Peptides
Thyrotropin TRH (25mg)
Thyroid hormones are considered to be growth and metabolism regulators. In order to maintain the synchrony of these regulating mechanisms and hemostasis, hormones released by the hypothalamus are called Thyrotropin-releasing hormone (TRH).(1) This hypothalamic hormone is posited to play a crucial role in the feedback loop that regulates thyroid function. Scientists consider the main function of Thyrotropin-releasing hormone (TRH) to be the stimulation of the pituitary gland to release Thyroid-Stimulating Hormone (TSH) which in turn plays a role in the maintenance of the levels of thyroid hormones.(2) More specifically, TSH acts directly on the thyroid gland to promote the synthesis and release of thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3). While TRH is an endogenous compound, a synthetic peptide was developed with the hopes of simulating TRH characteristics and is known as Thyrotropin, or Protirelin.(3) Overview Thyrotropin is the synthetic analogue of the endogenous peptide hormone Thyrotropin-releasing hormone.(3) Structurally analogous to TRH, Thyrotropin is a tripeptide composed of three amino acid residues connected in a sequential form.(3) Researchers consider Thyrotropin to potentially function via binding to the thyrotropin-releasing hormone (TRH) receptors TRH-1 and TRH-2.(4)(5)(6) This interaction stimulates a cascade of biochemical events within the cell, highlighting the significant impact of these hormonal interactions on overall endocrine system function. On binding with these receptors, which are mediated by G proteins, a possible cascade of signals may be generated. First, a hydrolase enzyme may be activated, which in turn may cause a breakdown of an existing compound, producing inositol. Research indicates that Inositol may bind with another receptor, a calcium channel, thereby resulting in possible increased cellular levels of calcium which may activate protein kinase C, potentially leading to elevated phosphorylation of secondary messenger enzymes. All these signals carry the collective potential to modify gene expression in the nucleus of a cell, which may transduce the TRH binding signal to stimulate the pituitary gland to release TSH, thus regulating thyroid hormone production in the thyroid gland. This detailed mechanism is essential for maintaining metabolic balance and responding to physiological demands. Specifications: Molecular Formula: C16H22N6O4 Molecular Weight: 362.39 g/mol Other Known Titles: Protirelin Research and Clinical Studies Thyrotropin Releasing Peptide and The Central Nervous System Studies have investigated the potential of Thyrotropin-releasing hormone within the central nervous system, particularly its potential to modulate neurotransmitter systems, focusing on its actions in superfused rat hippocampal slices subjected to potassium-induced depolarization.(7) Although specific mechanisms are not fully delineated, Thyrotropin-releasing hormone seems to exert notable actions under certain conditions. The experiments demonstrated that while Thyrotropin-releasing hormone did not modify basal levels of glutamate or aspartate, it significantly inhibited their release during neuronal activation triggered by potassium. This suggests that Thyrotropin-releasing hormone may play a role in controlling the release of excitatory neurotransmitters during heightened neuronal activity, indicative of a modulatory capacity that could be relevant in conditions of neural excitability such as seizures or neurodegenerative states. The observed actions of Thyrotropin-releasing hormone might be mediated through its interaction with high-affinity receptors associated with G-protein coupled receptor pathways, which involve complex intracellular signaling cascades including calcium mobilization. The inhibition of glutamate and aspartate release appears to be calcium-dependent, raising the possibility that Thyrotropin-releasing hormone might influence calcium channels or the associated release machinery. Interestingly, the inhibitory action on neurotransmitter release did not follow a straightforward response curve, suggesting intricate receptor interactions or the influence of additional regulatory mechanisms Thyrotropin Releasing Peptide and Amyotrophic Lateral Sclerosis Researchers are considering the potential function of Thyrotropin in Amyotrophic Lateral Sclerosis (ALS).(8) Researchers suggest that Thyrotropin may act as a neuromodulator during the hyperactivity of the hypothalamic nervous system, which may assert some mitigation of Amyotrophic Lateral Sclerosis (ALS) symptoms.(9) Thyrotropin Releasing Peptide and Behavioral Research Initial clinical studies conducted to assess the potential of the peptide were somewhat hindered as researchers considered the peptide might not be able to cross the blood brain barrier.(10) Scientists consider the blood brain barrier to be one of the most difficult membranes to cross as it is composed of closely spaced cells in order to prevent toxic substances from crossing over and reaching the brain.(11) In this study,(10) the peptide was presented into the spinal theca (or cerebrospinal fluid). Eight test subjects with depressive symptoms were enrolled in a double-blind clinical trial study. Upon analysis, it was observed by the researchers that five out of the eight subjects exhibited an apparent 50% or more reduction in depressive behavior. It is suggested that the peptide's modes of action could potentially be linked to its interactions with certain neurotransmitter systems. Thyrotropin-releasing peptide is hypothesized to affect the pathways of serotonin and dopamine, both of which play significant roles in regulating mood. These actions might be facilitated through TRH receptors, which are prominently found in areas of the brain such as the amygdala and hippocampus, key sites for behavioral regulation. Additionally, it is conceivable that Thyrotropin-releasing peptide could influence these neurotransmitter systems by modifying their synthesis, the release of neurotransmitters, or their reuptake at the points where neurons communicate, known as synapses. Furthermore, Thyrotropin-releasing peptide is reported to exhibit actions on behavior that are contingent upon the existing neural or physiological conditions of the individual. For example, Thyrotropin-releasing peptide may have the capacity to restore balance to both overactive and underactive neural conditions by altering neurotransmitter levels appropriately. This hypothesis is supported by the observations of behavioral enhancements noted in clinical studies like this one, where changes in mood are described as quick yet short-lived, indicating a temporary recalibration of neural processes rather than a permanent alteration. This dynamic response could be indicative of Thyrotropin-releasing peptide’s capacity to adjust to and moderate varying neurological states. In another study,(12) 44 subjects were presented with the "Thyrotropin test". Out of the 44 test subjects, 19 exhibited an apparently blunted response to the test, indicating possible hypothyroidism, whereas 6 exhibited an apparently higher response to the test. Five of these subjects with a high augmented response were reported to naturally produce antithyroid antibodies. Through this study, researchers posited that the peptide may serve to indicate improper functioning of the thyroid gland, or determine any possible behavioral depressors. Thyrotropin Releasing Peptide and Blood Pressure In one clinical study which sought to conduct diagnostic tests on test subjects, it was suggested by the researchers that the peptide might contribute to an elevation in blood pressure rate. In this study,(13) eight subjects were examined one day before, the day after, and four weeks after heart surgery. All these subjects were given Thyrotropin. While the peptide did not appear to induce any significant changes in the levels of heart rate and thyroid hormones, the blood pressure rates reportedly increased on all three days. These results indicate that Thyrotropin may lead to increased blood pressure rates, and hence it is important for the clinical researcher to be aware of the subjects' pre-existing heart conditions when it comes to peptide experimentation. Researchers have further experimented with the peptide to investigate its specific mechanisms.(14) When the preoptic suprachiasmatic nucleus (POS) and the medial preoptic nucleus (pom) in test models were exposed to Thyrotropin, there was a 7% increase in blood pressure and a 19% increase in heart rate observed. The response in these areas was noted to be more pronounced compared to other regions, suggesting a possible localized action of Thyrotropin within these nuclei. Interestingly, different responses were recorded in other areas of the hypothalamus, such as the posterior hypothalamic nucleus (NHP), where Thyrotropin not only increased heart rate but also blood pressure, whereas only heart rate increases were observed in the anterior (NHA) and dorsomedial (NDM) hypothalamic nuclei. Preliminary exploration into the underlying mechanisms suggests that these cardiovascular changes could potentially be mediated by a mix of autonomic nervous system regulations. It is posited that inhibition of the parasympathetic nerves could contribute to the heart rate increases in the POSregion. Conversely, in the NHP area, the response to Thyrotropin is thought to be mediated by adrenal catecholamine release, indicating a role of adrenal hormones in these actions. Further, the study indicates that activation of the cardiac sympathetic nerves may play a role in the NHA region, as responses to Thyrotropin were not prevented by either methylatropine preexposure or adrenalectomy. This observation suggests a potential mechanism whereby Thyrotropin acts through pathways independent of adrenal involvement or parasympathetic inhibition. It is also notable that Thyrotropin’s impact was not uniform across all tested areas, with a decrease in both blood pressure and heart rate observed in a specific pom region (A7050–7400). Thyrotropin peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Shahid MA, Ashraf MA, Sharma S. Physiology, Thyroid Hormone. [Updated 2021 May 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021. https://www.ncbi.nlm.nih.gov/books/NBK500006/ Michigan Medicine, University of Michigan Health. March 31, 2020. https://www.uofmhealth.org/health-library/ug1836 National Center for Biotechnology Information. "PubChem Compound Summary for CID 638678, Protirelin" PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/Protirelin. Boler J, Enzmann F, Folkers K, Bowers CY, Schally AV. The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide. Biochem Biophys Res Commun. 1969 Nov 6;37(4):705-10. https://pubmed.ncbi.nlm.nih.gov/4982117/ Kobayashi, Naotake et al. “Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).” ACS omega vol. 3,10 (2018): 13647-13666. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217654/ A. Eugene Pekary, Protirelin should be used with care in patients with ischemic heart disease, obstructive airway disease, or severe hypopituitarism (Parfitt, 1999). https://www.sciencedirect.com/topics/medicine-and-dentistry/protirelin Nie Y, Schoepp DD, Klaunig JE, Yard M, Lahiri DK, Kubek MJ. Thyrotropin-releasing hormone (protirelin) inhibits potassium-stimulated glutamate and aspartate release from hippocampal slices in vitro. Brain Res. 2005 Aug 23;1054(1):45-54. doi: 10.1016/j.brainres.2005.06.077. PMID: 16055093. Amyotrophic Lateral Sclerosis (ALS) Fact Sheet. National Institute of Neurological Disorders and Stroke. Miller SC, Warnick JE. Protirelin (thyrotropin-releasing hormone) in amyotrophic lateral sclerosis. The role of androgens. Arch Neurol. 1989 Mar;46(3):330-5. https://pubmed.ncbi.nlm.nih.gov/2563937/ Marangell LB, George MS, Callahan AM, Ketter TA, Pazzaglia PJ, L'Herrou TA, Leverich GS, Post RM. Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients. Arch Gen Psychiatry. 1997 Mar;54(3):214-22. https://pubmed.ncbi.nlm.nih.gov/9075462/ Blood-brain barrier. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/blood-brain-barrier Sternbach HA, Gold MS, Pottash AC, Extein I. Thyroid failure and protirelin(thyrotropin-releasing hormone) test abnormalities in depressed outpatients. JAMA. 1983 Mar 25. https://pubmed.ncbi.nlm.nih.gov/6402617/ Zaloga GP, Chernow B, Zajtchuk R, Chin R, Rainey TG, Lake CR. Diagnostic dosages of protirelin (TRH) elevate BP by noncatecholamine mechanisms. Arch Intern. https://pubmed.ncbi.nlm.nih.gov/6428340/ Diz DI, Jacobowitz DM. Cardiovascular effects produced by injections of thyrotropin-releasing hormone in specific preoptic and hypothalamic nuclei in the rat. Peptides. 1984 Jul-Aug;5(4):801-8. doi: 10.1016/0196-9781(84)90025-1. PMID: 6436799. Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
Syn-AKE (200mg)
Syn-AKE is a synthetic peptide with the sequence beta-alanyl-L-prolyl-3-aminomethyl-L-alanine benzyl amide acetic acid known as tripeptide-3. The structure of Syn-AKE is composed of the amino acids alanine, proline, and diamino butyrate, which are linked by peptide bonds.(1) The peptide is designed to mimic the activity of Waglerin-1, a polypeptide. Waglerin-1 is a muscle relaxant that is considered to block the action of acetylcholine in the neuromuscular junction, leading to a decrease in muscle contractions. When developing Syn-AKE, researchers aimed to develop a peptide with similar activity on muscle contractions as Waglerin-1. The peptide’s intended mechanism of action is temporarily inhibiting muscle contractions, which typically leads to a decrease in the depth of wrinkles on the skin of test subjects. This compound has been extensively researched for its potential anti-aging properties for the skin of various species, including reducing fine lines and wrinkles, improving skin texture, and increasing skin hydration solely because of its muscle-relaxing properties. Chemical Makeup Molecular formula: C23H37N5O7 Molecular weight: 495.57 g/mol Other known titles: Tripeptide-3, Syn-Ake acetate, SYN-AK, DTXSID40231699, EX-A3743 Research and Clinical Studies Syn-AKE Peptide Mechanism of Action Syn-AKE has been reported by researchers to mimic the action of Waglerin-1.(2) Waglerin-1 has been considered to have muscle-relaxant properties. According to researchers, this component is a 22-amino acid polypeptide, and may be potentially selective for the form of nicotinic acetylcholine receptors (nAChRs).(3) The nACh receptors transmit signals from nerve cells to muscle cells, ultimately leading to muscle contractions. By blocking the activity of nAChRs, Waglerin-1 apparently prevents the release of acetylcholine and blocks muscle contraction. Waglerin-1 is also suggested to have modulating impacts on the brain's neurotransmitter gamma-aminobutyric acid (GABA) receptors. These receptors are involved in regulating the activity of neurons and by modulating them, Waglerin-1 may cause significant risks in research settings. Contrastingly, initial research suggests Syn-AKE cannot affect GABA receptors in the brain and may lack the risks of Waglerin-1. Syn-AKE was designed to mimic the activity of Waglerin-1 by targeting the same nAChRs in the neuromuscular junctions. Specifically, Syn-AKE is a tripeptide that contains a sequence of amino acids similar to the region of Waglerin-1 that binds to nAChRs. Syn-AKE is thought to have great permeability through the skin and bind to the nAChRs in the muscles beneath it, possibly preventing them from responding to acetylcholine. Researchers suggest that the peptide may be particularly impactful against expression lines by relaxing facial muscles. According to experimental research, the peptide "was able to reduce the frequency of innervated muscle cell contractions by 82% (...) after 2h of [presentation]."(4) The antagonism of Syn-AKE towards the nAChRs may be reversible.(5)(6) Such a reversal may indicates that the potential of tripeptide-3 on the receptors are temporary and can be reversed once the peptide is no longer present. Syn-AKE Peptide and Fine Lines, Wrinkles According to researchers, Syn-AKE may induce an immediate minimization of muscle contraction, reducing fine lines and wrinkles.(7)(8) A three-month study including 37 female subjects aged 33 to 45 with mild-to-moderate wrinkles reported that Syn-AKE appeared to exhibit both immediate and long-term potential.(9) Assessments indicated statistically significant improvements in wrinkles shortly after presentation and at months 1 and 3. One of the largest studies conducted on Syn-AKE compared its potential with other peptides and a placebo in 45 test subjects. Syn-AKE was reported to exhibit some potential, gradually exhibiting greater action after repeated presentation and reaching more than 50% after four weeks. Researchers suggested that Syn-AKE "showed up to a 52% reduction in the appearance of wrinkle size in test volunteers after a 28-day application of a 4% formulation to the forehead twice a day"(10)(11) Syn-AKE peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Balaev, A. N., Okhmanovich, K. A., & Osipov, V. N. (2014). A shortened, protecting group free, synthesis of the anti-wrinkle venom analogue Syn-Ake exploiting an optimized Hofmann-type rearrangement. Tetrahedron Letters, 55(42), 5745-5747. Molles, B. E., Tsigelny, I., Nguyen, P. D., Gao, S. X., Sine, S. M., & Taylor, P. (2002). Residues in the epsilon subunit of the nicotinic acetylcholine receptor interact to confer selectivity of waglerin-1 for the alpha-epsilon subunit interface site. Biochemistry, 41(25), 7895–7906. https://doi.org/10.1021/bi025732d Gorouhi, F., & Maibach, H. I. (2009). Role of peptides in preventing or treating aged skin. International journal of cosmetic science, 31(5), 327–345. https://doi.org/10.1111/j.1468-2494.2009.00490.x Reddy, B., Jow, T., & Hantash, B. M. (2012). Bioactive oligopeptides in dermatology: Part I. Experimental dermatology, 21(8), 563–568. https://doi.org/10.1111/j.1600-0625.2012.01528.x Munawar, A., Ali, S. A., Akrem, A., & Betzel, C. (2018). Snake venom peptides: Tools of biodiscovery. Toxins, 10(11), 474. TATARINGA, G., & ZBANCIOC, A. M. (2021). Antirid peptides in cosmeceutical formula. Romanian Journal of PHARMACEUTICAL PRACTICE| Vol. XIV, 58(3). Chhipa, N. M., & Chaudhari, B. (2012). Toxin as a Medicine. Journal of Current Pharmaceutical Research, 9(1), 11-8. Trookman, N. S., Rizer, R. L., Ford, R., Ho, E., & Gotz, V. (2009). Immediate and Long-term Clinical Benefits of a Treatment for Facial Lines and Wrinkles. The Journal of clinical and aesthetic dermatology, 2(3), 38–43. Reddy, B. Y., Jow, T., & Hantash, B. M. (2012). Bioactive oligopeptides in dermatology: Part II. Experimental dermatology, 21(8), 569–575. https://doi.org/10.1111/j.1600-0625.2012.01527.x Pai, V. V., Bhandari, P., & Shukla, P. (2017). Peptides as cosmeceuticals. Indian Journal of Dermatology, Venereology and Leprology, 83, 9. Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
PNC-27 (5mg)
PNC-27 is a 27-amino acid peptide that has been studied for its potential to mitigate the activity and proliferation of cancer cells. It is derived from the third helix of the anti-cancer peptide α-helical segment of p53 (ASPP2), a protein involved in tumor suppression. PNC-27 has been suggested to induce cell death via necrosis in various cancer cell lines, including pancreatic cancer, ovarian cancer, and leukemia, among others. Researchers speculate that the PNC-27 peptide may specifically target cancer cells while not appearing to interact with other cells. Initially synthesized in 2000 as a part of a research project associated with immunodeficiency, specifically HIV, this peptide was reported to exhibit the ability to bind with the double minute (HDM2) protein, which is deemed overly expressed on the membranes of the carcinogenic cells. Interestingly, PNC-27 does not appear to induce apoptosis, a common pathway for many anticancer research chemicals, but rather may act upon the cells via inducing necrosis. This mode of action suggests a direct, physical disruption of the plasma membrane, possibly mediated by the formation of pores that compromise cell integrity, leading to necrosis. More specifically, binding with this protein appears to perforate the membrane of cancer cells by forming holes and causing membranolysis. This allows for the influx of ions and the efflux of cellular contents, ultimately leading to cell death.(1) Chemical Makeup(1) Molecular Formula: C188H293N53O44S Molecular Weight: 4031.7 g/mol Research and Clinical Studies PNC-27 Peptide and Selective Cell Death In 2009, a study aimed to evaluate whether the PNC-27 peptide may interact (and potentially induce necrosis) within non-cancerous cells. The researchers at the time believed that, based on the peptide structure, it might be able to bind with HDM-2 protein and interact singly with cancerous cells. HDM-2 protein is reportedly only present in cancerous cells. The study suggests that forming a 1:1 complex between PNC-27 and HDM-2 might be a key event in initiating the potential formation of transmembrane pores. The study employed theoretical and experimental approaches to understand the pore formation's interaction and structural basis. Conformational energy calculations indicated that PNC-27 might form stable complexes with HDM-2, possibly aligning the leader sequence to not interfere with the core interaction. Yet, it did appear to participate in the pore structure. Immuno-electron microscopy gave researchers visual data of these complexes at the cancer cell surface, with observed ring-shaped structures at the pore sites, which they speculated may contain PNC-27 bound to HDM-2. Importantly, these pore structures were not observed in normal cells exposed to PNC-27, underscoring the peptide's potentially selective toxicity towards cancer cells. Further, for this study, normal cells were implanted with HDM-2 protein. The PNC-27 peptide, which otherwise might not affect the cells, now showed affinity towards the modified cells.(2) PNC-27 Peptide and Lysis of Cancerous Cells Another study(3) conducted in 2010 aimed at understanding whether fragments of the peptide or the entire peptide might impact the formation of membrane pores. The hypothesis was that if the peptide remained intact, it might more effectively induce the membranolytic activity necessary for killing cancer cells. For this study, the peptide was induced with a green fluorescence chemical to the terminal containing an amino group and a red fluorescence chemical to the terminal containing the carboxyl group. This labeling strategy was crucial as it allowed the researchers to visually track the integrity of the peptide within the cellular environment. The breast tumor and control cells were then exposed to the modified peptide to see which color appeared on the membrane during membranolysis. Half an hour after the peptide, a bright yellow luminescence was reported upon membrane lysis, suggesting that the peptide was fully intact during this cellular membrane-killing process. This observation was critical as it suggested that the peptide's structure was preserved during the interaction with the cell membrane, which would be essential for any cytotoxic activity. As expected, this was only seen in the cancerous cells while the control cells remained viable. The study's researchers suggest that the intact form of PNC-27 may be crucial for its activity, as the peptide appears to selectively induce pore formation in cancer cell membranes—a process associated with the release of lactate dehydrogenase (LDH), a marker of cell lysis. The interaction of PNC-27 with cancer cell membranes was suggested to increase over time, correlating with increased LDH release and cell death. Kelley A. Sookraj et al. stated, "PNC-27 induces cancer cell membrane lysis by acting as the unmodified peptide, not fragments. The punctate yellow fluorescence is due to the interaction of PNC-27 with intramembrane targets of MCF-7 cells that do not exist in the membrane of the untransformed cell line. This interaction increases the lifetime of PNC-27. The absence of these targets in the membranes of the untransformed MCF-10-2A cells results in the initial uniform fluorescence of the double-labeled peptide in their membranes, after which the peptide is degraded." (3) PNC-27 Peptide and Non-solid Tumor Cells In 2014, another study(4) was initiated to determine the potential of the PNC-27 peptide on non-solid tissue tumor cells. As mentioned in the study, the purpose was “twofold: to investigate if these cells likewise express HDM-2 in their plasma membranes and to determine if our anti-cancer peptide induces tumor cell necrosis in these non-solid tissue tumor cells in a manner that depends on the interaction between the peptide and membrane-bound HDM-2.”(4) The non-solid tumor cells were exposed to PNC-27, and the action examined. As part of the control, murine leukocyte cells were used. Upon macroscopic analysis, it was suggested that the HDM-2 cells were expressed in the non-solid tissue tumor cells and that the PNC-27 peptide appeared to exhibit potential selectivity towards these cells. Researcher Katlin Davitt et al. stated: "... We conclude that the association of PNC-27 with HDM-2 in the cancer cell membrane [may] result in trans-membrane pore formation, which results in cancer cell death, as previously discovered in a number of different solid tissue tumor cells. Since K562 cells lack p53 expression, these effects of PNC-27 on this leukemia cell line [may] occur by a p53-independent pathway." (4) PNC-27 Peptide and Cancer Cells A study(5) was conducted on the peptide PNC-28, which is structurally and functionally very similar to the PNC-27 peptide. Both peptides are derived from p53 and appear to act only on the HDM-2 proteins in cancerous cells. In this study, the researchers evaluated the anti-tumor activity of PNC-28 against ovarian cancer cells and mouse xenograft models. They suggested that PNC-28 appeared to inhibit the growth of ovarian cancer cells and reduced tumor size in the mouse models. In another 2020 study,(6) an experiment was conducted to determine the PNC-27 peptide potential on non-stem cells from the leukemia cell lines. Researchers reported the study focused on “acute myelogenous leukemia cell lines: U937, acute monocytic leukemia; OCI-AML3, acute myelomonocytic leukemia and HL60, acute promyelocytic leukemia.” These particular cell lines were selected due to their distinct phenotypic and genotypic characteristics, which might shed light on the peptide's varying potential across different cancer cell types. After peptide exposure, it was observed that the HDM-2 protein appeared to be highly expressed in all leukemia cells, which were all targeted by the PNC-27 peptide.(6) PNC-27 peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References Davitt K, Babcock BD, Fenelus M, Poon CK, Sarkar A, Trivigno V, Zolkind PA, Matthew SM, Grin'kina N, Orynbayeva Z, Shaikh MF, Adler V, Michl J, Sarafraz-Yazdi E, Pincus MR, Bowne WB. The anti-cancer peptide, PNC-27, induces tumor cell necrosis of a poorly differentiated non-solid tissue human leukemia cell line that depends on expression of HDM-2 in the plasma membrane of these cells. Ann Clin Lab Sci. 2014 Summer;44(3):241-8. PMID: 25117093. https://pubmed.ncbi.nlm.nih.gov/25117093/ Sarafraz-Yazdi E, Mumin S, Cheung D, Fridman D, Lin B, Wong L, Rosal R, Rudolph R, Frenkel M, Thadi A, Morano WF, Bowne WB, Pincus MR, Michl J. PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis. Biomedicines. 2022; 10(5):945. https://doi.org/10.3390/biomedicines10050945 Sookraj KA, Bowne WB, Adler V, Sarafraz-Yazdi E, Michl J, Pincus MR. The anti-cancer peptide, PNC-27, induces tumor cell lysis as the intact peptide. Cancer Chemother Pharmacol. 2010 Jul;66(2):325-31. doi: 10.1007/s00280-009-1166-7. Epub 2010 Feb 25. PMID: 20182728. https://pubmed.ncbi.nlm.nih.gov/20182728/ Davitt K, Babcock BD, Fenelus M, Poon CK, Sarkar A, Trivigno V, Zolkind PA, Matthew SM, Grin'kina N, Orynbayeva Z, Shaikh MF, Adler V, Michl J, Sarafraz-Yazdi E, Pincus MR, Bowne WB. The anti-cancer peptide, PNC-27, induces tumor cell necrosis of a poorly differentiated non-solid tissue human leukemia cell line that depends on expression of HDM-2 in the plasma membrane of these cells. Ann Clin Lab Sci. 2014 Summer;44(3):241-8. PMID: 25117093. https://pubmed.ncbi.nlm.nih.gov/25117093/ Wilbur B. Bowne et al., The Penetratin Sequence in the Anti-cancer PNC-28 Peptide Causes Tumor Cell Necrosis Rather Than Apoptosis of Human Pancreatic Cancer Cells, Annals of Surgical Oncology 15(12):3588–3600 Published by Springer Science+Business Media, LLC 2008 The Society of Surgical Oncology, Inc. DOI: 10.1245/s10434-008-0147-0. https://webs.iiitd.edu.in/raghava/cancerppd/refpdf/18931881.pdf Anusha Thadi et al, Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells, Anticancer Research 40 (9):4857-4867, September 2020 DOI: 10.21873/anticanres.14488 Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin Blend (12mg)
Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin are all synthetic peptides which, albeit via different proposed mechanisms, have exhibited potential to stimulate growth hormone (GH) synthesis and secretion. Tesamorelin, a synthetic analogue of the growth hormone-releasing hormone (GHRH), appears to act by specifically stimulating the production and release of endogenous growth hormone (GH) due to its potential binding affinity for GHRH receptors. Structurally, Tesamorelin is a chain of 44 amino acids, containing a sequence that bears resemblance to GHRH. Intriguingly, modifications have been introduced to Tesamorelin to possibly fortify its defense against enzymatic breakdown. For instance, its C-terminus showcases a trans-3-hexenoic acid group alteration, a change sometimes referred to as an omega-amino acid modification, which is suggested to bolster the peptide's resilience to enzymatic degradation. Further, Tesamorelin's N-terminus is adorned with an acetyl group (CH₃CO-), a modification that might further amplify the molecule's stability and biological efficacy. Consequently, this peptide garners the designation N-(trans-3-hexenoyl)-[Tyr1]hGRF(1–44)NH2 acetate. When engaging with GHRH receptors located in regions like the pituitary and hypothalamus, it is theorized that Tesamorelin may stimulate the secretion of HGH from the resident pituitary cells. CJC-1295 (Mod GRF 1-29) is a synthetic peptide that appears to exhibit prolonged half-life as it is likely to resist enzymatic degradation. It is also known as CJC-1295 without DAC (Drug Affinity Complex). References suggest it as a tetrasubstituted variant of the shortest functional GHRH sequence, denoted GRF (1-29). Consequently, it is posited that this molecule may potentially engage with GHRH receptors on pituitary cells, possibly influencing the release of hGH. Research indicates that the peptide appears to act as a potent stimulator of GH secretion, similar to GHRH, which may show promise in promoting protein synthesis, muscle growth, and enhanced metabolic processes. Ipamorelin, a synthetic pentapeptide, appears to act as a selective agonist for the ghrelin receptor and may stimulate the release of GH. This is because ghrelin receptors are found in the pituitary gland, where they are called growth hormone secretagogue (GHS) receptors. It appears to display high specificity and minimal action on other hormonal systems, making it a target for research in GH stimulation. Chemical Makeup (1)(2)(3) Molecular Formula: Tesamorelin: C221H366N72O67S CJC-1295 (Mod GRF 1-29): C152H252N44O42 Ipamorelin: C38H49N9O5 Molecular Weight: Tesamorelin: 5136 g/mol CJC-1295 (Mod GRF 1-29): 3367.9 g/mol Ipamorelin: 711.8 g/mol Sequence Tesamorelin: Unk-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2 CJC-1295 (Mod GRF 1-29): L-tyrosyl-D-alanyl-L-alpha-aspartyl-L-alanyl-L-isoleucyl-L-phenylalanyl-L-threonyl-L-glutaminyl-L-seryl-L-tyrosyl-L-arginyl-L-lysyl-L-valyl-L-leucyl-L-alanyl-L-glutaminyl-L-leucyl-L-seryl-L-alanyl-L-arginyl-L-lysyl-L-leucyl-L-leucyl-L-glutaminyl-L-alpha-aspartyl-L-isoleucyl-L-leucyl-L-seryl-L-argininamide Ipamorelin: alpha-methyl-alanyl-L-histidyl-3-(2-naphthyl)-D-alanyl-D-phenylalanyl-L-lysinamide Other Known Titles CJC-1295 (Mod GRF 1-29): CJC 1295 with DAC Ipamorelin: Ipamorelin Acetate Research and Clinical Studies Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin Blend and the Pituitary Gland The Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin peptide blend appear to exhibit significant interactions with the pituitary gland, seemingly exerting potential impact through specific receptor binding and subsequent modulation of growth hormone (GH) release. Tesamorelin & CJC-1295 (Mod GRF 1-29) appear to engage with GHRH receptors through intricate molecular processes, potentially initiating various signaling pathways. Upon interaction with the GHRH receptor, it is posited that Tesamorelin & CJC-1295 (Mod GRF 1-29) may cause shifts in receptor configuration, possibly instigating intracellular communication channels.(4) There is suggestion amongst researchers that Tesamorelin & CJC-1295 (Mod GRF 1-29) might promote the generation of cyclic adenosine monophosphate (cAMP) within specific target cells. This may potentially be facilitated by the activation of adenylate cyclase, which might transform ATP to cAMP. Elevated cAMP levels are believed to possibly activate protein kinase A (PKA), a molecule that appears integral to intracellular signaling. PKA might then phosphorylate a range of target proteins, setting off subsequent cellular reactions. The hypothetical activation of the GHRH receptor by Tesamorelin & CJC-1295 (Mod GRF 1-29), coupled with the proposed cAMP-PKA signaling sequence, may stimulate hGH production and dispersal from somatotrophs located in the pituitary gland. The HGH secreted from these cells may also play a role in the formation of insulin-like growth factor-1 (IGF-1).(5) CJC-1295 (Mod GRF 1-29) peptide has four amino acid substitutions in its structure, which appears to enhance its GH-related activity as well as its potential resistance towards the proteolytic enzymes. These modifications are also believed to assist “at least 90% of the peptide” to bind covalently to blood albumin, with trace amounts potentially binding to fibrinogen and immunoglobulin G (IgG).(5) As per the researchers, “No other chemical species have been found bound to DAC-GRF after administration This binding extends the half-life of the active pharmacophore, resulting in a markedly prolonged duration of action in several animal species.”(5) Ipamorelin, on the other hand, appears to act as a selective agonist for the GHS (ghrelin) receptor, which is also present on somatotrophs within the pituitary gland. Its binding to GHS (ghrelin) receptors is believed to induce GH release with high specificity and minimal impact on other hormonal systems. Research-based outcomes have indicated that Ipamorelin influence in certain test models may lead to increased GH secretion, without significantly affecting prolactin, or ACTH levels.(6) In vitro analyses indicate that Ipamorelin's interaction with GHS receptors possibly influences somatotroph cells within the anterior pituitary gland. This interaction appears to initiate a series of intracellular signaling cascades. One posited mechanism is the activation of phospholipase C (PLC), which, according to some researchers, might subsequently facilitate the release of inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 might then prompt the release of calcium ions (Ca2+) from intracellular reserves, whereas DAG potentially activates protein kinase C (PKC). Such elevation in intracellular calcium and the probable activation of PKC are suggested to culminate in the observed exocytosis of vesicles containing growth hormone from pituitary cells.(7) Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin Blend and the GI Tract Ipamorelin is believed to primarily interact with the ghrelin receptor within the GI tract. Upon binding to the ghrelin receptors, Ipamorelin may elicit a variety of responses including promoting gut motility and improving intestinal absorption. Moreover, Ipamorelin has shown promise in attenuating inflammation and promoting tissue repair in various models of GI injury. As per researchers, Ipamorelin may “increase total body fat percentages” , identifying the peptide as a “potent and selective stimulator of GH that can significantly influence the GI system, body composition, and adiposity.”(6) Investigators explored the potential impacts of Ipamorelin on gastric functions, contrasting its effects with a placebo. They were particularly interested in its suggested ability to hasten gastric emptying. To assess this, they utilized a method that monitored leftover radioactivity in the stomach a quarter-hour after introducing a particular substance via intragastric gavage. It appears that abdominal surgeries might potentially slow down gastric emptying, an effect that was notably evident in the placebo group. In comparison, Ipamorelin seemed to accelerate this process. Such findings hint at Ipamorelin's potential to boost the pace of gastric emptying. Further, the group aimed to understand how this compound influenced the contractile behavior of gastric smooth muscles when exposed to acetylcholine and electrical field stimulation. Information gathered indicated that intestinal surgeries might notably reduce the contractile reactions to these simulations. However, this suppression appeared to be lessened when Ipamorelin was combined with ghrelin. This raises the possibility that Ipamorelin may not only promote gastric muscle contractility but also possibly offset the inhibitory effects resulting from certain surgical procedures. (8) Synergistic Action of Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin Blend The rationale for combining these peptides lies in their supposed distinct mechanisms of action and potential to enhance growth hormone (GH) secretion synergistically. The apparent synergy of all these peptides lies in their individual potential to increase lean mass and muscle growth. For example, a recent scientific investigation proposed that the potential impacts of Tesamorelin on muscle tissue integrity may be examined using CT scans. Following a placebo-controlled experiment, the CT-scan findings suggest a possible association between Tesamorelin and improvements in muscle density and size. Notably, some muscle groups, especially the rectus abdominis, psoas major, and paraspinal muscles, reportedly showed more evident changes. These changes were characterized by either an increase in muscle size and density or a reduction in fat content. Statistically, these alterations were different compared to the placebo group. Although some theorize that Tesamorelin's effects might be related to molecules like IGF-1, the study did not find a notable connection between changes in IGF-1 levels and shifts in muscle size or density.(9) Further, preliminary research involving CJC-1295 (Mod GRF 1-29) 1-29 indicates a potential rise in nocturnal growth hormone levels, as well as serum levels of IGF-I and IGFBP-3, and GHBP concentrations.(10) Consequently, male research models exposed to the peptide over a span of four months seemingly gained an average of 1.26 kg in lean body mass. Additionally, research suggests that the peptide might influence an increase in skin thickness among males and may possibly enhance insulin sensitivity. Similarly, preliminary studies have suggested that Ipamorelin might exhibit effects similar to those seen with Tesamorelin concerning skeletal muscle and bone structures. However, these findings are still awaiting further confirmation. Going further, there is a working hypothesis amongst researchers that Ipamorelin may interact with, and possibly increase, IGF-I levels. These interactions appeared to align with an increase in muscle fiber size, overall muscle mass, and hence, a potential boost in skeletal muscle strength during this mouse-based study.(11) Tesamorelin & CJC-1295 (Mod GRF 1-29) & Ipamorelin blend is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 9831659, Ipamorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Ipamorelin. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 56841945. https://pubchem.ncbi.nlm.nih.gov/compound/56841945. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 16137828, Tesamorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Tesamorelin. Spooner, L. M., & Olin, J. L. (2012). Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. The Annals of pharmacotherapy, 46(2), 240–247. https://doi.org/10.1345/aph.1Q629 Zhou, F., Zhang, H., Cong, Z., Zhao, L. H., Zhou, Q., Mao, C., Cheng, X., Shen, D. D., Cai, X., Ma, C., Wang, Y., Dai, A., Zhou, Y., Sun, W., Zhao, F., Zhao, S., Jiang, H., Jiang, Y., Yang, D., Eric Xu, H., ... Wang, M. W. (2020). Structural basis for activation of the growth hormone-releasing hormone receptor. Nature communications, 11(1), 5205. https://doi.org/10.1038/s41467-020-18945-0 Sinha DK, Balasubramanian A, Tatem AJ, Rivera-Mirabal J, Yu J, Kovac J, Pastuszak AW, Lipshultz LI. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol. 2020 Mar;9(Suppl 2):S149-S159. doi: 10.21037/tau.2019.11.30. PMID: 32257855; PMCID: PMC7108996 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108996/ Jiménez-Reina, L., Cañete, R., de la Torre, M. J., & Bernal, G. (2002). Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro. Histology and histopathology, 17(3), 707–714. https://doi.org/10.14670/HH-17.707 Greenwood-Van Meerveld, B., Tyler, K., Mohammadi, E., & Pietra, C. (2012). Efficacy of ipamorelin, a ghrelin mimetic, on gastric dysmotility in a rodent model of postoperative ileus. Journal of experimental pharmacology, 4, 149–155. https://doi.org/10.2147/JEP.S35396 Adrian S, Scherzinger A, Sanyal A, Lake JE, Falutz J, Dubé MP, Stanley T, Grinspoon S, Mamputu JC, Marsolais C, Brown TT, Erlandson KM. The Growth Hormone Releasing Hormone Analogue, Tesamorelin, Decreases Muscle Fat and Increases Muscle Area in Adults with HIV. J Frailty Aging. 2019;8(3):154-159. doi: 10.14283/jfa.2018.45. PMID: 31237318; PMCID: PMC6766405. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766405/ Khorram, O., Laughlin, G. A., & Yen, S. S. (1997). Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. The Journal of clinical endocrinology and metabolism, 82(5), 1472–1479. https://doi.org/10.1210/jcem.82.5.3943 Andersen, N. B., Malmlöf, K., Johansen, P. B., Andreassen, T. T., Ørtoft, G., & Oxlund, H. (2001). The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 11(5), 266–272. https://doi.org/10.1054/ghir.2001.0239 Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
GHK-Cu (Copper) (50mg)
GHK-Cu is a naturally occurring copper-binding peptide composed of 3 amino acids, i.e. glycyl-L-histidyl-L-lysine.(1) -Cu refers to the chemical addition of copper. GHK-Cu (Copper) is a small tripeptide found in plasma and reportedly releases at the time of injury. The concentration of GHK-Cu declines with age. At 20 years, the average concentration of GHK-Cu of 200 ng/mL declines to 80 ng/mL by 60 years.(1) Studies(4) have suggested when the plasma GHK peptide is added to the cell culture in nanomolar amounts; the peptide has the potential to induce a wide range of responses from growth stimulation to toxic cell differentiation. During the isolation of the peptide, researchers suggested that it exhibited potential chelating properties and might co-isolate with almost the same amount of copper ions and a fifth of the amount of iron found in the cells. When the peptide was incubated in the isolated cells as a bound complex with copper and iron molecules, maximal potential was reported. Overview Studies(5) have suggested that the peptide exhibits potential in gene expression and may to reset elements of the genome. By this potential mechanism, GHK-Cu peptide may restore impaired cells, including carcinogenic cells and COPD cells. GHK-Cu peptide has been researched for its potential across a variety of functions(1) including that it may tighten and reverse the thinning of aging skin structure, supporting the extracellular matrix, that it may restore the skin barrier and moderate texture, hyperpigmentation and lesions, may support tissue repair and mitigate inflammation, may stimulate increasing hair follicle size, may exert antioxidant properties and, finally, may exhibit gene restructuring potential. Specifications Molecular Formula: C14H23CuN6O4 Molecular Weight: 340.38 g/mol Other Known Titles: glycyl-L-histidyl-L-lysine-copper 2+ Research and Clinical Studies GHK Peptide Initial Research This 1980s study(6) suggested the biological potential of the naturally occurring peptide in tissue repair. GHK peptide may host copper (II) ions due to possible copper affinity and may thereby stimulate the synthesis of collagen and increase the accumulation of total proteins and DNA at the injury site. Dermal wounded rats were used for this study. At the time of injury, the release of GHK peptide was induced. ‘Emergency response molecules’ were released from the matrix at the site of injury. Once released, GHK appeared to bind with Cu ions found in the blood and then stimulate the synthesis of decorin protein. Decorin protein is responsible for the synthesis of collagen and regulation of wound healing and anti-tumor defense mechanism. Further studies in the 2000s,(7) suggested that the GHK-Cu peptide hosts the potential to not only stimulate the collagen synthesis but also stimulate the production of tissue inhibitors, TIMP-1 and TIMP-2. GHK Peptide and Tissue Repair In this study,(8) the main aim was to understand the action of the GHK-Cu peptide complex when applied to the open wounds in comparison to zinc oxide. 18 New Zealand white rabbits were used for this study, divided into three groups – one group was presented with GHK-Cu, second group with zinc oxide and third group with placebo. Woulds were induced on each rabbit and the rabbits were presented with the respective compounds for 21 consecutive days. After 21 days, it was suggested by the researchers that the group delivered with the GHK-Cu peptide complex appeared to exhibit increased healing compared to the group given zinc oxide or placebo. In this study,(9) the main aim was to understand the action of the GHK-Cu peptide complex as compared to helium neon laser. Laser applications were measured at 1 J cm2 and 3 J cm2. 24 New Zealand white rabbits were used for this study, divided into three groups and presented with respective concentrations of the GHK-Cu peptide complex and helium neon laser application. Experimental wounds were created on all the rabbits and all rabbits were studied for 28 consecutive days with the respective compounds. After the study, it was suggested by the researchers that rabbits studied with GHK-Cu peptide and higher concentration of the laser application appeared more receptive toward wound healing than the other group. The rabbits presented with GHK-Cu peptide exhibited an apparent decline in neutrophil counts and increase in neovascularization. GHK Peptide and Metastasis In this 1983 study,(1) the actions of the mixture of GHK-Cu complex and ascorbic acid (Vitamin C) on the growth of the sarcoma (tumor) cells was observed. 180 mice with cancerous growths were exposed to this mixture. Researchers suggested the mixture had the potential to induce a decline in the growth of carcinogenic cells in the subject mice. It was later reported by the researchers that GHK-Cu peptide complex exhibited some potential in increasing the expression of caspase and the associated genes, as well as gene expression associated with DNA repair. Specifically, this peptide seemed to suppress the growth of two types of cancer cells in experimental settings: SH-SY5Y neuroblastoma cells, which are a model for studying nerve cell behavior and pathology, and U937 histiocytic lymphoma cells, which are used to study the immune system's response to cancer. Additionally, the peptide might have reactivated the apoptosis pathway, a type of programmed cell death crucial for removing faulty cells, as evidenced by activity in caspases 3 and 7, which are enzymes that play key roles in apoptosis. Conversely, in a study of non-cancerous cells, GHK appeared to promote the growth of NIH-3T3 fibroblasts, which are healthy cells often used as a standard model to examine cell division and growth. GHK Peptide and Ulcers This clinical study(10) was carried out in diabetic subjects with neuropathic ulcers. All subjects were enrolled in a standard wound care protocol, where only the subjects with sharp ulcer wound or debridement were entered into this randomized, placebo controlled clinical trial. The study was carried out using GHK-Cu peptide complex gel. All subjects were divided into different groups, where one group was presented with the peptide gel, whereas others were given standard care with a placebo application. Following the study, researchers suggested that the subjects given the gel exhibited apparently elevated healing at 98%+. The gel complex appeared to have the potential to induce closure of 98.5% of plantar ulcers whereas the control only reportedly induced 60.8% of ulcer healing. GHK Peptide and Behavioral Properties In this study,(1) GHK-Cu was delivered to mice to measure pain mitigation. Mice were placed on a moderately hot plate. Due to heat and the pain, it would usually take longer for mice to lick their paws; however, upon delivery the peptide, the time taken to lick their paws reduced compared to control environments. Researchers suggested the mice got ‘comfortable’ and their pain was eased faster with the presence of GHK-Cu. In this study,(11) male rats were deposited into a maze, which was intended to induce anxiety and cause behavioral changes. If anxious, rats were observed to restrict arm movement, keeping "close arms"; whereas "open arm" behavior was shown in rats with lessened levels of anxiety. As a part of the study, once the peptide was delivered, the time spent by the rats in "open arms" state in the maze was monitored. After the study, it was reported by the researchers that the peptide exhibited some potential in increasing "open arms" states in the subjects. In an additional study,(12) two rats were placed in a small cage and were then given minor electric shocks. As a result of these shocks, the rat would become agitated and attack the second rat. Twelve minutes before this experiment, GHK-Cu peptide was delivered to both rats. It was noted by the researchers that the number of attacks, after the electric shocks, reduced by 5 times than usual. GHK-Cu and Antioxidative potential A study has investigated the potential of Glycyl-L-histidyl-L-lysine (GHK) to regulate the presence of reactive oxygen species (ROS) within laboratory cells, with a focus on its ability to mitigate oxidative stress through interactions with various ROS types.(13) GHK is proposed to act as an endogenous antioxidant, potentially due to its selective targeting and neutralization of certain radicals, specifically hydroxyl (·OH) and peroxyl (ROO·) radicals. The antioxidant properties of GHK were assessed using two primary techniques: flow cytometry, a method for analyzing various cellular characteristics, and electron spin resonance (ESR) spin-trapping, which is employed to detect free radicals. Throughout these evaluations, GHK appeared to lower ROS levels induced by tert-butyl hydroperoxide (t-BOPD), a chemical known to promote oxidative stress within cells. The ESR data revealed that GHK was notably positive in reducing the concentrations of ·OH and ROO· radicals, although it had a seemingly modest action on superoxide (O2 -·) radicals. Additional examinations utilizing ESR assessed the relative potential of GHK in neutralizing ·OH radicals compared to other antioxidants like carnosine and reduced glutathione (GSH), both recognized for their antioxidant capabilities. Preliminary results suggest that GHK could be more proficient at neutralizing ·OH radicals compared to these alternatives. GHK-Cu and Antioxidative potential A study has investigated the possible mechanisms through which the peptide complex GHK-Cu could influence anti-inflammatory actions, particularly against lung tissue inflammation induced by cigarette smoke (CS).(14) It is hypothesized that GHK-Cu may influence various biochemical pathways and molecular markers related to inflammation and oxidative stress, although the specific mechanisms remain somewhat uncertain. In experiments involving mouse models exposed to CS, exposure to GHK-Cu was linked to a potential decrease in the production of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), found in bronchoalveolar lavage fluid—fluid used to capture cells and soluble factors from the airways and lung tissues. These results tentatively suggest that GHK-Cu might help mitigate the inflammatory responses triggered by cigarette smoke. Additionally, there was a noted possible reduction in the activity of myeloperoxidase (MPO), an enzyme that serves as a marker for neutrophil-driven inflammation and oxidative stress, in lung tissues that received GHK-Cu exposure. This observation could indicate a potential role of GHK-Cu in limiting the activation or mobilization of neutrophils, possibly curtailing the oxidative bursts and consequent inflammation. At the molecular level, the research proposes that GHK-Cu may interact with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. NF-κB plays a critical role in the initiation and perpetuation of inflammation. The peptide complex is thought to possibly inhibit NF-κB activation by affecting the phosphorylation of IκBα, a protein that inhibits NF-κB. This interaction could hypothetically result in lower expression of genes that promote inflammation, controlled by NF-κB. Furthermore, the study suggests that GHK-Cu could potentially influence the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is integral to cellular defenses against oxidative damage. GHK-Cu is posited to possibly boost the expression and nuclear translocation of Nrf2 in lung tissues, thereby promoting the transcription of genes that combat oxidative stress and possibly enhancing the cellular resilience against oxidative damage. The investigation further examines how GHK-Cu interacts with markers of oxidative stress, such as malondialdehyde (MDA) and glutathione (GSH). MDA is a product of lipid peroxidation and an indicator of oxidative stress, while GSH is a vital antioxidant that plays a crucial role in cellular defense mechanisms. The experimentation with GHK-Cu is associated with a tentative reduction in MDA levels and a possible restoration of GSH levels, suggesting a potential ameliorative action on oxidative stress. GHK-Cu and Lipid Peroxidation A theoretical model posits that GHK could play a role in mitigating the discharge of iron from ferritin.(15) Ferritin, a protein complex that stores iron, releases it in a form that can facilitate lipid peroxidation, a process where free radicals attack lipids, leading to cell damage. It is suggested that GHK might inhibit the assembly of iron complexes within injured tissues, which could, in turn, decrease inflammation. Further exploration of GHK's role reveals that it may interact with specific biological pathways that govern the release of iron from ferritin. This interaction might restrict the release of iron by up to 87%, although this is a provisional estimate. Such a significant reduction in iron release could conceivably diminish both inflammation and oxidative stress, the latter being a condition where damaging oxidative processes occur more rapidly than the body's ability to counteract them, in the affected tissues. GHK-Cu peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Pickart, Loren, and Anna Margolina. “Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data.” International journal of molecular sciences vol. 19,7 1987. 7 Jul. 2018, doi:10.3390/ijms19071987. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073405/ Pickart L, Freedman JH, Loker WJ, Peisach J, Perkins CM, Stenkamp RE, Weinstein B. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature. 1980 Dec 25;288(5792):715-7. doi: 10.1038/288715a0. PMID: 7453802. https://pubmed.ncbi.nlm.nih.gov/7453802/ L.O. Pilgeram, L.R. Pickart, Control of fibrinogen biosynthesis: The role of free fatty acid, Journal of Atherosclerosis Research, Volume 8, Issue 1, 1968, Pages 155-166, ISSN 0368-1319, https://doi.org/10.1016/S0368-1319(68)80089-4 Pickart L, Freedman JH, Loker WJ, Peisach J, Perkins CM, Stenkamp RE, Weinstein B. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature. 1980 Dec 25;288(5792):715-7. doi: 10.1038/288715a0. PMID: 7453802. https://pubmed.ncbi.nlm.nih.gov/7453802/ Pickart L, Vasquez-Soltero JM, Margolina A. GHK and DNA: resetting the human genome to health. Biomed Res Int. 2014;2014:151479. doi: 10.1155/2014/151479. Epub 2014 Sep 11. PMID: 25302294; PMCID: PMC4180391. https://pubmed.ncbi.nlm.nih.gov/25302294/ Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. 1988 Oct 10;238(2):343-6. doi: 10.1016/0014-5793(88)80509-x. PMID: 3169264. https://pubmed.ncbi.nlm.nih.gov/3169264/ Siméon A, Emonard H, Hornebeck W, Maquart FX. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci. 2000 Sep 22;67(18):2257-65. doi: 10.1016/s0024-3205(00)00803-1. PMID: 11045606. https://pubmed.ncbi.nlm.nih.gov/11045606/ Cangul IT, Gul NY, Topal A, Yilmaz R. Evaluation of the effects of tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Vet Dermatol. 2006 Dec;17(6):417-23. doi: 10.1111/j.1365-3164.2006.00551.x. PMID: 17083573. https://pubmed.ncbi.nlm.nih.gov/17083573/ Gul NY, Topal A, Cangul IT, Yanik K. The effects of tripeptide copper complex and helium-neon laser on wound healing in rabbits. Vet Dermatol. 2008 Feb;19(1):7-14. doi: 10.1111/j.1365-3164.2007.00647.x. PMID: 18177285. https://pubmed.ncbi.nlm.nih.gov/18177285/ Mulder GD, Patt LM, Sanders L, Rosenstock J, Altman MI, Hanley ME, Duncan GW. Enhanced healing of ulcers in patients with diabetes by treatment with glycyl-l-histidyl-l-lysine copper. Wound Repair Regen. 1994 Oct;2(4):259-69. doi: 10.1046/j.1524-475X.1994.20406.x. PMID: 17147644. https://pubmed.ncbi.nlm.nih.gov/17147644/ Bobyntsev II, Chernysheva OI, Dolgintsev ME, Smakhtin MY, Belykh AE. Anxiolytic effects of Gly-His-Lys peptide and its analogs. Bull Exp Biol Med. 2015 Apr;158(6):726-8. doi: 10.1007/s10517-015-2847-3. Epub 2015 Apr 23. PMID: 25900608. https://pubmed.ncbi.nlm.nih.gov/25900608/ Sever'yanova LА, Dolgintsev ME. Effects of Tripeptide Gly-His-Lys in Pain-Induced Aggressive-Defensive Behavior in Rats. Bull Exp Biol Med. 2017 Dec;164(2):140-143. doi: 10.1007/s10517-017-3943-3. Epub 2017 Nov 27. PMID: 29181666. https://pubmed.ncbi.nlm.nih.gov/29181666/ Sakuma, S., Ishimura, M., Yuba, Y., Itoh, Y., & Fujimoto, Y. (2018). The peptide glycyl-ʟ-histidyl-ʟ-lysine is an endogenous antioxidant in living organisms, possibly by diminishing hydroxyl and peroxyl radicals. International journal of physiology, pathophysiology and pharmacology, 10(3), 132–138. Zhang, Q., Yan, L., Lu, J., & Zhou, X. (2022). Glycyl-L-histidyl-L-lysine-Cu2+ attenuates cigarette smoke-induced pulmonary emphysema and inflammation by reducing oxidative stress pathway. Frontiers in molecular biosciences, 9, 925700. https://doi.org/10.3389/fmolb.2022.925700 Miller, D. M., DeSilva, D., Pickart, L., & Aust, S. D. (1990). Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation. Advances in experimental medicine and biology, 264, 79–84. https://doi.org/10.1007/978-1-4684-5730-8_11 Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
VIP (6mg)
Vasoactive Intestinal Peptide, or VIP, is a short peptide hormone composed of 28 amino acid residues found naturally in both peripheral and central nervous systems.(1) Researchers speculate that the apparently wide distribution of the peptide indicates its pleiotropic potential as a neurotransmitter, vasodilator, and possibly as an immune regulator and secretagogue.(1) VIP has a vast spectrum of potential, including but not limited to neuromodulation and neurotransmission functions. Given the wide range of its possible relevance in various research contexts, VIP has been of immense interest among researchers for further exploration.(2)(3) Overview Scientists posit that the VIP peptide binds with three types of G protein-coupled receptors, namely VPAC1, VPAC2, and PAC1. Upon binding with these receptors, the pathway associated with adenylate cyclase (key regulatory enzyme) may be activated, possibly resulting in biological activity.(4) The primary difference between the three receptors is their localization. Research indicates that VPAC1 is mainly expressed in the brain and peripheral areas, such as the liver, lungs, intestine, and immune cells, whereas VPAC2 is expressed in the central nervous system and other peripheral areas such as the pancreas, heart, kidney, skeletal muscles, gastrointestinal and reproductive tract, and PAC1 is predominant in the brain and adrenal region.(4) Owing to the wide distribution of the receptors, researchers suggest that VIP and receptor binding might affect different targets in the central and peripheral system (depending on receptor location). Chemical Makeup Molecular Formula: C147H237N43O43S Molecular Weight: 3326.8 g/mol Other Known Titles: PHM27, Vasoactive intestinal polypeptide Research and Clinical Studies VIP Peptide and Inflammation Research(5) has suggested that VIP, which appears to be produced directly by immune cells themselves, exhibits various potential immunological actions to maintain an equilibrium of the immune system. Several studies have suggested that VIP possesses anti-inflammatory potential in both innate (hereditary) immunity and adaptive (acquired) immunity. In innate immunity, VIP has been posited to inhibit the synthesis of inflammatory chemicals such as cytokines and chemokines, while in adaptive immunity, VIP may inhibit responses of the inflammatory Th1-type cells and may promote Th2-type cell responses. Due to its potential to reduce Th1-type inflammatory cell actions, VIP may improve intestinal immunity and decrease inflammation.(6) One study explored the potential interactions between VIP and inflammation within the context of necrotizing enterocolitis (NEC), primarily using murine models. VIP, lauded for its potential anti-inflammatory characteristics, might regulate intestinal epithelial barrier integrity and homeostasis. The research posits that the decreased expression of VIP-ergic neurons in the NEC-affected ileum may be linked to heightened inflammation and compromised barrier function. In this experimental setup, NEC was induced in neonatal C57BL/6 murine models between postnatal days 5 and 9. The study measured NEC severity, intestinal inflammation markers like IL-6 and TNFα, and the expression of tight junction proteins such as Claudin-3. The results indicated that VIP mRNA expression and immunoactivity appeared substantially reduced in NEC models compared to controls. Exogenous VIP apparently reduced NEC severity and decreased the levels of proinflammatory cytokines IL-6 and TNFα in the NEC + VIP group compared to the NEC group alone. This suggests that VIP might have a role in moderating inflammatory responses. Furthermore, the research suggested that VIP might help preserve tight junction integrity. Specifically, Claudin-3 expression, considered crucial for tight junction function and intestinal barrier integrity, was enhanced in the NEC + VIP group relative to the NEC group alone. This finding implies a potential mechanism by which VIP might maintain barrier function amidst inflammatory conditions. VIP Peptide and the Blood Brain Barrier The blood-brain barrier (BBB) and blood-spinal barrier (BSB) are considered a crucial part of the nervous system, providing cellular protection to the tissues and blood vessels of the central nervous system. The blood-brain barrier appears to filter everything from oxygen to nutrition factors, which may potentially enter these neurological vessels and affect immune function. Compromise of the blood-brain barrier may lead to severe physiological impacts. Research has suggested that VIP may exhibit some neuroprotective potential, which might support proper maintenance of the blood-brain barrier.(9) VIP is possibly involved in several functions, such as neurotransmission, vasodilation, and immune modulation. By activating adenylate cyclase (AC), VIP may play a pivotal role in the production of cyclic adenosine monophosphate (cAMP), a regulator of immune responses, including those involving regulatory T cells (Tregs). The disruption of these functions due to autoimmune reactions against VIP or its receptors might potentially lead to increased permeability of the BBB and BSB, commonly referred to as "leakiness," which may facilitate further autoimmune events. This may result in exacerbated neuroinflammatory and neurodegenerative processes. The Virchow-Robin spaces (VRS), perivascular areas surrounding small vessels in the central nervous system, are particularly noted for their contributions to the integrity of the BBB and BSB. These spaces may contain receptors for VIP and are involved in modulating immune responses. Autoimmune responses targeting these receptors may impair the function of the BBB and BSB, hence the potential role of VIP in their preservation. This is currently under investigation in several experimental models of neurodegeneration.(10)(11) VIP Peptide and Cardiac Fibrosis The pathophysiology of cardiac fibrosis is considered to have a high association with angiotensinogen receptors and angiotensinogen converting enzymes (ACE), both of which may lead to vascular inflammation. Research(12) has suggested that VIP peptide may promote some reduction in these angiotensinogen expressions – possibly similar in action to ACE inhibitor compounds. As a result, VIP may mitigate cardiac fibrosis and possibly reverse heart muscle scarring. This is also posited based on observations that lower VIP concentrations correspond with increased fibrosis and are nearly undetectable in end-stage cardiomyopathy. To probe this association further, the study experimented with VIP introduced to murine models on a high-salt diet and assessed changes in myocardial VIP levels, fibrosis quantification via histomorphometry, and the expression of pro-fibrotic mediators through quantitative rt-PCR. Findings suggested that VIP-exposed murine models may have exhibited significantly higher myocardial VIP levels than controls, alongside notably lower fibrosis metrics. Not all pro-fibrotic mediators were impacted by VIP infusion; that stated, significant reductions in angiotensinogen (Agt) and angiotensin receptor type 1a (AT1a) mRNA expression were noted, indicating a potential downregulation of the renin-angiotensin system—a key pathway implicated in fibrotic processes. The study cautiously infers that the observed decrease in myocardial fibrosis may be attributed, at least in part, to the downregulation of key components of the renin-angiotensin system, moderated by elevated VIP levels. This hypothesis aligns with the noted decreases in Agt and AT1a mRNA expression post-VIP exposure. However, the mechanisms through which VIP may exert these actions remain uncertain and warrant further investigation. Moreover, while VIP appeared to influence some pro-fibrotic mediators, it did not appear to alter others, such as TGFβ, TNFα, CTGF, and NFκB, suggesting that the anti-fibrotic actions of VIP might be selective or mediated through alternative pathways not examined in this study. VIP and Behavioral Responses in Animals Studies(13) have suggested that VIP neurons may be activated when animals process behavioral responses. Activating the VIP neurons in the hypothalamus region may also trigger the secretion of prolactin hormones, which is considered the primary trigger of behaviors such as affiliation, gregariousness, pair bonding, and aggression. More specifically, it appears that VIP and its associated VPAC receptors, which are distributed across both hypothalamic and extrahypothalamic regions, may ultimately result in its potential on various behavioral and reproductive functions. Further, VIP's influence on prolactin (PRL) secretion is linked to various reproductive behaviors across different experimental models, as changes in VIP levels within the hypothalamus closely mirror fluctuations in plasma PRL levels corresponding to different reproductive stages. This suggests that VIP might have a role in modulating behaviors preparatory to offspring care. Moreover, VIP's role in circadian rhythm regulation, particularly through its interactions in the suprachiasmatic nucleus (SCN), where it modulates the activity of GABAergic cells, highlights its importance in the synchronization of biological rhythms. These include the potential timing of ovulation and responses to photoperiod changes, which might be crucial for understanding seasonal reproduction patterns in both mammals and birds. The study also delves into VIP’s roles in social behavior networks, indicating that VIP might influence behaviors such as aggression and pair bonding through itsinteractions with other neuropeptides, including oxytocin and vasopressin, in these networks. Intriguingly, the study posits that VIP’s interaction with these neuropeptides might modulate responses to social and environmental stressors, potentially affecting an animal’s social dynamics and behaviors. In terms of aggression, VIP is thought to potentially alter aggressive behaviors, as indicated in studies where manipulation of VIP levels in the hypothalamic regions appeared to have influenced aggressive responses in certain avian species. This action may also be mediated through the interactions of VIP with other signaling molecules within key areas of the brain known to regulate aggression. The full role of VIP in behavioral responses is still under exploration. VIP peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Delgado, M., & Ganea, D. (2013). Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino acids, 45(1), 25–39. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883350/ Iwasaki, M., Akiba, Y., & Kaunitz, J. D. (2019). Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system. F1000Research, 8, F1000 Faculty Rev-1629. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743256/ Welsh, D. K., Takahashi, J. S., & Kay, S. A. (2010). Suprachiasmatic nucleus: cell autonomy and network properties. Annual review of physiology, 72, 551–577. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758475/ Vosko, A. M., Schroeder, A., Loh, D. H., & Colwell, C. S. (2007). Vasoactive intestinal peptide and the mammalian circadian system. General and comparative endocrinology, 152(2-3), 165–175. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994114/ Gonzalez-Rey E, Delgado M. Role of vasoactive intestinal peptide in inflammation and autoimmunity. Curr Opin Investig Drugs. 2005 Nov;6(11):1116-23. https://pubmed.ncbi.nlm.nih.gov/16312132/ Seo S, Miyake H, Alganabi M, Janssen Lok M, O'Connell JS, Lee C, Li B, Pierro A. Vasoactive intestinal peptide decreases inflammation and tight junction disruption in experimental necrotizing enterocolitis. https://pubmed.ncbi.nlm.nih.gov/31668399/ Chorny A, Gonzalez-Rey E, Delgado M. Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation. Ann N Y Acad Sci. 2006 Nov;1088:187-94. https://pubmed.ncbi.nlm.nih.gov/17192565/ Chorny, A., Gonzalez-Rey, E., Fernandez-Martin, A., Pozo, D., Ganea, D., & Delgado, M. (2005). Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders. Proceedings of the National Academy of Sciences of the United States of America, 102(38), 13562–13567. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1224633/ Staines DR, Brenu EW, Marshall-Gradisnik S. Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment? Neuropsychiatr Dis Treat. 2009;5:81-9. Epub 2009 Apr 8. PMID: 19557103; PMCID: PMC2695238. https://pubmed.ncbi.nlm.nih.gov/19557103/ Mosley RL, Lu Y, Olson KE, Machhi J, Yan W, Namminga KL, Smith JR, Shandler SJ, Gendelman HE. A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson's Disease. Front Cell Neurosci. 2019 Sep 18;13:421. https://pubmed.ncbi.nlm.nih.gov/31619964/ Solés-Tarrés, I., Cabezas-Llobet, N., Vaudry, D., & Xifró, X. (2020). Protective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide and Vasoactive Intestinal Peptide Against Cognitive Decline in Neurodegenerative Diseases. Frontiers in cellular neuroscience, 14, 221. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380167/ Karen A. Duggan, George Hodge, Juchuan Chen, Tegan Hunter, Vasoactive intestinal peptide infusion reverses existing myocardial fibrosis in the rat, European Journal of Pharmacology, Volume 862, 2019, 172629, ISSN 0014-2999. https://www.sciencedirect.com/science/article/pii/S0014299919305813 Kingsbury MA. New perspectives on vasoactive intestinal polypeptide as a widespread modulator of social behavior. Curr Opin Behav Sci. 2015 Dec 1;6:139-147. https://pubmed.ncbi.nlm.nih.gov/26858968/ Domschke, S., Domschke, W., Bloom, S. R., Mitznegg, P., Mitchell, S. J., Lux, G., & Strunz, U. (1978). Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects. Gut, 19(11), 1049–1053. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1412244/ Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
FOXO4-DRI (10mg)
Organisms host multiple transcription factor proteins. One such class of transcription factor proteins is the FOXO group or forkhead family of transcription factor-O,(2) which includes four members: FOXO1, FOXO3, FOXO4, and FOXO6. The FOXO4 factor is considered to regulate various cell pathways, including insulin signaling, cell cycle progression, and other functions that regulate growth and differentiation. A synthetic version of the FOXO4 protein is FOXO4-DRI, which was developed to be identical to a fragment of the endogenously available FOXO4 protein, except for the alteration in its amino acid structure. It includes only a specific part of the FOXO4 sequence crucial for interacting with p53. FOXO4-DRI peptide, or Proxofim, is an acronym for Forkhead box O transcription factor 4-D-Retro-Inverso peptide.(3) FOXO4-DRI peptide is the same as FOXO4 protein, except that the L amino acids in its structure are replaced by D amino acids. As a result of this, FOXO4-DRI peptide may be less susceptible to the normal clearance mechanism as compared to FOXO4. It is important to note that this alteration not only potentially increases its stability but also may affect how it interacts with other cellular components compared to its natural counterpart. Overview The retro inverso peptides (DRI peptides) are linear chains of amino acids, where the sequence is "reversed," reversing the chirality of the structure (i.e., L amino acid structure altered to D amino acid and vice versa). D amino acids represent the mirror image of the naturally occurring L amino acids in the biological proteins. The main potential advantage of exchanging L amino acid with D amino acid is that the latter may be more resistant to degradation, making the protein structure more durable. The main focus of FOXO4-DRI peptide research is focused on its potential to prevent the binding of the FOXO4 protein with p53 protein.(4) This interaction may be crucial as FOXO4, when bound to p53, may inhibit some of p53's key functions involved in cell cycle regulation and apoptosis. The p53 protein is an endogenous regulator protein, considered to regulate the progression of the cell cycle, including cell death. p53’s potential as a tumor suppressor is well-documented, primarily functioning to stop the proliferation of cells that have suffered DNA damage. When FOXO4 protein binds with p53, it does not appear to allow p53 to bind with DNA, thereby preventing apoptosis and cell death. This interruption may lead to the accumulation of senescent cells - those that have stopped dividing but do not die, contributing to cell aging. This process may be inhibited in the presence of FOXO4-DRI peptide, allowing p53 to bind with DNA and thereby help the cell cycle to continue to death. This potential restoration of p53’s function by the FOXO4-DRI peptide might enable it to trigger the programmed cell death of senescent cells, essentially clearing out cells that might otherwise contribute to the decline in tissue function seen in aged cell cultures. FOXO4-DRI peptide is selective in nature and exerts this potential action only on cells that have become dysfunctional over time due to aging, known as senescent cells.(5) As a result of this biological pathway, the functioning of the tissues may be improved, aiding cell growth and differentiation. Chemical Makeup Molecular Formula: C228H388N86O64 Molecular Weight: 5358.05 g/mol Other Known Titles: Forkhead box protein O4, Proxofim, FOXO4a, AFX, AFX1, MLLT7 Research and Clinical Studies FOXO4-DRI Peptide and Senescence FOXO4-DRI peptide research indicates that the peptide may not wholly stop cell senescence; however, it does appear to have the potential to slow down the process by possibly preventing naturally occurring FOXO4-mediated resistance to apoptosis during senescence. More specifically, researchers have observed that senescent cells resisted apoptosis due to elevated FOXO4 levels, which seem to regulate this process by interacting with p53.(6) By inducing apoptosis in senescent and damaged cells, this peptide may increase the regeneration of cells. One 2017 study(6) experimented on aged mouse models, including a fast-aging model (XpdTTD/TTD mice), presented with either the protein compound or a control. The experimental murine models appeared to have exhibited improved fitness, better renal functioning, and increased fur density. This may be related to its potential to decrease the burden of senescent cells. These cells appear to contribute to the aging process and age-related diseases through the senescence-associated secretory phenotype (SASP), which fosters a pro-inflammatory environment detrimental to tissue function and integrity. By potentially reducing the presence and impact of senescent cells, FOXO4-DRI might thereby restore tissue homeostasis and reduce biomarkers of cell aging. FOXO4-DRI Peptide and Cardiovascular Function Research from 2002(7) has suggested that levels of proteasome enzymes decrease over time. These enzymes are considered to play a primary role in removing cells identified as damaged or dysfunctional within an organism. The naturally occurring FOXO4 protein appears to regulate the levels of proteasome enzymes, but it does not necessarily help reduce damaged cells. Studies in the FOXO4-DRI peptide suggest it may boost natural processes while possibly also eliminating dysfunctional cells. FOXO4-DRI and Insulin Signaling In the context of longevity, FOXO4's activities are often linked through the insulin and insulin-like growth factor signaling (IIS) pathway. This pathway influences how cells respond to stress and growth signals, potentially extending lifespan by enhancing stress resistance and cellular survival mechanisms.(8) Furthermore, FOXO4's role in the IIS pathway suggests it might modulate the actions of diet and environmental factors on cell aging, acting as a mediator between external factors and cellular longevity pathways. FOXO4-DRI and Oxidative Stress Scientific hypotheses posit that FOXO4 may act as a regulatory linchpin cellular response to oxidative stress. By mediating the transcription of crucial antioxidative enzymes, FOXO4 may help mitigate oxidative stress and maintain cellular integrity and function during episodes of high oxidative load or inflammation. This dual potential in responding to both oxidative stress and inflammation may enhance the protective capabilities of FOXO4, making it a potential factor in the cell’s longevity and resilience. 2017(9) studies suggest that when cells encounter oxidative stress—marked by excess free radicals—this imbalance may trigger several defensive responses within the cell. One key player in this response is posited to be MST1, a protein that increases its activity in the presence of oxidative stress. MST1's activation may create a cascade within the cell, signaling through the p38 AMPK and JNK pathways. These pathways are posited to play a role in communicating stress signals and preparing the cell to counteract the incoming damage. Further into the cascade, H2O2, a common reactive oxygen species, activates the small GTPase Ral. The activation of Ral leads to the phosphorylation of FOXO4 at specific sites. This phosphorylation, which occurs via the JNK pathway, is considered to be crucial as it modifies FOXO4, preparing it for its role in the cell's nucleus. Interestingly, the same pathway may also be utilized during inflammatory responses, mediated by the tumor necrosis factor-alpha (TNF-α). This overlap suggests that FOXO4’s activation by oxidative stress and inflammation might follow similar mechanisms, pointing to a broader role of FOXO4 in stress and immune response contexts. Once phosphorylated, FOXO4 translocates to the nucleus—the command center of the cell. In the nucleus, FOXO4 activates the transcription of genes encoding antioxidant enzymes like manganese superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX). These enzymes may play critical roles in detoxifying reactive oxygen species, thereby protecting the cell from oxidative damage. FOXO4-DRI may inhibit the FOXO4 translocation to the nucleus, potentially reducing oxidative stress defenses but primarily in senescent cells. FOXO4-DRI and Neurological Function While the pathophysiology of certain neurological diseases remains unclear, it is presumed by researchers that there are changes in the proteasome enzyme activity over time, which may lead to cognitive impairment. Research(10) has suggested that proteasome activities are downregulated in neurological disorders. It is unknown whether this downregulation is the primary cause of the disorder, but it is likely to be a contributing factor. Clinical research has suggested that the levels of FOXO proteins in the central nervous system may be altered in research models of neurodegenerative disorders (NDDs).(11) This has led to the hypothesis that exogenous FOXO protein, such as FOXO4-DRI peptide, may help regulate optimal levels of FOXO proteins, thereby preventing or alleviating the progression of any NDDs associated with this mechanism. FOXO4-DRI Peptide and Hypogonadism A study(4) was conducted to explore the potential of FOXO4-DRI peptide in age-related male late-onset hypogonadism. An in vitro model composed of senescent Leydig cells was used. Leydig cells are considered crucial for testosterone production. These Leydig cells were previously isolated from male mice and given a hydrogen peroxide chemical to induce senescence. The researchers observed that FOXO4 transitions into the nucleus following the induction of the senescence in the cell. This nuclear presence of FOXO4 seems to be involved in maintaining the viability of senescent cells by possibly modulating downstream senescence-associated pathways, detailed by changes in p53, Ser15-phospho-p53, and p21 protein levels. When these isolated senescence cells were presented with FOXO4-DRI peptide, researchers reported that the peptide appeared to block FOXO4 proteins, allowing p53 to bind with DNA, which led to the nuclear exclusion of p53 and induction of apoptosis of the senescent Leydig cells. This suggests that FOXO4-DRI may selectively target and eliminate senescent cells, potentially alleviating some dysfunctions associated with aged Leydig cells, such as reduced testosterone synthesis. FOXO4-DRI peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA. Structure and evolution of transcriptional regulatory networks. Curr Opin Struct Biol. 2004 Jun;14(3):283-91. https://pubmed.ncbi.nlm.nih.gov/15193307/ Sun, Yan et al. “FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis.” Frontiers in cell and developmental biology vol. 9 659731. 23 Sep. 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495124/ Huang, Yuzhao et al. “Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes.” Frontiers in bioengineering and biotechnology vol. 9 677576. 29 Apr. 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695/ Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., Xia, K., Feng, X., Li, Y., Liang, X., Sun, X., Deng, C., & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging, 12(2), 1272–1284. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614/ Krimpenfort P, Berns A. Rejuvenation by Therapeutic Elimination of Senescent Cells. Cell. 2017 Mar 23;169(1):3-5. https://pubmed.ncbi.nlm.nih.gov/28340347/ Marjolein P. Baar et al, Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Vol 169 Issue 1, https://doi.org/10.1016/j.cell.2017.02.031 Anne-Laure Bulteau, Luke I. Szweda, Bertrand Friguet, Age-Dependent Declines in Proteasome Activity in the Heart, Archives of Biochemistry and Biophysics, Volume 397, Issue 2, 2002, Pages 298-304, ISSN 0003-9861, https://doi.org/10.1006/abbi.2001.2663 Murtaza G, Khan AK, Rashid R, Muneer S, Hasan SMF, Chen J. FOXO Transcriptional Factors and Long-Term Living. Oxid Med Cell Longev. 2017;2017:3494289. doi: 10.1155/2017/3494289. Epub 2017 Aug 15. https://pubmed.ncbi.nlm.nih.gov/28894507 Lee, S., & Dong, H. H. (2017). FoxO integration of insulin signaling with glucose and lipid metabolism. The Journal of endocrinology, 233(2), R67–R79. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480241/ Ciechanover A, Brundin P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron. 2003 Oct 9;40(2):427-46. https://pubmed.ncbi.nlm.nih.gov/14556719/ Wei Hu, Zhi Yang, Wenwen Yang, Mengzhen Han, Baoping Xu, Zihao Yu, Mingzhi Shen, Yang Yang, Roles of forkhead box O (FoxO) transcription factors in neurodegenerative diseases: A panoramic view, Progress in Neurobiology, Volume 181, 2019, 101645, ISSN 0301-0082, https://doi.org/10.1016/j.pneurobio.2019.101645 Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
Acetyl Hexapeptide-3 (Argireline) (200mg)
Acetyl Hexapeptide-3 is a synthetic peptide commonly researched for its potential action in reducing wrinkle formation in skin tissues. Researchers developed Acetyl Hexapeptide-3 as a competitive SNAP25 (synaptosome-associated protein 25 kDa) inhibitor. SNAP-25 is a component of the SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, which is posited to be a central regulator of synaptic vesicle Ca(2+)-dependent exocytosis - a key process in the release of signaling molecules and cellular communication. This inhibition is thought to occur due to the apparent similarity between the amino acid sequence pattern from the N-terminal end of SNAP-25 and Acetyl Hexapeptide-3. This is hypothesized to prevent the formation of the SNARE complex and inhibit the exocytosis of messengers. By apparently inhibiting exocytosis, Acetyl Hexapeptide-3 may potentially block the release of acetylcholine, a neurotransmitter involved in muscle contractions that mediates the communication between nerve and muscle cells. Conducting research with Acetyl Hexapeptide-3 is considered a milder and less invasive alternative to bacterial toxins because the peptide may have the potential to act directly through the skin tissues and reach any superficially underlying muscle cells.(2) The peptide may also have research applications in other areas related to skin tissue and muscle tissue studies, such as collagen synthesis, muscle spasms, and scarring. Furthermore, palmitoylated peptide versions have been posited to block the function of pain-mediating neurons. Chemical Makeup Molecular formula: C34H60N14O12S Molecular weight: 888.99 g/mol Other known titles: Acetyl Hexapeptide-8, Argireline Research and Clinical Studies Acetyl Hexapeptide-3 and Wrinkles Acetyl Hexapeptide-3 was apparently designed to mimic the action of BoNTs while passing through the skin layers. One study suggested that an emulsion containing Hexapeptide led to an apparent reduction in wrinkle depth by up to 30% after 30 days in 10 test subjects.(2) An additional study investigated the impact of Acetyl Hexapeptide-3 on the skin properties of 24 test subjects and reported similar results.(3) Subjects were randomly assigned to a peptide or placebo group for 60 days. Skin microtopography and transepidermal water loss (TEWL) were estimated at different times throughout the experiment. The authors suggested that Acetyl Hexapeptide-3 had possible anti-wrinkle activity and might decrease TEWL, indicating increased water retention and hydration of the skin tissues. The potential of the peptide does not appear to depend on the type of skin model. Further data has also posed similar findings. For example, another clinical study that involved 52 test subjects was conducted over 29 days to evaluate the potential impact of Acetyl Hexapeptide-3 in wrinkle improvement.(4) After the study, the scientists observed apparently improved skin wrinkle morphology and skin hydration in all groups. In another clinical study, the scientists report that compared to the placebo, "the total anti-wrinkle efficiency …] was 48.9%, the depth of the wrinkles was notably reduced" in the Acetyl Hexapeptide-3 group.(5) Experiments with murine models suggest that Acetyl Hexapeptide-3 may help improve wrinkles and fine lines by interacting with collagen synthesis, although this mechanism is poorly studied. For example, one study in aged murine models which were given the peptide for six weeks exhibited an apparent improvement in the histological structure of the skin tissue, with an increase in type I collagen fibers and a decrease in type III collagen fibers.(6) The study concluded that Acetyl Hexapeptide-3 might rejuvenate aging skin tissues through a potential impact on its histological structure. Acetyl Hexapeptide-3 and Muscle Spasms Acetyl Hexapeptide-3 has been studied in the context of involuntary muscle spasms, such as blepharospasms, characterized by involuntary contractions of the eyelid muscles. One study investigated the potential of Acetyl Hexapeptide-3 for blepharospasm in a clinical setting.(7) The study involved 24 test subjects with blepharospasm in a double-blind, placebo-controlled, randomized design. The primary outcome measured was the time until the spasm before the experiment returned, and the spasm grade was assessed via the Jankovic Blepharospasm Rating Scale (JBRS). There was a trend for a longer period until the return of the spasm in the active group compared to the placebo group, with an average of 3.7 months versus 3.0 months. Additionally, the active group tended to have better JBRS scores- or a lower grade of blepharospasm- than those in the placebo group. Interestingly, the researchers also report that "One-third (4/12) of the [subjects] in the active group had a considerable extension of symptom control after [neurotoxins] (range: 3.3-7.1 months)." Acetyl Hexapeptide-3 and Scarring According to one retrospective study, Acetyl Hexapeptide-3 may support the mitigation of scar tissues, such as the one that may develop following the damage of skin cells.(8) Scientists measured skin tissue quality parameters, took photographs, and performed a clinical assessment before and after the study.(8) This apparent effect on scarring tissues may be due to the aforementioned potential of Acetyl Hexapeptide-3 to minimize the production of collagen type 3 fibers. Collagen type 3 fibers are typical for scar tissues and are identified as having low elasticity and a structure that differentiates from surrounding tissues. Moreover, this was observed as a potential factor that increased the elasticity of regenerating tissues. More specifically, the authors reported that scar tissue elasticity increased "from 33.5% to 40.5%” in certain areas of the skin tissues. Acetyl Hexapeptide-3 and Pain Perception Acetyl Hexapeptide-3 has undergone various in vitro examinations to determine its possible effects on cell and molecular activities linked to neurotransmission and pain sensation. For instance, the palmitoylated version of Acetyl Hexapeptide-3, called DD04107, has been studied for its potential analgesic activity in chronic inflammatory and neuropathic pain models.(9) It was suggested to be potentially impactful in blocking the inflammatory recruitment of ion channels and the release of calcitonin gene-related peptides, resulting in anti-hyperalgesia and anti-allodynia. Further, the study purported that the palmitoylated form of Acetyl Hexapeptide-3 might hinder the release of neuromodulators, which are considered crucial to pain-related signaling. This may potentially be achieved by disrupting SNAP-25 activity and blocking the Ca(2+)-dependent release of these neuromodulators. Consequently, this modified form of Acetyl Hexapeptide-3 might prevent the activation of TRPV1 channels, which are involved in inflammatory processes, further showcasing its potential to alleviate hyperalgesia and allodynia. TRPV1 channels, primarily located on sensory nerve fibers responsible for pain perception, are considered to be triggered by various elements such as heat, inflammatory substances, and chemical irritants. Activation of these channels is considered a key step in pain signal generation and transmission. In another experiment, carrageenan-induced inflammation models were used to simulate acute inflammatory pain, and the palmitoylated Acetyl Hexapeptide-3 has been proposed to exhibit anti-inflammatory effects, through decreased paw swelling (an inflammation indicator) and reduced mechanical sensitivity.(10) Additionally, this peptide's actions have been assessed in chronic inflammatory pain models, like Complete Freund's Adjuvant (CFA)-induced inflammation. CFA-induced inflammation is an experimental method in scientific research to simulate chronic inflammatory conditions in laboratory models, typically murine models. CFA, a complex mixture, contains inactivated and dried mycobacteria, usually Mycobacterium tuberculosis, emulsified in mineral oil. This mixture prompts a robust and persistent inflammatory response. In such models, it has been observed to apparently reduce both thermal hyperalgesia and mechanical allodynia, suggesting its potential in influencing chronic inflammatory pain. The palmitoylated version of Acetyl Hexapeptide-3 is also considered for its potential to alleviate pain linked to peripheral neuropathy caused by various factors. It was reported by the researchers to potentially have a concentration-responsive capability to lessen mechanical hyperalgesia in animal models of such neuropathies. Acetyl Hexapeptide-3 peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Grosicki, M., Latacz, G., Szopa, A., Cukier, A., & Kieć-Kononowicz, K. (2014). The study of cellular cytotoxicity of argireline - an anti-aging peptide. Acta biochimica Polonica, 61(1), 29–32. Blanes-Mira, C., Clemente, J., Jodas, G., Gil, A., Fernández-Ballester, G., Ponsati, B., Gutierrez, L., Pérez-Payá, E., & Ferrer-Montiel, A. (2002). A synthetic hexapeptide (Argireline) with antiwrinkle activity. International journal of cosmetic science, 24(5), 303–310. https://doi.org/10.1046/j.1467-2494.2002.00153.x Raikou, V., Varvaresou, A., Panderi, I., & Papageorgiou, E. (2017). The efficacy study of the combination of tripeptide-10-citrulline and acetyl hexapeptide-3. A prospective, randomized controlled study. Journal of cosmetic dermatology, 16(2), 271–278. https://doi.org/10.1111/jocd.12314 An, J. H., Lee, H. J., Yoon, M. S., & Kim, D. H. (2019). Anti-Wrinkle Efficacy of Cross-Linked Hyaluronic Acid-Based Microneedle Patch with Acetyl Hexapeptide-8 and Epidermal Growth Factor on Korean Skin. Annals of dermatology, 31(3), 263–271. https://doi.org/10.5021/ad.2019.31.3.263 Wang, Y., Wang, M., Xiao, X. S., Pan, P., Li, P., & Huo, J. (2013). The anti wrinkle efficacy of synthetic hexapeptide (Argireline) in Chinese Subjects. Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology, Advance online publication. Wang, Y., Wang, M., Xiao, X. S., Huo, J., & Zhang, W. D. (2013). The anti-wrinkle efficacy of Argireline. Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology, 15(4), 237–241. https://doi.org/10.3109/14764172.2013.769273 Lungu, C., Considine, E., Zahir, S., Ponsati, B., Arrastia, S., & Hallett, M. (2013). Pilot study of acetyl hexapeptide-8 in the treatment for blepharospasm in patients receiving botulinum toxin therapy. European journal of neurology, 20(3), 515–518. https://doi.org/10.1111/ene.12009 Palmieri, B., Noviello, A., Corazzari, V., Garelli, A., & Vadala, M. (2020). Skin scars and wrinkles temporary camouflage in dermatology and oncoesthetics: focus on acetyl hexapeptide-8. La Clinica terapeutica, 171(6), e539–e548. https://doi.org/10.7417/CT.2020.2270 Ponsati, B., Carreño, C., Curto-Reyes, V., Valenzuela, B., Duart, M. J., Van den Nest, W., Cauli, O., Beltran, B., Fernandez, J., Borsini, F., Caprioli, A., Di Serio, S., Veretchy, M., Baamonde, A., Menendez, L., Barros, F., de la Pena, P., Borges, R., Felipo, V., Planells-Cases, R., … Ferrer-Montiel, A. (2012). An inhibitor of neuronal exocytosis (DD04107) displays long-lasting in vivo activity against chronic inflammatory and neuropathic pain. The Journal of pharmacology and experimental therapeutics, 341(3), 634–645. https://doi.org/10.1124/jpet.111.190678 Butrón, D., Zamora-Carreras, H., Devesa, I., Treviño, M. A., Abian, O., Velázquez-Campoy, A., Bonache, M. Á., Lagartera, L., Martín-Martínez, M., González-Rodríguez, S., Baamonde, A., Fernández-Carvajal, A., Ferrer-Montiel, A., Jiménez, M. Á., & González-Muñiz, R. (2021). DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target. Bioorganic chemistry, 115, 105231. https://doi.org/10.1016/j.bioorg.2021.105231 Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.
GHRP-6 (5mg / 10mg)
Growth hormone releasing hexapeptide, or GHRP-6, belongs to a group of synthetic peptides developed with the potential to stimulate the secretion and regulate growth hormone levels. Similar to most such peptides, GHRP-6 is an analog of the naturally occurring opioid peptide and neuromediator called met-enkephalin. Yet, researchers suggest it may lack the opioid activity generally associated with these enkephalins.(1) Instead, GHRP-6 appears to interact with the so-called growth hormone secretagogue receptors (GHS-Rs) which eventually turn out to be ghrelin receptors. Thus, the peptide may also be defined as growth hormone secretagogue (GHS). It is a small, low molecular weight, synthetic peptide, which has been researched for its potential in growth hormone stimulation.(2) Initially, growth hormone releasing peptides (GHRP) were developed with the intention of mimicking the mechanism of action of growth hormone releasing hormones (GHRHs). When GHRH was first isolated in 1984, scientists hypothesized that these compounds might operate differently; with GHRPs exhibiting an apparent affinity to bind with ghrelin receptors.(3) Ghrelin is also known as the hunger hormone, and it is naturally produced by the stomach when empty. Researchers suspected that GHRPs, like the endogenously found hormone ghrelin, may appear to govern action via hypothalamic stimulation and may have the potential to influence various functions, including metabolism and nutrient absorption. Overview Research was conducted to determine if GHRP-6 requires endogenous GHRH presence in order to exert its potential. In one study,(4) the researchers evaluated the impact of GHRP-6 exposure following either GHRH antagonist or saline presence in the research models. Blood samples were collected incrementally for the next few hours and the concentrations of growth hormones was measured. Following the study, the researchers suggested that hGH levels were lower in models presented with GHRH antagonist. They posited further that endogenous GHRH may be necessary for GHRP-6 to exert potential action. While the mechanism of GHRP-6 remains under study,(4) further research studies have suggested that GHRPs may act by binding with two receptors, GHS-R1a, and CD36. In addition to hGH release, GHRP-6 also appears to have the potential to reduce cellular death through binding with CD36 receptors, possibly stimulating prosurvival cellular pathways.(2) This remains under investigation. Earlier it was hypothesized that GHRP-6 may work through a double mechanism, producing possible activities at the pituitary gland and hypothalamus. In a study to investigate this mechanism of action,(5) two research model groups were evaluated, one group of hypothalamus-pituitary disconnection and one control model. Each subject was either presented GHRH, GHRP-6, or a combination of both. After presentation, the hGH levels were measured in all. In the control group, the highest levels of hGH were found in models given both GHRH and GHRP-6, followed by GHRP-6 models, and lastly the GHRH models. These results appeared to be converse in the research models of hypothalamic pituitary disconnection, with the least levels of HGH reported in those exposed to both GHRP-6 and GHRH. The GHRH subjects appeared to have the same levels of hGH as controls, whereas the hGH levels were reportedly reduced in models exposed to GHRP-6 alone. Two hypotheses were extended by the researchers from this study – first, GHRP-6 action may be induced primarily in the presence of GHRH and second, that GHRP-6 may act on hypothalamic pituitary axis in order to produce its potential. Furthermore, researchers posited that GHRP-6 may potentially show an affinity toward CD36 receptors. These receptors are thought to fulfill various functions, such as possibly playing a part in lipid metabolism by acting as a scavenger receptor for lipids, aiding in their absorption, and possibly influencing immune responses by controlling phagocytosis and inflammation. The pathways involving CD36 might also have a role in the regulation of angiogenesis.(6) Chemical Makeup Molecular Formula: C46H56N12O6 Molecular Weight: 873.03 g/mol Other Known Titles: Growth Hormone Releasing Peptide-6 Research and Clinical Studies GHRP-6 Peptide and Hypothyroidism Hypothyroidism is typically characterized by reduced levels of growth hormone secretion. The main aim of this study(7) was to determine whether GHRP-6, a supposed hGH release-stimulating agent, might be used to mitigate hGH level reduction. Research models of hypothyroidism were evaluated following random exposure to three different concentrations of GHRH, and GHRP-6. Following the completion of the study, it was observed by the researchers that the models exposed to GHRP-6 alone and with combination of GHRP-6 and GHRH appeared to induce significantly higher levels of growth hormones than GHRH alone. The possible reasoning behind this is that GHRP-6 may differ from GHRH, with the potential as a functional antagonist of somatostatin at the pituitary level, which may be potentially why GHRP-6 may exert possibly increased action on hypothyroidism compared to GHRH. GHRP-6 Peptide and Cortisol Hormone Release In this study,(8) the action of GHRP-6 peptide on the hormone release and sleep electroencephalogram (EEG) during the night time was studied. Research models were exposed with either the GHRP-6 peptide or a placebo. After the peptide, it was observed by the researchers that GHRP-6 appeared to induce higher secretion of both growth hormones and cortisol (ACTH) hormones. Throughout the night, particularly during the first half, cortisol hormone release and stage 2 sleep appeared to be enhanced, while the other sleep EEG variables remained apparently unchanged. This study suggested that not only may GHRP-6 possibly induce growth hormone release, but it also may act on the hypothalamus and pituitary gland axis, mobilizing cortisol hormone release. GHRP-6 Peptide and Organ Function The main goal of this study(9) was to determine the action of GHRP-6, either alone or in combination with epidermal growth factor (EGF), on multiple organ failure. The first iteration of this study was conducted on the experimental models of injury and multiple organ failure, while the second iteration of the study was conducted on rat intestine and colonic cancer cells. The first study suggested that GHRP-6 may impact the gut epithelial cells and increase cell migration by three times a control rate, without an apparent impact on cell proliferation. In the second model, multiple organ failure caused severe hepatic and intestinal damage and lipid peroxidation. Presentation of GHRP-6 appeared to reduce these damages by a reported 50-85%, with additional activity when GHRP-6 was presented in combination with EGF. GHRP-6 Peptide and GI transit The main aim of this study(10) was to investigate the potential of GHRP-6 on delayed gastrointestinal (GI) transit induced by diabetes. An experimental mouse model, with alloxan-induced diabetes, was used for this study. Alloxan is a synthetic uric acid derivative compound, commonly used for experiments, which induces diabetes upon presentation.(11) All experimental mice were presented with GHRP-6 at interval concentrations. Based on the study analysis, researchers posited that the diabetes appeared to reduce the levels of gastric emptying (GE), intestinal transit (IT) and colonic transit (CT) in mice. Upon GHRP-6 presentation, the levels of GE and IT reportedly improved, with no reported fluctuation in CT levels. GHRP-6 Peptide and Neuroprotection The peptide GHRP-6 has been associated by researchers with the safeguarding and restoration of nerve tissue. Research explored its impact on the IGF-1 (insulin-like growth factor-1) system within the brains of mouse models.(12) The potential benefits of GH, especially its apparent growth-promoting action, are often believed to be mediated via IGF-1. One study concentrated on the impact of peptides such as GHRP-6 on the brain's IGF-1 system. Results indicated that exposure to GHRP-6 for a week appeared to elevate IGF-1 mRNA levels in the hypothalamus, cerebellum, and hippocampus, but not in the cerebral cortex, suggesting that GH and GHRP-6 might enhance IGF-1 production in specific areas of the brain. The study also examined the expression of the IGF receptor and IGFBP-2, a protein that binds IGF, finding no notable changes in their activity following the introduction of the peptide. However, the phosphorylation of Akt and the Bcl-2-associated death promoter (BAD) was observed in areas with increased IGF-1 levels, indicating that GH and GHRP-6 may initiate cellular survival pathways in reaction to growth factors. Bcl-2-associated death promoter belongs to the Bcl-2 family of proteins, which is vital for cell death regulation, whereas Akt is a kinase that plays a role in various cellular processes including metabolism, apoptosis, growth, transcription, and migration. There were no observed alterations in MAPK or glycogen synthase kinase-3beta activity. The study noted an increase in the antiapoptotic protein Bcl-2 in areas with raised IGF-1, while the proapoptotic protein Bax levels remained consistent, hinting at a shift towards cell preservation over apoptosis. Lastly, IGFBP-5, linked with neuronal survival, showed significant elevation primarily in the hypothalamus, pointing to a potential neuroendocrine role. GHRP-6 Peptide and Muscle Tissue Some research suggests that GHRP-6 may exhibit anabolic capabilities, possibly through a presumed stimulation of growth hormone and IGF-1. An experiment involving cultured myoblast cells indicated that this peptide might enhance the production of myogenic marker proteins, insulin-like growth factor-1, collagen type I, and the metabolic processes within the myoblasts.(13) Therefore, the researchers inferred that GHRP-6 might potentially enhance muscle tissue by promoting the synthesis of collagen type I and crucial proteins. GHRP-6 may also have anabolic potential through a possible stimulatory effect in GH synthesis, and consequently may induce a possible increase in IGF-1. GHRP-6 has been posited to potentially trigger GH release in a specific manner across multiple species which may be considerably greater than physiological GH synthesis by the anterior pituitary gland cells. To delve deeper into the mechanisms behind the potential of the peptide, a study experimented with both GHRP-6 and GHRH. The researchers commented that GHRP-6 apparently elicited a GH secretion with a peak of 15.7 ± 4.4 μg/L and an area under the curve (AUC) of 674 ± 187 μg/L/90mins. These figures appeared to be higher than those elicited by GHRH stimulation that mimics the natural synthesis, and led to an increase of 6.8 ± 1.1 μg/L for the peak and 412 ± 71 μg/L/90mins for the AUC, respectively.(14) Another similar study also reported an apparent GH peak of about 15.4 μg/L produced by the anterior pituitary cells, under the potential influence of GHRP-6, while the the physiological peak in GH levels was reported to have reached a maximum of just 5.5 μg/L.(15) GHRP-6 Peptide and Tissue Recovery As indicated, GHRP-6 is believed to stimulate not only ghrelin (GHS-Rs) receptors, which are linked to GH production, but also CD36 receptors, potentially mediating anti-inflammatory and other advantageous effects. A preclinical study involving murine models exposed to GHRP-6 for 30 days suggested a possibility for faster wound healing and diminished hypertrophic scar development by lessening inflammation and the expression of fibrotic cytokines, pointing to its potential utility in enhancing wound appearance.(16) Similarly, in a separate preclinical investigation, the stimulation of ghrelin receptors was posited to improve wound healing in rats subjected to combined radiation and burn injury, through a reduction in pro-inflammatory agents, particularly TNF-α, and the alteration of signaling pathways related to inflammation and healing.(17) Furthermore, it was reported that following 60 days of GHRP-6 exposure, there was a potential decrease in liver fibrosis and a reduction in fibrogenic factors such as TGF-β and CTGF, with fibrotic areas and nodularity decreasing by 75% and more than 60%, respectively.(18) This indicates the potential for GHRP-6 to possibly mitigate fibrosis and enhance the healing process in experimental settings. GHRP-6 peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Rico M, Lorenzo MT, Pazo JA, Vega FV, De la Cruz LF. GHRP-6 in heifer and cow adenohypophisial cells separated by elutriation. J Physiol Biochem. 1999 Mar;55(1):33-9. PMID: 10494658. Berlanga-Acosta, Jorge et al. “Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects.” Clinical Medicine Insights. Cardiology vol. 11 1179546817694558. 2 Mar. 2017, doi:10.1177/1179546817694558. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392015/ Bowers, C.Y., et al (2012). Ghrelin: A history of its discovery. In Ghrelin in Health and Disaeas (pp. 1-35), Human press Inc. https://mayoclinic.pure.elsevier.com/en/publications/ghrelin-a-history-of-its-discovery Naushira Pandya, Roberta DeMott-Friberg, Cyril Y. Bowers, Ariel L. Barkan, Craig A. Jaffe, Growth Hormone (GH)-Releasing Peptide-6 Requires Endogenous Hypothalamic GH-Releasing Hormone for Maximal GH Stimulation, The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 4, 1 April 1998, Pages 1186–1189. https://academic.oup.com/jcem/article-abstract/83/4/1186/2865313 Popovic V, Damjanovic S, Micic D, Djurovic M, Dieguez C, Casanueva FF. Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level. J Clin Endocrinol Metab. 1995 Mar;80(3):942-7. doi: 10.1210/jcem.80.3.7883854. PMID: 7883854. https://pubmed.ncbi.nlm.nih.gov/7883854/ Demers, A., McNicoll, N., Febbraio, M., Servant, M., Marleau, S., Silverstein, R., & Ong, H. (2004). Identification of the growth hormone-releasing peptide binding site in CD36: a photoaffinity cross-linking study. The Biochemical journal, 382(Pt 2), 417–424. https://doi.org/10.1042/BJ20040036 Pimentel-Filho FR, Ramos-Dias JC, Ninno FB, Façanha CF, Liberman B, Lengyel AM. Growth hormone responses to GH-releasing peptide (GHRP-6) in hypothyroidism. Clin Endocrinol (Oxf). 1997 Mar;46(3):295-300. doi: 10.1046/j.1365-2265.1997.1270942.x. https://pubmed.ncbi.nlm.nih.gov/9156038/ Frieboes RM, Murck H, Maier P, Schier T, Holsboer F, Steiger A. Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology. 1995 May;61(5):584-9. https://doi.org/10.1159/000126883 Cibrián D, Ajamieh H, Berlanga J, León OS, Alba JS, Kim MJ, Marchbank T, Boyle JJ, Freyre F, Garcia Del Barco D, Lopez-Saura P, Guillen G, Ghosh S, Goodlad RA, Playford RJ. Use of growth-hormone-releasing peptide-6 (GHRP-6) for the prevention of multiple organ failure. Clin Sci (Lond). 2006 May;110(5):563-73. https://pubmed.ncbi.nlm.nih.gov/16417467/ Zheng, Q., Qiu, W. C., Yan, J., Wang, W. G., Yu, S., Wang, Z. G., & Ai, K. X. (2008). Prokinetic effects of a ghrelin receptor agonist GHRP-6 in diabetic mice. World journal of gastroenterology, 14(30), 4795–4799. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739343/ Kristina Szabadfi, et al., Therapeutic Areas I: Central Nervous System, Pain, Metabolic Syndrome, Urology, Gastrointestinal and Cardiovascular, in Comprehensive Medicinal Chemistry II, 2007. https://www.sciencedirect.com/topics/medicine-and-dentistry/alloxan Frago LM, Pañeda C, Dickson SL, Hewson AK, Argente J, Chowen JA. Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection. Endocrinology. 2002 Oct;143(10):4113-22. doi: 10.1210/en.2002-220261. PMID: 12239123. Lim, C. J., Jeon, J. E., Jeong, S. K., Yoon, S. J., Kwon, S. D., Lim, J., Park, K., Kim, D. Y., Ahn, J. K., & Kim, B. W. (2015). Growth hormone-releasing peptide-biotin conjugate stimulates myocytes differentiation through insulin-like growth factor-1 and collagen type I. BMB reports, 48(9), 501–506. https://doi.org/10.5483/bmbrep.2015.48.9.258 Cordido, F., Peñalva, A., Dieguez, C., & Casanueva, F. F. (1993). Massive growth hormone (GH) discharge in obese subjects after the combined administration of GH-releasing hormone and GHRP-6: evidence for a marked somatotroph secretory capability in obesity. The Journal of clinical endocrinology and metabolism, 76(4), 819–823. https://doi.org/10.1210/jcem.76.4.8473389 Frieboes, R. M., Murck, H., Maier, P., Schier, T., Holsboer, F., & Steiger, A. (1995). Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology, 61(5), 584–589. https://doi.org/10.1159/000126883 Mendoza Marí, Y., Fernández Mayola, M., Aguilera Barreto, A., García Ojalvo, A., Bermúdez Alvarez, Y., Mir Benítez, A. J., & Berlanga Acosta, J. (2016). Growth Hormone-Releasing Peptide 6 Enhances the Healing Process and Improves the Esthetic Outcome of the Wounds. Plastic surgery international, 2016, 4361702. https://doi.org/10.1155/2016/4361702 Liu, C., Huang, J., Li, H., Yang, Z., Zeng, Y., Liu, J., Hao, Y., & Li, R. (2016). Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats. Scientific reports, 6, 27499. https://doi.org/10.1038/srep27499 Berlanga-Acosta, J., Vázquez-Blomquist, D., Cibrián, D., Mendoza, Y., Ochagavía, M. E., Miranda, J., ... & Guillén-Nieto, G. E. (2012). Growth Hormone Releasing Peptide 6 (GHRP6) reduces liver fibrosis in CCl4 chronically intoxicated rats. Biotecnología Aplicada, 29(2), 60-72. Dr. MarinovDr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.