortexin had a stimulating effect, which resulted in improved functional, quantitative indicators of memory and thinking. Moreover, cortexin enhanced the expression of receptors in the T and Blymphocytes of healthy peo ple and secondary immunodeficiency patients [46]. [25]

Retinalamina (Leu-Glu-Asp) (LED) Tripeptide Isolated from retina

◉ ⫸The preparation regulates retinal metabolism, stimulates functions of retinal cells, improves interactions between pigment epithelium and external parts of photoreceptors, enhances the activity of retinal macrophages, and normalizes blood coagulation and fibrinolytic activity [66, 69]. Reti nalamin protects vascular endothelium and collagen fibers of perivascular connective tissue and promotes the restoration of the damaged vessel wall [53, 69].

Retinalamin significantly increased receptor expression in T and B lymphocytes and also enhanced the phagocytic activity of neutrophiles. ⫷[25] Activate neuronal diferentiation. [3]

The Peptide / Biological Function matrix on the right highlights the primary biological functions of each peptide.

The binding kinetics of five of these peptides to DNA was determined utilizing the Internal Coordinate Mechanics binding score (ICM-Score). [13]

* Clinical trials described below.

** See dedicated page for GHK-Cu

*** See unabridged peptide page Peptides-CAR. 26,

🔷 ? 🔷

Epitalon

The addition of epitalon in telomerase-negative human fetal fibroblast culture induced expression of the catalytical subunit, enzymatic activity of telomerase, and telomerase elongation, which can be due to reactivation of telomerase gene in somatic cells and indicates the possibility of prolongation of life-span of a cell population and of the whole organism.

Increased the life-span of imagoes (flies) significantly by 11-16% when applied at unprecedentedly low concentrations —from 0.001 X 10 6 to 5 X 10 6wt% of the culture medium. The effective concentrations of Epitalon were 16,000-80,000,000 times lower than those of melatonin. In another experiment, the mean life-span of female VES and male NA-flies increased under the influence of Epitalon by 26%. In NA females the meanlife-span grew by 35% and in NA males, by 29%. [5]

Activation of proliferation and maturation of thymic cortical thymocytes, hyperplasia and medullar differentiation of the epithelial cells in the thymus and epithelioid cells in the spleen of AKR mice under long-term Epithalamin treatment in comparison to controls.

⫸ Its application in senescent monkeys aged 20-26 years resulted in the complete normalization of initially disturbed melatonin and glucose blood levels and in the restoration of tissue sensitivity to insulin and cortisol circadian rhythm. 2 Thus, the comprehensive long-term investigation of Epithalamin in 6 animal species demonstrated its unique geroprotective activity. [2, 5]

The results of applying the bioregulators demonstrated a significant improvement in the state of the patients’ health. The administration of the peptide bioregulator distinctly inhibited the development of age-related immune disorders in the patients with accelerated aging.73 Prolonged application of the medications decreased the functional age of the central nervous system, thus, improving its functioning. Epithalamin (Epitalon) normalized the initially raised level of cortisol in the patients. This effect remained stable for 3 years after applying the bioregulator. A stable decrease in cortisol concentration was considered a favorable factor for IHD patients, since it normalized lipid metabolism and improved certain immune functions. Epithalamin revealed its modulating effect on the functional state of sexual glands in elderly men and women. The ability of Epithalamin to normalize carbohydrate metabolism as well as to intensify bone tissue density appeared extremely important.

Study 1: Epitalon was injected intramuscularly daily at 10 mg for 10 days (100 mg per course). The research was double blind. The bioregulators we reapplied in combination with a standard treatment for the corresponding indication. The patients were repeatedly examinedin 10 days after the end of the therapy course and later in 4 months to assess the efficacy of the performed correction indifferent periods after the administration of Epithalamin. The bioregulation treatment was repeated in one year. Consequently,the patients underwent 2 courses of bioregulators over 2 years. In Group II, Epithalamin normalized the same immune indices, aswell as ACTH, TSH, cortisol, and insulin. The levels of cholesterol, uric acid, AP, GGT, and LDH came back to normal in 10days and remained stable. The application of Epithalamin decreased mortality1.95 and 1.79 times, correspondingly. The combined use of Epithalamin and thimic biorcgulator, Thymalim decreased mortality 2 times and a half as compared to the control. The results of applying peptide biorcgulators in patients for 6 years deserve a special attention. The rate of their mortality went down 4.1-fold as compared to the control.[5]

Study 2: The investigation included 152 persons (71 men and 81 women) who were under continuous observation at the Institute out patient department. The investigated group consisted chiefly of patients with ischemic heart disease (IHD) resulting from the accelerated development of age-related changes in the cardiovascular system and entire organism. The patients had no concomitant nervous, endocrine, and respiratory pathologies. Along with IHD patients the group of persons showing accelerated aging comprised 68 persons without any organic cardiovascular, endocrine or respiratory pathologies. Afterward, all the patients were divided into 3 groups by stratification randomization method. Group 1 was control. Group II were administered with Epithalamin. All the agents were injected at 10 mg intramuscularly daily at 2-3 days’ intervals, with 5 consecutive doses (50mg) per course. The interval between courses constituted 5-6 months. The patients were under treatment for 3 years (6 courses of the treatment in total). During the period of examination the patients normally did not take any strong medications. The efficacy of Epithalam in was assessed in dynamics according to the indices of the patients’ subjective state of health, functional age of their physiological systems, physical and mental workability, immunity, state of their bone tissue, liver detoxication ability, blood lipid spectrum, tolerance to carbohydrates, oxygen tissue exchange, vegetative regulation, and the functional state of endocrine glands.73 The results of applying the bioregulators demonstrated a significant improvement in the state of the patients’ health. Theadministration of the peptide bioregulator distinctly inhibited thedevelopment of age-related immune disorders in the patients with accelerated aging. [73] Prolonged application of the medications decreased the functionalage of the central nervous system, thus, improving its functioning. Epithalamin normalized the initially raised level of cortisol in the patients. This effect remained stable for 3 years after applying thebioregulator. A stable decrease in cortisol concentration wasconsidered a favorable factor for IHD patients, since it normalizedlipid metabolism and improved certain immune functions.Epithalamin revealed its modulating effect on the functional stateof sexual glands in elderly men and women. The ability of Epithalamin to normalize carbohydrate metabolism as well as tointensify bone tissue density appeared extremely important. Homeostasis normalization in thepatients was accompanied by a mortality decrease during 8 years— 1.6-fold, in case of Epithalamin. [73] ⫷[5]

Thus, annual treatment course with thymus and pineal preparations led to a reliable decrease in mortality (33.3% mortality rate as compared to controls of 81.8%) (Table 3 at Right>), to improvement of brain function and that of immune, endocrine, cardio-vascular systems, increased density of osseous tissue. It is noteworthy that application of preparation of the thymus led to a two fold decrease in frequency of acute respiratory disease. The restoration of nocturnal melatonin secretion level in patients subjected to administration of preparation of the pineal gland is of special significance. These results suggest good prospects for tackling demographic issues (Khavinson and Mikhailova 2007).

Epigenetic Regulation by Small Peptides

Epigenetic regulation of gene expression includes chromatin remodeling, DNA modification, ncRNA function, RNA methylation, and mitochondrial DNA methylation and hydroxymethylation. [13]

Addressing Alzheimers Disease with Small Peptides

The development of therapeutic agents based on ultrashort peptides may offer a promising addition to the multifunctional treatment of Alzheimer’s disease (AD). The hypothesis that peptide regulation of gene expression can be mediated by the interaction of short peptides with histone proteins, cis- and transregulatory DNA elements and effector molecules (DNA/RNA-binding proteins and non-coding RNA). [13]

NOTES:

Various studies have incorporated various administration schedules for their trials.

◉ Epitalon was injected intramuscularly daily at 10 mg for 10 days (100 mg per course). This was repeated at one year.

◉ Another study injected at 10 mg intramuscularly daily at 2-3 days’ intervals, with 5 consecutive doses (50mg) per course. The interval between courses constituted 5-6 months. The patients were under treatment for 3 years (6 courses of the treatment in total). [5]

This unrelated study would indicate that maximum benefit from the administration of ~Epitalon* would be monthly. > Finally, our therapeutic regimen appeared to require monthly administration to have continuous effects. [10]

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KE peptide regulates the gene expression of EPS15, MCM10 homolog, Culline 5, APG5L, FUSED,

ZNF01, FLJ12848 fis, ITPK1, SLC7A6, FLJ22439 fis, KIAA0029, FLJ13697 fis, KIAA0699, FLJ10914,

Gdap1, MSTP028, MLLT3, and PEP, as well as the synthesis of cytoskeleton proteins and the proliferation

and metabolism of cells, which explains its high biological activity. (Khavinson and Malinin, 2005).

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The choices for obtaining Khavinson Peptides are limited. Most of them are in China and Russia.

Limitless Life Nootropics, is located in the US and are diligent about the quality of their products. They respond to request for information and ship orders quickly. They have generously offered ARC readers and subscribers a 15% discount. Use the Coupon Code ⫸ ark15 ⫷ at checkout. The LLN logo on the right is a direct link to their site.

Peptides America: Your reliable supplier of authentic Russian Khavinson peptides in the USA. The mission is to make the world a better place. A request for information from this site has gone un-answered. They are included here because they list all know biologically active peptides in their available inventories.

Over the Counter, provides most Khavinson Peptides as well as a wide variety of supplements and medicines. OTC stocks everything from Oxytocin to Melatoinin. Located in Russia, shipping has become quite expensive since the conflict with Ukraine began. All shipments are carefully tracked and you get conformation emails from Pavel immediately when deliveries are made or even attempted. OTC is a good company.

◉ We have produced an extensive list of peptide providers including China, England, Russia, Ukraine and US. Email us using the link below if you would like to receive a copy.