Medicines & Treatments
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.
Receptor Grade IGF-1 LR3 (1mg)
Between 1940 and 1950, the growth hormone somatotropin was identified and researched. It was tentatively suggested that this hormone might enhance sulfate uptake in normal control rat serum, implying an increase in amino acid uptake or synthesis. However, this connection was not definitively established. This so-called "sulfate factor" was subsequently isolated from the rat serum and named "somatomedin." Concurrently, an independent study explored the components responsible for producing insulin-like activity. It was hypothesized during this investigation that these components might be "somatomedins," leading to the designation of these compounds as "insulin-like growth factors."(1) Further explorations into the insulin-like growth factors involved gene-targeting approaches to potentially enhance their bioavailability and potency. During these studies, a variant called Receptor Grade IGF-1 LR3 was developed. This variant included an additional arginine residue and featured an elongated structure at the N-terminal (by 13 amino acids), resulting in a protein composed of 83 amino acids, compared to the 70 amino acids found in natural IGF-1.(1) Receptor Grade IGF-1 LR3 peptide, a polypeptide amino acid also known as Long arginine 3 IGF-1, or LR3-IGF-1, has been suggested to exhibit potential action similar to Insulin-like Growth factor-1, or IGF-1.(2) IGF-1 is a naturally produced protein comprised of 70 amino acids. Structurally similar to insulin, this Receptor Grade IGF-1 LR3 has the potential primarily to regulate cell tissue and development. Several synthetic variations of IGF-1, such as recombinant IGF-1 (rhIGF-1), were developed to mimic the natural protein identically and stimulate similar actions as IGF-1. Another example is Receptor Grade IGF-1 LR3, which researchers speculate exhibits an increased affinity and anabolic potential while binding less to IGF-1 binding proteins (IGF-1BPs). This variant has been developed particularly for evaluation in cell growth studies. Moreover, the designation of Receptor Grade refers to the purity of the material, which is considered higher than Media Grade IGF-1 LR3. Structurally, IGF-1 LR3 contains an extended N-terminal structure and arginine acid at residue 3. Hence, it is named IGF-1 Long R3.(3) Owing to the altered structure, Receptor Grade IGF-1 LR3 has been suggested to bind poorly with IGF-binding proteins, shortening its duration of action. Overview IGF proteins appear to exert potential via binding with IGF-1 receptors; however, researchers posit that these IGF binding proteins, including Receptor Grade IGF-1 LR3, may function either via IGF receptor-dependent mechanism or via IGF-independent mechanisms.(1)(4) A study(1) was conducted where a murine model was exposed to the endogenous IGF-1 with IGF-1 LR3. During this study, it was suggested that upon exposure, the synthetic protein exhibited the potential to quickly clear the serum and distribute into tissues. Increased concentrations of the IGF-1 LR3 tracer were apparently detected in specific organs, including the kidneys, ovaries, and adrenal glands, in mouse models. This distribution pattern indicates that organs critical to metabolism and reproductive processes might have differing abilities to absorb or retain IGF-1 LR3 compared to IGF-I. It is proposed that these variations might arise due to IGF-1 LR3's reduced tendency to bind with IGFBPs. IGFBPs are proteins that regulate the availability of IGFs in circulation, influencing their interaction with various tissues. The decreased binding of IGF-1 LR3 to IGFBPs may affect its bioavailability and interactions with specific tissues in research settings. Researchers suggest Receptor Grade IGF-1 LR3 has the potential to induce a signaling mechanism in the organism, either via autocrine mode (where the tissue cell stimulates itself) or via paracrine mode (where the tissue cell stimulates the nearby cell). The increased potential bioavailability of these autocrine and paracrine IGF-1 LR3 proteins may prove vital to inducing any possible action. Chemical Makeup Molecular Formula: C400H625N111O115S9 Molecular Weight: 9117.5 g/mol Other Known Titles: Long-(arg3) insulin-like growth factor-I, Insulin-like growth factor long chain R3 Research and Clinical Studies Receptor Grade IGF-1 LR3 Peptide and Tissue Anabolism The body of research examining the anabolic capabilities of IGF-1 LR3 remains insufficient, primarily because this peptide is designed for evaluation in cell culture studies. However, limited studies using murine models hint at a considerable anabolic potential of IGF-1 LR3. In particular, one investigation involved normal and dexamethasone-induced catabolic murine models.(3) The researchers commented that “LR3IGF-I, were approx. 2.5-fold more potent than IGF-I” in promoting anabolic observations. These included weight gain, increased weight of visceral organs, and potentially improved feed efficiency when the murine models were exposed to it continuously. Another observation from studies on murine models exposed to catabolic agents revealed a reduction in the excretion of Nτ-methylhistidine, a marker of muscle protein degradation, which was notably more pronounced with IGF-1 LR3—potentially three times greater than with IGF-I. These observations indicate that IGF-1 LR3 may exhibit superior anabolic actions under specific experimental conditions, although this is not uniformly seen across all measured parameters. Therefore, it is conceivable that Receptor Grade IGF-1 LR3 may manifest an even greater anabolic capacity than IGF-1, according to multiple comparative studies on the anabolic properties of IGF-1. For example, there is a 2005 clinical study(6) where the action of rhIGF-1 on models of IGF-1 deficiency and growth disorders was studied. RhIGF-1 is the recombinant form of insulin-like growth factor-1, and has been researched for its potential in mitigating growth hormone (GH) insensitivity. RhIGF-1 is a synthetic form of IGF-1.(11) Research models of GH deficiencies were examined in the course of this controlled study, where rhIGF-1 was presented once daily to all the models. The heights and lengths were measured before and after the study. Researchers suggested that results indicated an average increase in height by 7cm per year in all subjects presented with rhIGF-1. Hence, this study posits that IGF-1 analogs may have a positive potential within the context of growth hormone deficiency research. Receptor Grade IGF-1 LR3 and Metabolic Activity Studies(7) have suggested that IGF-binding proteins, including Receptor Grade IGF-1 LR3, may have the potential to induce glucose uptake and, thereby, glucose metabolism through the possible activation of signaling mechanisms. Namely, this may have occurred through a signaling mechanism involving PI3K and AMPK pathways. For example, it can be hypothesized that upon binding to their respective receptors, IGF-1 analogs potentially trigger a cascade of biochemical events involving the PI3K pathway. This pathway, integral to cellular growth and survival, might also play a pivotal role in mediating the actions of IGF-1 on glucose uptake. Activation of PI3K might lead to the stimulation of protein kinase B (Akt), a key regulator in the pathway, enhancing glucose transporter translocation to the cell membrane and increasing glucose uptake. Concurrently, the AMPK pathway, studied for its potential in energy balance and metabolism regulation, may be indirectly influenced by IGF-1 analogs. It is conceivable that the modulation of AMPK activity by these analogs may enhance cellular glucose uptake under energy stress conditions. This activation potentially promotes the translocation of GLUT4, a major glucose transporter, to the cell surface, thus facilitating glucose entry into cells. Receptor Grade IGF-1 LR3 and Muscle This study(8) was conducted on female mice to examine the action of Receptor Grade IGF-1 LR3 on reducing myostatin. Myostatin is a muscle protein that primarily prevents muscle cell differentiation and growth. Reducing the action of myostatin may potentially increase lean muscle mass and reduce fat mass. In this study(8) it was suggested that different IGF-1 analogs, including IGF-1 LR3, have the potential to counteract the negative action of myostatin protein, possibly helping to prevent apoptosis and protecting muscle cells. Since Receptor Grade IGF-1 LR3 has an apparently longer half-life than IGF-1 (according to the researchers), the potential action of Receptor Grade IGF-1 LR3 was considered. Receptor Grade IGF-1 LR3 peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Yakar, S et al., 40 YEARS OF IGF1: Insulin-like growth factors: actions on the skeleton (Jul 2018). Journal of Molecular Endocrinology, vol. 61 Issue 1. https://doi.org/10.1530/JME-17-0298 Growth hormone, athletic performance, and aging. Harvard Health Publishing, Harvard Medical School. https://www.health.harvard.edu/diseases-and-conditions/growth-hormone-athletic-performance-and-aging Tomas, F. M., Knowles, S. E., Owens, P. C., Chandler, C. S., Francis, G. L., Read, L. C., & Ballard, F. J. (1992). Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats. The Biochemical journal, 282 ( Pt 1)(Pt 1), 91–97. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1130894/ Mohan S, Baylink DJ. IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol. 2002 Oct;175(1):19-31. https://pubmed.ncbi.nlm.nih.gov/12379487/ Anderson, L. J., Tamayose, J. M., & Garcia, J. M. (2018). Use of growth hormone, IGF-I, and insulin for anabolic purpose: Pharmacological basis, methods of detection, and adverse effects. Molecular and cellular endocrinology, 464, 65–74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723243/ IGF1 Deficiency, Recombinant Human Insulin-Like Growth Factor (rhIGF-1) Treatment of Short Stature Associated with IGF-1 Deficiency. https://clinicaltrials.gov/ct2/show/NCT00125190?cond=IGF1+Deficiency Assefa, B., Mahmoud, A. M., Pfeiffer, A., Birkenfeld, A. L., Spranger, J., & Arafat, A. M. (2017). Insulin-Like Growth Factor (IGF) Binding Protein-2, Independently of IGF-1, Induces GLUT-4 Translocation and Glucose Uptake in 3T3-L1 Adipocytes. Oxidative medicine and cellular longevity, 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750484/ Naisi Li, Qiyuan Yang, Ryan G. Walker, Thomas B. Thompson, Min Du, Buel D. Rodgers, Myostatin Attenuation In Vivo Reduces Adiposity, but Activates Adipogenesis, Endocrinology, Volume 157, Issue 1, 1 January 2016, Pages 282–291. https://doi.org/10.1210/en.2015-1546 William E. Sonntag, Anna Csiszar, Raphael de Cabo, Luigi Ferrucci, Zoltan Ungvari, Diverse Roles of Growth Hormone and Insulin-Like Growth Factor-1 in Mammalian Aging: Progress and Controversies, The Journals of Gerontology: Series A, Volume 67A, Issue 6, June 2012, Pages 587–598, https://doi.org/10.1093/gerona/gls115 Mario Thevis (13 December 2010). Mass Spectrometry in Sports Drug Testing: Characterization of Prohibited Substances and Doping Control Analytical Assays. John Wiley & Sons. pp. 252. https://books.google.ca/books?id=dWHQMev5mHwC&pg=PA252& Rosenbloom AL. Mecasermin (recombinant human insulin-like growth factor I). Ad Ther. 2009 Jan; 26(1):40-54. https://pubmed.ncbi.nlm.nih.gov/19198769/ 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.
Kisspeptin-10 (10mg)
Kisspeptin-10 is a naturally occurring peptide protein encoded by the KISS1 gene.(2) Kisspeptin is a product of the KISS1 gene, produced by the cleavage of the original 145-amino acid polypeptide to a smaller peptide. This smaller peptide, composed of 54-amino acids, is cleaved further to become Kisspeptin 45-54, also known as Kisspeptin 10.(6) KISS1 is a gene that is considered to suppress metastases of melanomas and breast carcinomas, thereby inhibiting abnormal cell growth and potentially preventing cancer.(2) Initially considered to be a metastasis suppressor, Kisspeptin-10 was later suggested to possess a different expression profile, which may potentially allow it to function on the hypothalamus and pituitary gland, thereby impacting the reproductive system.(3) Several independent studies in the mid-2000s suggested that Kisspeptin-10 may play a role in hypogonadotropic hypogonadism, as the peptide is considered to be a ligand of the G-protein coupled receptor 54 (GPR54).(5) Research continues to explore this potential aspect of the Kisspeptin-10 peptide. Hypogonadism is a system disorder wherein reproductive organs produce less or no sex hormones. One of the forms of hypogonadism is called hypogonadotropic hypogonadism, where the organism suffers from hypogonadism due to under-functioning of the pituitary gland or hypothalamus.(1) GnRH is considered to stimulate the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Both FSH and LH are considered to regulate reproductive function.(1) Lack of these hormones, i.e. GnRH, FSH, and LH, are considered the main factors of hypogonadotropic hypogonadism. Overview GPR54, also called the KISS1 receptor (KISS1R),(7) has been suggested by researchers to be an important GnRH receptor.(1) They further suggest that Kisspeptin-10 exhibits action by possibly binding to GPR54 receptors, which may activate the reproductive axis by stimulating the release of GnRH and gonadotropin neurons.(7) Kisspeptin-10 is a 54 amino acid peptide which is considered to be a product of the KISS1 gene. Researchers have isolated smaller peptide fragments such as Kisspeptin 10, 13, and 14, which all have been suggested to possess some biological activity towards GPR54.(7) These smaller peptides have been posited to bind with a low affinity to the GPR54 receptors and possibly stimulate calcium mobilization, arachidonic acid release, and extracellular protein kinase phosphorylation.(7) These events may depolarize the Kisspeptin-10 neurons, possibly leading to the depolarization of the GnRH neurons and modulating gonadotropin release, to some extent.(9) Research studies on Kisspeptin-10 have explored its potential in a wide variety of functions and impacts, and several hypotheses have been presented on the peptide's possible mechanisms of action, including some notable hypotheses below:(8) That the Kisspeptin-10 peptide may potentially stimulate GnRH release; The peptide may potentially stimulate endogenous gonadotropin release in less-fertile animal models; Peptide concentrations may possibly induce desensitization and suppression of the hypothalamus, pituitary gland, and gonadal axis. Chemical Makeup Molecular Formula: C63H83N17O14 Molecular Weight: 1302.4 g/mol Other Known Titles: Kisspeptin 45-54 Research and Clinical Studies Kisspeptin-10 and Reproduction As part of one 2017 study,(10) a literature review was conducted for all articles published from 1999 to 2016. Upon review of the articles, it was suggested that experimental data may support the hypothesis that the Kisspeptin-10 system (including the KISS1 gene and its products, GPR54 receptors) may possibly regulate the release of gonadotropin hormones. Furthermore, certain studies were conducted in experimental animal models with similar characteristics as hypogonadotropic hypogonadism (HH) and polycystic ovarian syndrome (PCOS). These studies suggested that reproductive disorders such as HH and PCOS may occur due to abnormalities in the KISS1 and GPR54 system. The outcome of this literature review suggested that Kisspeptin-10 may be a neuropeptide regulator of GnRH release. Kisspeptin-10 and Delayed Hormonal Development The main goal of this study(13) was to evaluate the potential of Kisspeptin-10 peptide in research models of stunted development. Researchers hypothesized that the peptide might stimulate the gonadal hormonal release and regulate the reproductive system in the experimental models. The study randomly introduced either Kisspeptin-10 or gonadotropin-releasing hormone (GnRH). The levels of luteinizing hormone (LH) were monitored overnight. All research models were then exposed to GnRH for 6 days, then evaluated for LH levels. A total 47% of the experimental group exhibited positive impacts as a possible result of Kisspeptin-10 presence, with increased levels of LH hormone. An additional 6% of the group exhibited an intermediate response, and the remaining 47% exhibited no response as a result of peptide exposure. Kisspeptin-10 and Emotional Modulation The main purpose of this study(14) was to understand the potential of Kisspeptin-10 on limbic brain activity. Following Kisspeptin-10 exposure in the research models, results were monitored via neuroimaging and psychometric analysis. The data from the study suggested that the peptide appeared to have led to some enhanced limbic brain activity. The models appeared to exhibit an increased response towards sexual and bonding stimuli. Kisspeptin-10 and Reproductive Hormone Release The key objective of this study(15) was to establish the potential of Kisspeptin-10 on reproductive hormone release. Kisspeptin-10 was presented to both male and female experimental models. Results in the males indicated that the levels of FSH and LH were increased following peptide exposure. In the females, no alterations were reported in the levels of LH and FSH during the menstrual cycle. However, during the preovulatory phase, the levels of FSH and LH were reportedly elevated. Kisspeptin-10 and Food Intake Kisspeptin-10 is considered to be widely distributed in brain sites, including the hippocampus, cerebellum, posterior hypothalamus, and septum. Owing to its apparently vast distribution and presence in the food intake regulating nuclei, such as Arc, found in the hypothalamus, this study(11) was conducted to examine the potential impact of Kisspeptin-10 on food intake. This experiment was conducted on adult male mice aged between 6 and 8 weeks, caged under normal temperatures and conditions. These mice were subjected to a standard rodent diet and tap water. Overnight fasted mice and the experimentally fed mice were presented with different concentrations of Kisspeptin-10 or placebo. Results suggested that the peptide in the overnight fasted mice may have decreased food intake during the first 3-to-12-hour period. The food intake then reportedly increased during the 12-to-16-hour period, resulting in a similar food intake compared to the placebo group. This result suggested that the peptide led to a decrease in meal frequency and total meal time and increased intervals between meals. However, meal size and eating rate were almost similar to that of the placebo mice. To delve deeper into the subject, researchers have undertaken studies to investigate the potential actions of Kisspeptin-10 on food intake by examining the apparent influence of the peptide on appetite regulation in the central nervous system. The scientists suggested that the peptide may have some influence on the expression of genes related to neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). It has also been posited to have a potential impact on the concentrations of dopamine, norepinephrine, serotonin (also known as 5-hydroxytryptamine or 5-HT), dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid within hypothalamic cells (specifically Hypo-E22 cells). Findings indicate that Hypo-E22 cells might be receptive to Kisspeptin-10, which may potentially elevate NPY gene expression. Conversely, it appeared to suppress the expression of BDNF. Furthermore, Kisspeptin-10 may have reduced serotonin and dopamine concentrations, though norepinephrine levels seemed to remain stable. This reduction in dopamine and serotonin was reflected by an increase in the ratios of their metabolites, dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin, respectively, following exposition to the peptide. The observed enhancement in NPY gene expression, alongside the diminution of BDNF expression and serotonin activity, may suggest the hunger-influencing potential of Kisspeptin-10.(12) Studies in Impaired Kisspeptin-10 Systems As part of this study,(13) the energetic and metabolic potential of Kisspeptin-10 was compared between control mice and mice with impaired Kisspeptin systems. Results suggested that female mice with impaired Kisspeptin systems exhibited dramatic increases in body weight and significantly impaired glucose tolerance levels. While the peptide exposed and impaired female mice ate less than the control female mice, they were more obese, with reduced locomotor activity and respiratory rate. No reported difference was found between control male mice and male mice with impaired Kisspeptin systems. Both exhibited normal body weight and glucose levels. Kisspeptin-10 and Neuroprotection The accumulation of amyloid-beta (Aβ) and alpha-synuclein (α-syn) within cholinergic neurons is believed to damage and potentially cause dysfunction within important central nervous system structures. However, it has been proposed that Kisspeptin-10 may attach to Aβ on the outside of cells, which may, in turn, possibly reduce the harmful actions of Aβ.(16) Studies have suggested that Kisspeptin-10 peptides may counteract the damaging actions of Aβ, prion protein (PrP), and Islet Amyloid Polypeptide (IAPP) without being hindered by the antagonists of the kisspeptin receptor (GPR-54) or the neuropeptide FF (NPFF) receptor. Given the resemblance between the non-amyloid-β component (NAC) of α-syn and the C-terminus of Aβ, it has been speculated that Kisspeptin-10 might also lessen the toxicity caused by α-syn in cholinergic neurons.(17) Research involving cholinergic cells has indicated that while high concentrations of Kisspeptin-10 may increase toxicity, lower concentrations may potentially decrease the toxicity induced by both the wild-type and the E46K mutant forms of α-syn. Computational studies have supported these observations by suggesting a potentially actionable interaction between Kisspeptin-10 and the C-terminal residues of α-syn. The molecular dynamics simulations indicated that the complexes formed between Kisspeptin-10 and α-syn appeared to have demonstrated good stability. Researchers have also delved into investigating whether the activation of GPR54 (the receptor for the Kisspeptin gene) is crucial for the potential of Kisspeptin-10 to bind to the C-terminal pockets of α-syn. In one study, ChAT-positive SH-SY5Y neurons were genetically modified to produce either the wild-type or the E46K mutant version of α-syn, and the actions of Kisspeptin-10 on the neuronal damage caused by α-syn were assessed through flow cytometry and immunocytochemistry methods.(18) Results suggested that Kisspeptin-10 may have lessened both apoptosis and mitochondrial damage in cholinergic neurons affected by either form of α-syn. Notably, the seeming protective action of Kisspeptin-10 did not appear to be impacted when introduced alongside a GPR54 antagonist, kisspeptin-234 (KP-234), implying that the activation of GPR54 may not be necessary for the actions of Kisspeptin-10. Additionally, it was observed that Kisspeptin-10 may have reduced the presence of α-syn and choline acetyltransferase (ChAT) in neurons that overexpressed the wild-type and E46K mutant α-syn, further highlighting its potential neuroprotective capacity. Kisspeptin-10 peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Hypogonadotropic hypogonadism. US National Library of Medicine. https://medlineplus.gov/ency/article/000390.htm KISS1 KiSS-1 metastasis suppressor [Homo sapiens (humans)]. https://www.ncbi.nlm.nih.gov/gene/3814 Hussain, Mehboob A et al. “There is Kisspeptin - And Then There is Kisspeptin.” Trends in endocrinology and metabolism: TEM vol. 26,10 (2015): 564-572. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587393/ Pasquier, J., Kamech, N., Lafont, A., Vaudry, H., Rousseau, K., & Dufour, S. (2014). MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors, Journal of Molecular Endocrinology, 52(3), T101-T117. https://jme.bioscientifica.com/view/journals/jme/52/3/T101.xml Messager, S., Chatzidaki, E. E., Ma, D., Hendrick, A. G., Zahn, D., Dixon, J., Thresher, R. R., Malinge, I., Lomet, D., Carlton, M. B., Colledge, W. H., Caraty, A., & Aparicio, S. A. (2005). Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proceedings of the National Academy of Sciences of the United States of America, 102(5), 1761–1766. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545088/ Mead, E. J., Maguire, J. J., Kuc, R. E., & Davenport, A. P. (2007). Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. British journal of pharmacology, 151(8), 1143–1153. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189831/ Rønnekleiv, O. K., & Kelly, M. J. (2013). Kisspeptin excitation of GnRH neurons. Advances in experimental medicine and biology, 784, 113–131. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019505/ Prague JK, Dhillo WS. Potential Clinical Use of Kisspeptin. Neuroendocrinology. 2015;102(3):238-45. doi: 10.1159/000439133. Epub 2015 Aug 7. https://pubmed.ncbi.nlm.nih.gov/26277870/ Tng E. L. (2015). Kisspeptin signalling and its roles in humans. Singapore medical journal, 56(12), 649–656. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678402/ Zeydabadi Nejad, S., Ramezani Tehrani, F., & Zadeh-Vakili, A. (2017). The Role of Kisspeptin in Female Reproduction. International journal of endocrinology and metabolism, 15(3), e44337. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702467/ Stengel, A., Wang, L., Goebel-Stengel, M., & Taché, Y. (2011). Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport, 22(5), 253–257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063509/ Orlando G, Leone S, Ferrante C, Chiavaroli A, Mollica A, Stefanucci A, Macedonio G, Dimmito MP, Leporini L, Menghini L, Brunetti L, Recinella L. Effects of Kisspeptin-10 on Hypothalamic Neuropeptides and Neurotransmitters Involved in Appetite Control. Molecules. 2018 Nov 24;23(12):3071. doi: 10.3390/molecules23123071. PMID: 30477219; PMCID: PMC6321454. Kristen P. Tolson et.al, Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. The Journal of Clinical Investigation. Published June 17, 2014. https://www.jci.org/articles/view/71075 Chan, Y. M., Lippincott, M. F., Kusa, T. O., & Seminara, S. B. (2018). Divergent responses to kisspeptin in children with delayed puberty. JCI insight, 3(8), e99109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931121/ Comninos, A. N., Wall, M. B., Demetriou, L., Shah, A. J., Clarke, S. A., Narayanaswamy, S., Nesbitt, A., Izzi-Engbeaya, C., Prague, J. K., Abbara, A., Ratnasabapathy, R., Salem, V., Nijher, G. M., Jayasena, C. N., Tanner, M., Bassett, P., Mehta, A., Rabiner, E. A., Hönigsperger, C., Silva, M. R., Dhillo, W. S. (2017). Kisspeptin modulates sexual and emotional brain processing in humans. The Journal of clinical investigation, 127(2), 709–719. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272173/ Milton NG, Chilumuri A, Rocha-Ferreira E, Nercessian AN, Ashioti M. Kisspeptin prevention of amyloid-β peptide neurotoxicity in vitro. ACS Chem Neurosci. 2012 Sep 19;3(9):706-19. doi: 10.1021/cn300045d. Epub 2012 May 30. PMID: 23019497; PMCID: PMC3447396. Simon, C., Soga, T., Ahemad, N., Bhuvanendran, S., & Parhar, I. (2022). Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro. International journal of molecular sciences, 23(9), 5193. https://doi.org/10.3390/ijms23095193 Simon, C., Soga, T., & Parhar, I. (2023). Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner. International journal of molecular sciences, 24(7), 6056. https://doi.org/10.3390/ijms24076056 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.
Palmitoyl Tetrapeptide-7 (200mg)
Palmitoyl Tetrapeptide-7 is a small peptide composed of four amino acids: palmitoyl, glycine, glutamine, and arginine.(1) It is a synthetic peptide analog of the natural matrikine peptide, which is considered to play a vital role in regulating extracellular matrix (ECM) turnover and other related cellular activities. Initial research suggests that the Palmitoyl Tetrapeptide-7 peptide may stimulate the synthesis of ECM components, such as collagen and elastin, and may inhibit the production of pro-inflammatory cytokines. It has also been hypothesized to modulate gene expression involved in ECM remodeling, cell proliferation, and inflammation.(2) Moreover, Palmitoyl Tetrapeptide-7 may function by suppressing the activity of interleukin-6 (IL-6), a pro-inflammatory cytokine that plays a role in the apoptosis of skin cells (cell aging and death) and inflammation. IL-6 secretion is considered to increase with time, leading to the degradation of the ECM, and resulting in a loss of flexibility and structural integrity in the skin barrier. Chemical Makeup(1) Molecular Formula: C34H62N8O7 Molecular Weight: 694.9 g/mol Other Known Titles: Pal-Gly-Gln-Pro-Arg-OH, N-Palmitoylrigin , Palmitoyl-GQPR, Rigin Research and Clinical Studies Palmitoyl Tetrapeptide-7 Mechanism of Action Based on animal studies, Palmitoyl Tetrapeptide-7 has been suggested to potentially inhibit the activity of matrix metalloproteinases (MMPs) in animal models.(3) MMPs are a group of enzymes that may degrade ECM proteins during normal tissue growth. By downregulating MMP activity, Palmitoyl Tetrapeptide-7 may prevent ECM damage and may allow cells to restore and maintain the ECM. More specifically, the peptide might stimulate the production of key components of the skin's extracellular matrix, such as laminin IV and V as well as collagen VII. Laminins may be essential for the structural stability and integrity of the basement membrane, while collagen VII is considered critical in anchoring fibrils that connect the dermis to the epidermis. By potentially enhancing the production of these molecules, Palmitoyl Tetrapeptide-7 might contribute to the maintenance and repair of the skin barrier, thereby improving skin tissue resilience. The peptide is also thought to potentially decrease IL-6 secretion, a cytokine that is believed to play a pivotal role in promoting inflammation. By possibly reducing the levels of IL-6, Palmitoyl Tetrapeptide-7 may act to diminish inflammation, particularly following UVB exposure, which is considered to trigger inflammatory responses in the skin.(4) Palmitoyl Tetrapeptide-7 and Oral Conditions Given the inhibitory potential of the peptide on matrix metalloproteinases (MMPs), research teams have thought to examine the potential action of Palmitoyl Tetrapeptide-7 in mitigating the symptoms of certain oral conditions. MMPs enzymes may break down extracellular matrix (ECM) proteins, including those in the oral cavity. While these enzymes are considered to play a role in various physiological and pathological processes, including tissue repair, wound healing, and inflammation, excessive MMP activity might result in tissue damage and may cause various oral diseases, such as periodontitis, caries, and oral cancer. Studies have also suggested that MMP activity may be upregulated in some oral conditions, including periodontitis, characterized by the destruction of periodontal tissues. The possible inhibition of MMP activity by Palmitoyl Tetrapeptide-7 might potentially prevent or slow the progression of periodontitis (and other oral ailments) by preserving the integrity of the ECM.(3) Palmitoyl Tetrapeptide-7 and Skin Damage Studies suggest that the peptide may stimulate the synthesis of collagen, a key component of the extracellular matrix in the skin, and may produce anti-inflammatory action, which might reduce damage caused by environmental factors such as UV radiation and pollution. Research has suggested that combining Palmitoyl Tetrapeptide-7 with Palmitoyl Oligopeptide (Matrixyl 3000) may synergistically stimulate collagen production and reduce inflammation. This synergy, which the study describes as "dramatic," may help improve skin texture and reduce the depth and length of wrinkling that may occur along the stratum corneum of the epidermal barrier.(5) According to the studies, “Matrixyl 3000 is a synergistic combination of two skin-active peptides, Palmitoyl oligopeptide and Palmitoyl-tetrapeptide-7, which appears promising based on the preliminary data from the manufacturer… However, it remains to be proven effective by independent published clinical studies.” As discussed, Palmitoyl Tetrapeptide-7 may be particularly targeting stimulation of collagen type VII.(4) Collagen type VII is posited to be a vital component of the skin tissues' architecture, primarily contributing to the stability and structural integrity of the dermal-epidermal junction. It is thought to play a key role in anchoring fibrils that connect the outer epidermis to the deeper dermis. This specific collagen might form a crucial part of the basement membrane, potentially serving as a scaffold that maintains the structural cohesion between these skin layers. The presence and functionality of collagen type VII are considered essential for the prevention of blistering disorders, which occur when there is a breakdown in this connection between the dermis and epidermis. Moreover, collagen type VII may also play a role in skin tissue healing. This type of collagen could be critical in skin recovery and repair by possibly facilitating the reattachment of the epidermis to the underlying tissue after an injury. It is posited that enhancing the synthesis of collagen VII might improve wound healing outcomes, particularly in environments compromised by age or dermal afflictions. Palmitoyl Tetrapeptide-7 and Wrinkle Depth The peptide, sometimes classified as an “anti-aging” compound, is so named due to its perceived potential action and enhancement of integral protein production within the skin, as discussed above. In a randomized, double-blind, placebo-controlled clinical study, 20 research models were presented with a cream containing Palmitoyl Tetrapeptide-7 for 12 weeks. The cream was applied twice daily to observable wrinkles along the skin. At the end of the study period, the researchers reported that the cream containing Palmitoyl Tetrapeptide-7 appeared to have reduced the depth and length of the wrinkles compared to the placebo cream.(6) The researchers also observed an apparently significant increase in skin elasticity in the group that received the Palmitoyl Tetrapeptide-7 cream. In another study, 20 research models were exposed to the peptide compound twice a day for four weeks, and instrumental measurements were taken to assess the improvement of biomarkers of cell aging and ECM decline. The study reported an apparent reduction in fine wrinkles by 5.97% after two weeks and 14.07% after four weeks, and a reported increase in skin elasticity by 6.81% after two weeks, and 8.79% after four weeks. Dermal density was reportedly increased by 16.74% after two weeks, and 27.63% after four weeks.(7) Palmitoyl Tetrapeptide-7 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 10078408, Palmitoyl tetrapeptide-7. Mondon P, Hillion M, Peschard O, Andre N, Marchand T, Doridot E, Feuilloley MG, Pionneau C, Chardonnet S. Evaluation of dermal extracellular matrix and epidermal-dermal junction modifications using matrix-assisted laser desorption/ionization mass spectrometric imaging, in vivo reflectance confocal microscopy, echography, and histology: effect of age and peptide applications. J Cosmet Dermatol. 2015 Jun;14(2):152-60. doi: 10.1111/jocd.12135. Epub 2015 Mar 27. PMID: 25817264. https://pubmed.ncbi.nlm.nih.gov/25817264/ Sorsa T, Tjäderhane L, Salo T. Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis. 2004 Nov;10(6):311-8. doi: 10.1111/j.1601-0825.2004.01038.x. PMID: 15533204. https://pubmed.ncbi.nlm.nih.gov/15533204/ Resende, Diana I S P et al. “Usage of Synthetic Peptides in Cosmetics for Sensitive Skin.” Pharmaceuticals (Basel, Switzerland) vol. 14,8 702. 21 Jul. 2021, doi:10.3390/ph14080702 Matrixyl 3000 (palmitoyl oligopeptide & palmitoyl tetrapeptide-7): Back to the future of skin care. Marta Salvador-Ferreira et al. Trending Anti-Aging Peptides. MDPI Journal, Vol 7, Issue 4. https://www.mdpi.com/2079-9284/7/4/91 Hahn Hyung Jin et al. Instrumental evaluation of anti‑aging effects of cosmetic formulations containing palmitoyl peptides, Silybum marianum seed oil, vitamin E and other functional ingredients on aged human skin, Experimental and Therapeutic Medicine, Jun 2016. 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.
AICAR (50mg)
AICAR is an analog of adenosine monophosphate (AMP), a nucleotide that is considered to play an important role in cellular energy metabolism. It has been studied for its potential applications in research, particularly in reducing reperfusion injury after tissue ischemia and mitigating metabolic disorders. AICAR has been suggested to exert this potential by apparently activating AMP-activated protein kinase (AMPK), an enzyme that regulates various metabolic processes. AMPK potentially plays a role in restoring energy balance. It might do this by inhibiting anabolic processes: energy-consuming pathways like protein and fatty acid synthesis. Simultaneously, it might activate catabolic processes, such as the breakdown of glucose and fats, which generate ATP, thereby increasing the energy supply. There is also a possibility that AMPK influences various other cellular processes, including autophagy (the process by which cells clean out damaged components), mitochondrial biogenesis (the creation of new mitochondria), and the regulation of inflammation and stress responses. This broad range of actions suggests that AMPK might be involved in regulating several aspects of cellular and organismal function. By potentially activating AMPK, AICAR is posited to possibly increase glucose uptake in skeletal muscle, enhance insulin sensitivity, and improve glucose tolerance. AICAR has also been suggested by researchers to have anti-inflammatory potential and may improve physical performance in certain experimental models. Chemical Makeup Molecular formula: C9H15N4O8P Molecular Weight: 338.21 g/mol Other known titles: AICA ribonucleotide Research and Clinical Studies AICAR Peptide and Tissue Protection AICAR may have organ-protective potential, especially against ischemia and reperfusion injury. The nucleotide has been suggested to potentially reduce myocardial infarction size and improve cardiac function in an animal model of myocardial ischemia-reperfusion injury.(1) One meta-analysis aimed to investigate the potential of AICAR on cardiovascular tissues.(2) The data was collected from 5 randomized, placebo-controlled, double-blind clinical studies. From the results, AICAR was suggested to reduce myocardial tissue infarction size and cardiac cell death and apparently improve the overall outcome of the experiment. The study concluded that AICAR may "reduce [...] adverse cardiovascular outcomes." Researchers posited that the apparent protective potential of AICAR may be due to its action on cellular metabolism. AICAR may potentially alter it to become more resistant to lack of oxygen by apparently upregulating the availability of energy that can be used even in anaerobic conditions. One such process is the apparent increase in the availability of myocardial glucose. To achieve that, AICAR may promote myocardial glycogenolysis (glycogen degradation) by activating AMPK. This was suggested by experiments using isolated hearts from halothane-anesthetized murine models. In these studies, AICAR appeared to increase glycogenolysis in the myocardium of murine models, while its action on glycogen synthesis was reportedly negligible. This observation hints at a potential role for AMPK activation in glycogenolysis. Further, AICAR was noted to potentially increase myocardial levels of 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranotide (ZMP), which is AICAR's active intracellular form. However, there was no apparent change in the activity of glycogen synthase (GS) and glycogen phosphorylase (GP) in tissue homogenates, nor did AICAR seem to affect the levels of glucose-6-phosphate and adenine nucleotides in freeze-clamped tissues of these murine models. These findings suggest the possibility that ZMP might allosterically activate GP, leading to glycogenolysis in the intact hearts of the murine models, thereby providing glucose that can be used for energy even in less optimal conditions for the cells.(3) AICAR may have protective action in other tissues as well. One study investigated the potential of AICAR, an AMPK activator, on an experimental murine model of ethanol-induced hepatic steatosis.(4) The study observed that chronic ethanol exposure appeared to result in a histologically and biochemically fatty liver. Upon AICAR presentation, it appeared to attenuate the degree of change in the liver tissues. AICAR was also posited to decrease the hepatic sterol regulatory element-binding protein 1c (SREBP-1c) and reduce fatty acid synthase (FAS) enzyme expression, reducing triglyceride synthesis in murine models’ livers. SREBP-1c is posited to be a protein apparently involved in lipid metabolism, primarily in liver tissues. It is a member of the SREBP family, which appears to be transcription factors that regulate the expression of genes required to synthesize cholesterol, fatty acids, and triglycerides. Therefore, it is possible that a decrease in SREBP-1c might lead to a reduction in fatty acid synthesis. FAS is an enzyme that is considered to play a crucial role in synthesizing fatty acids. It is suggested to play a role in the process of converting acetyl-CoA and malonyl-CoA, small molecules, into palmitate, a long-chain saturated fatty acid. FAS expression also appears to be regulated by SREBP-1c. AICAR Peptide and Insulin Sensitivity Studies suggest that AICAR may have the potential to improve the insulin sensitivity of various tissues due to its potential to activate the AMPK inside cells and make them draw in glucose. One experimental model aimed to investigate whether AICAR could potentially enhance glucose transport in equine skeletal muscle.(5) Upon presentation, AICAR appeared to decrease glucose and increase insulin concentration without affecting lactate concentration. AICAR was also observed to potentially increase the ratio of phosphorylated to total AMPK in skeletal muscle and may have upregulated GLUT8 protein expression. The apparent increase in the expression of the GLUT8 protein in the cells could potentially enhance the movement of glucose into cells, thereby possibly improving insulin sensitivity. A study also aimed to determine whether AICAR may stimulate glucose uptake in muscle.(6) AICAR and physical activity were employed to stimulate muscle AMPK activity and glucose uptake. Results expressed the possibility that both AICAR and physical activity may increase glucose uptake in muscle. Still, AICAR may also increase glucose uptake in other tissues, thereby potentially increasing peripheral and overall insulin sensitivity. Researchers also suggested that AICAR might potentially increase the phosphorylation of extracellular signal-regulated kinase 1/2. Phosphorylation is a chemical process where a phosphate group is added to the enzymes ERK1 and ERK2. These enzymes are part of a specific signaling pathway known as the MAP kinase/ERK pathway, posited to regulate various cellular activities like division, differentiation, and response to stress. Another study observed that AICAR may potentially reduce hepatic tissues’ glucose output, lower glucose concentrations, stimulate hepatic tissues’ fatty acid oxidation, and inhibit lipolysis, thereby reducing plasma-free fatty acid availability.(7) Although AMPK phosphorylation in skeletal muscle was not reported to be increased, the researchers reported acetyl-CoA carboxylase phosphorylation to be significantly increased. This enzyme is considered to play a potential role in fatty acid metabolism. It apparently catalyzes acetyl-CoA conversion to malonyl-CoA, a crucial step in fatty acid synthesis. Thus, this inactivation could potentially lead to a decrease in fatty acid synthesis and an apparent increase in fatty acid oxidation to fuel the cells with energy. AICAR Peptide and Endurance Researchers posit that AICAR may potentially activate AMPK, glycogen phosphorylase, and fructose-1,6-bisphosphatase.(8) Some studies have suggested these potential actions may contribute to enhanced oxidative metabolism and mitochondrial biogenesis.(9) Increasing the number and function of mitochondria may benefit muscle endurance. For example, one experiment suggested that AICAR may induce metabolic genes and enhance running endurance in sedentary murine models by 44%.(10) The results suggest that peptides may target the AMPK-PPARδ pathway to enhance training adaptation or increase endurance without exercise. PPARδ, or Peroxisome Proliferator-Activated Receptor Delta, is a type of nuclear receptor that possibly plays a role in regulating genes involved in energy metabolism. It is thought that PPARδ may be involved in processes like fat-burning and mitochondrial biogenesis (the creation of new mitochondria, which are the energy-producing structures in cells). The AMPK-PPARδ pathway potentially represents a link between the sensing of energy status by AMPK and the gene regulatory functions of PPARδ. When activated, this pathway might promote adaptations in muscle cells similar to those induced by endurance training. These adaptations could include increased mitochondrial content and a shift in muscle fiber type towards more endurance-oriented fibers, potentially leading to enhanced endurance capacity.(10) Another experiment in murine models(11) also reported that the presentation of "an agonist of the AMP-activated protein kinase showed an increase in endurance compared to exercise-trained controls." Furthermore, in a murine model for Duchene muscular dystrophy, AICAR was observed by researchers to have the potential to enhance the impact of exercise and improve muscle function, probably by stimulating autophagy.(12) An infusion of AICA-riboside resulted in increment-correlated increases in forearm blood flow but did not appear to impact glucose uptake in skeletal muscle. The increase in blood flow appeared to be mediated by nitric oxide, as an inhibitor of endothelial NO synthase apparently attenuated it. These findings suggest that AICAR may exert impact in improving blood flow into muscle and acting as a NO-booster, which is also an important factor for improving performance during prolonged physical activity.(13) AICAR Peptide and Malignant Cell Lines Research indicates that AICAR may trigger apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) test models. One study proposes that this process might involve the activation of caspase-3, -8, and -9, along with the release of cytochrome C.(14) Additionally, incubating B-CLL cells with AICAR seems to lead to the phosphorylation of AMPK, hinting at AICAR's potential role in activating this protein. The research further explored whether the entry of AICAR into the cell and its conversion to AICA ribotide (ZMP) is necessary for apoptosis. It employed inhibitors like Nitrobenzylthioinosine (NBTI), 5-iodotubercidin, and adenosine. These inhibitors were suggested to potentially reduce AICAR-induced apoptosis and AMPK phosphorylation. However, inhibitors of protein kinase A and mitogen-activated protein kinases did not appear to prevent AICAR-induced apoptosis in B-CLL cells. The study also noted that AICAR did not appear to affect p53 levels or phosphorylation, suggesting a p53-independent apoptosis mechanism in B-CLL cells. A comparison was made between normal B lymphocytes, T cells, and B-CLL cells' sensitivity to AICAR-induced apoptosis. The findings indicated that normal B lymphocytes and B-CLL cells were similarly sensitive to AICAR-induced apoptosis, whereas T cells from B-CLL subjects appeared to show only minor sensitivity. Notably, AMPK phosphorylation did not seem to occur in T cells exposed to AICAR. Furthermore, upon exposure to AICAR, B-CLL cells appeared to have higher intracellular levels of ZMP compared to T cells. This observation suggests that ZMP accumulation may be crucial in activating AMPK and inducing apoptosis in these cells. AICAR peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Cieslik, K. A., Taffet, G. E., Crawford, J. R., Trial, J., Mejia Osuna, P., & Entman, M. L. (2013). AICAR-dependent AMPK activation improves scar formation in the aged heart in a murine model of reperfused myocardial infarction. Journal of molecular and cellular cardiology, 63, 26–36. https://doi.org/10.1016/j.yjmcc.2013.07.005 Mangano D. T. (1997). Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group. JAMA, 277(4), 325–332. https://doi.org/10.1001/jama.277.4.325 Longnus, S. L., Wambolt, R. B., Parsons, H. L., Brownsey, R. W., & Allard, M. F. (2003). 5-Aminoimidazole-4-carboxamide 1-beta -D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. American journal of physiology. Regulatory, integrative and comparative physiology, 284(4), R936–R944. https://doi.org/10.1152/ajpregu.00319.2002 Tomita, K., Tamiya, G., Ando, S., Kitamura, N., Koizumi, H., Kato, S., Horie, Y., Kaneko, T., Azuma, T., Nagata, H., Ishii, H., & Hibi, T. (2005). AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcoholism, clinical and experimental research, 29(12 Suppl), 240S–5S. https://doi.org/10.1097/01.alc.0000191126.11479.69 de Laat, M. A., Robinson, M. A., Gruntmeir, K. J., Liu, Y., Soma, L. R., & Lacombe, V. A. (2015). AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle. Veterinary journal (London, England : 1997), 205(3), 381–386. https://doi.org/10.1016/j.tvjl.2015.05.018 Cuthbertson, D. J., Babraj, J. A., Mustard, K. J., Towler, M. C., Green, K. A., Wackerhage, H., Leese, G. P., Baar, K., Thomason-Hughes, M., Sutherland, C., Hardie, D. G., & Rennie, M. J. (2007). 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. Diabetes, 56(8), 2078–2084. https://doi.org/10.2337/db06-1716 Boon, H., Bosselaar, M., Praet, S. F., Blaak, E. E., Saris, W. H., Wagenmakers, A. J., McGee, S. L., Tack, C. J., Smits, P., Hargreaves, M., & van Loon, L. J. (2008). Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia, 51(10), 1893–1900. https://doi.org/10.1007/s00125-008-1108-7 Višnjić D, Lalić H, Dembitz V, Tomić B, Smoljo T. AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review. Cells. 2021 May 4;10(5):1095. doi: 10.3390/cells10051095. PMID: 34064363; PMCID: PMC8147799. Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011 Sep 15;25(18):1895-908. doi: 10.1101/gad.17420111. PMID: 21937710; PMCID: PMC3185962. Narkar, V. A., Downes, M., Yu, R. T., Embler, E., Wang, Y. X., Banayo, E., Mihaylova, M. M., Nelson, M. C., Zou, Y., Juguilon, H., Kang, H., Shaw, R. J., & Evans, R. M. (2008). AMPK and PPARdelta agonists are exercise mimetics. Cell, 134(3), 405–415. https://doi.org/10.1016/j.cell.2008.06.051 Goodyear, L. J. (2008). The exercise pill—too good to be true?. New England Journal of Medicine, 359(17), 1842-1844. Bueno Júnior, C. R., Pantaleão, L. C., Voltarelli, V. A., Bozi, L. H., Brum, P. C., & Zatz, M. (2012). Combined effect of AMPK/PPAR agonists and exercise training in mdx mice functional performance. PloS one, 7(9), e45699. https://doi.org/10.1371/journal.pone.0045699 Bosselaar, M., Boon, H., van Loon, L. J., van den Broek, P. H., Smits, P., & Tack, C. J. (2009). Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle. American journal of physiology. Endocrinology and metabolism, 297(3), E759–E766. https://doi.org/10.1152/ajpendo.00141.2009 Campàs, C., Lopez, J. M., Santidrián, A. F., Barragán, M., Bellosillo, B., Colomer, D., & Gil, J. (2003). Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. Blood, 101(9), 3674–3680. https://doi.org/10.1182/blood-2002-07-2339 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.
Gonadorelin (GnRH) (10mg)
Gonadorelin is the synthetic version of the naturally occurring gonadotropin hormone-releasing hormone (GnRH). GnRH is considered to be a major regulator in the secretion of gonadotropins, i.e. follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are considered to manage and regulate the endocrine functioning and maturation of the gonads.(1) Gonadorelin is a synthetic peptide composed of ten amino acids, all joined to one another in a sequential form.(2) Gonadorelin is structurally similar to the endogenous GnRH.(3) Structurally identical to the endogenous GnRH hormones, Gonadorelin has been dubbed a GnRH agonist by researchers and exhibits some potential in regulating the levels of gonadotropins and maintaining regular reproductive functions.(2) Overview The peptide has been suggested to stimulate the synthesis and release of gonadotropins, the luteinizing hormone, and the follicle-stimulating hormone by possibly stimulating the GnRH receptors in the anterior pituitary gland cells.(4) This is mainly the reason why Gonadorelin is referred to by researchers as a "GnRH agonist," as it may possibly induce the same action as GnRH. Researchers have also suggested that excessive exposure to Gonadorelin may induce the opposite action - namely, the downregulation of GnRH receptors at the pituitary gland. This peptide hormone binds to the receptors, which, for a short period, may at first stimulate the secretion of the gonadotropins. Eventually, scientists believe the receptors become less sensitive towards this peptide, aka downregulation of the receptors, which then reversibly inhibits the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).(4) Research on this peptide and other GnRH analogs are underway, and several research hypotheses have been presented, which may be summarized thus: Gonadorelin may help researchers meter hypothalamus and pituitary gland functions; It may possibly induce ovulation; It may be a potential anticarcinogenic agent; It may reduce the likelihood of neurological deterioration. All of these hypotheses are under examination in ongoing scientific research. Chemical Makeup Molecular Formula: C55H75N17O13 Molecular Weight: 1182.31 g/mol Other Known Titles: Growth Hormone Releasing Factor, Somatocrinin, Somatoliberin Research and Clinical Studies Gonadorelin Peptide and Post-Cycle Recovery Exogenous androgens may potentially suppress the function of the hypothalamic-pituitary-gonadal (HPG) axis, which is considered to form between the structures of the hypothalamus, the pituitary gland, and the gonads. For example, exogenous androgens are suggested to mediate negative feedback to the pituitary gland, thereby suppressing the release of LH and FSH. Once the exposure to exogenous androgens has ceased, HPG may slowly recover, but Gonadorelin may offer a potential mechanism to speed up the process. For example, one study reported exogenous androgen exposure, which led to LH and FSH being suppressed to less than 0.5 IU/L while endogenous testosterone produced by testicular cells was down to 4.5 nmol/L. Short exposure to Gonadorelin resulted in apparent increases up to 7.9 IU/L for LH, up to 2.4 IU/L for FSH, and 13.3 nmol/L for endogenous testosterone. Moreover, these improvements were apparently sustained for over 12 months without further exposition to the peptide.(5) Gonadorelin Peptide and Testicular Function Studies have investigated the potential of intermittent Gonadorlein exposure on the HPG axis, which may mimic the natural synthesis of GnRH and its action on the pituitary cells. In particular, this scenario was studied in models of hypothalamic dysfunction, where the production of native GnRH appeared to have been disturbed. Researchers have shared that Gonadorelin may effectively " kick-start” the HPG axis in such scenarios, which involves sequential stimulation of the pituitary gland cells to synthesize LH and FSH, and then the testicular cells to produce androgens. They comment that intermittent exposure to the peptide for 5 to 6 months may ultimately result in successful spermatogenesis. This process appears to be highly dependent on the endogenous production of testosterone by testicular cells.(6)(7) Further research has also suggested that Gonadorelin may help facilitate the descent of the testes, which is considered a part of the development of the HPG axis. Researchers posit that the peptide may have roughly 40% success rate at inducing such processes, related to the maturation of the HPG axis and testicular structures in particular.(8) Gonadorelin Peptide and Cancer Cells Research in cancer cell proliferation in both clinical and animal studies suggests that excessive exposure of breast cells to mitogens, namely estrogen and progesterone, may increase the risk of their transformation into cancer cells. Potentially blocking the action of these mitogens, thereby reducing the exposure of the healthy cells to them, may reduce the risk of cancer development.(9) Researchers suggest that GnRH agonists such as Gonadorelin may exhibit some potential in mitigating the action of mitogens in healthy cells. Studies(10) examining research models of high testosterone, a marker for hyperandrogenemia (a condition characterized by excessive androgen synthesis), are at higher risk of developing breast cancer. The source of androgen, and thereby the potential source of breast cancer, may possibly be counteracted with GnRH analogs, as researchers are hypothesizing that the peptide may induce a reduction in the substrate for estrogen synthesis but may not necessarily inhibit the synthesis of estrogen completely. Researchers have also explored the potential of Gonadorelin in experimental studies intended to inhibit the production of luteinizing hormones. The researchers suggested that due to the potential for downregulating GnRH receptors, the peptide may lead to a decline in the production of testosterone and dihydrotestosterone. The development of carcinogenic cells from prostate cells may depend on these testosterone levels, which the exposure to GnRH analogs such as Gonadorelin might inhibit.(11) Gonadorelin Peptide and Spermatogenesis In a clinical trial,(12) seven male test subjects were presented with a GnRH analog similar to Gonadorelin every day for up to 16 weeks and a compound of testosterone enanthate bimonthly (a form of TRT). Basal serum follicle-stimulating hormone, luteinizing hormones, and testosterone levels were monitored throughout the study period. Between 14 to 16 weeks, it was noted by the researchers that the average sperm count in the test subjects had reportedly reduced by an average of 93%, also causing azoospermia in three of the subjects, which is characterized by a complete absence of sperms in the ejaculate. Subsequently, once the study was completed, the average sperm count returned to normal, indicating that the possible action of the peptide hormone may be reversible and act as a temporary contraceptive (when combined with TRT). Gonadorelin Peptide and Neuroprotection Research(13) has suggested that luteinizing hormones may have some impact on the brain, primarily the hippocampus, which is the memory center of the brain, and in some scenarios, may possibly induce some dysfunction. These researchers posited that one way of mitigating neurological dysfunction might be to block the production and release of luteinizing hormones, which may potentially be achieved through the introduction of GnRH analogs such as Gonadorelin. Testosterone has also been studied by scientists for its potential to preserve memory function and may be beneficial to brain function. Hence, inhibiting the entire gonadal axis may not be fully beneficial. This is why GnRH, which researchers suggest only induces selective inhibitory action on luteinizing hormones, may exhibit potential in future research studies.(13) Gonadorelin Peptide and Diagnostics In this clinical study,(14) the synthetically developed peptide Gonadorelin was presented in 11 female test subjects during the middle of the follicular phase of the menstrual cycle. All subjects exhibited an apparent increase in the basal levels of gonadotropins following peptide presence. In addition, 10 test subjects with amenorrhea were presented with the peptide. Amenorrhea is characterized by a lack of menstruation. After the study, researchers reported that basal levels of gonadotropins, particularly the luteinizing hormone levels, appeared to increase in the short term but remained steady in the long term. This study suggested that Gonadorelin's potential pituitary secretion of luteinizing hormones and follicle-stimulating hormones may not depend on the basal levels of these hormones. However, it may depend on the functioning of the hypothalamic and pituitary axis. Gonadorelin peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering. References: Marques P, Skorupskaite K, George JT, et al. Physiology of GNRH and Gonadotropin Secretion. [Updated 2018 Jun 19]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc. https://www.ncbi.nlm.nih.gov/books/NBK279070/ National Center for Biotechnology Information. PubChem Compound Summary for CID 638793, Gonadorelin. Philip GA Thomas, Alain Fontbonne, Drugs and reproduction. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/gonadorelin-acetate van Breda, E., Keizer, H. A., Kuipers, H., & Wolffenbuttel, B. H. (2003). Androgenic anabolic steroid use and severe hypothalamic-pituitary dysfunction: a case study. International journal of sports medicine, 24(3), 195–196. https://doi.org/10.1055/s-2003-39089 Blumenfeld, Z., Makler, A., Frisch, L., & Brandes, J. M. (1988). Induction of spermatogenesis and fertility in hypogonadotropic azoospermic men by intravenous pulsatile gonadotropin-releasing hormone (GnRH). Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 2(2), 151–164. https://doi.org/10.3109/09513598809023623 Zhang, L., Cai, K., Wang, Y., Ji, W., Cheng, Z., Chen, G., & Liao, Z. (2019). The Pulsatile Gonadorelin Pump Induces Earlier Spermatogenesis Than Cyclical Gonadotropin Therapy in Congenital Hypogonadotropic Hypogonadism Men. American journal of men's health, 13(1), 1557988318818280. https://doi.org/10.1177/1557988318818280 Muzzi, G., Bartolotta, E., Cherubini, V., & Lomiento, D. (1990). Effetti del trattamento con LH-RH sintetico spray nasale nel criptorchidismo [Effects of the treatment using synthetic LH-RH nasal spray in cryptorchism]. La Pediatria medica e chirurgica : Medical and surgical pediatrics, 12(1), 53–55. Lepor, Herbert. “Comparison of single-agent androgen suppression for advanced prostate cancer.” Reviews in urology vol. 7 Suppl 5,Suppl 5 (2005): S3-S12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1477619/ Spicer DV, Pike MC. Sex steroids and breast cancer prevention. J Natl Cancer Inst Monogr. 1994;(16):139-47. https://pubmed.ncbi.nlm.nih.gov/7999456/ Secreto G, Sieri S, Agnoli C, Grioni S, Muti P, Zumoff B, Sant M, Meneghini E, Krogh V. A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women. Breast Cancer Res Treat. 2016 Aug;158(3):553-61. https://pubmed.ncbi.nlm.nih.gov/27393623/ Zerbib M. Analogues de la GnRH dans le traitement du cancer de la prostate [GnRH analogs and prostate cancer treatment]. Ann Urol (Paris). 2005 Oct;39 Suppl 3:S66-72. French. doi: 10.1016/s0003-4401(05)80011-7. https://pubmed.ncbi.nlm.nih.gov/16302714/ Bhasin S, Yuan QX, Steiner BS, Swerdloff RS. Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in men: effects of long term treatment with GnRH agonist infusion and androgen. J Clin Endocrinol Metab. 1987 Sep;65(3):568-74. https://pubmed.ncbi.nlm.nih.gov/3114307/ R.L Bowen, et al, Not All Androgen Deprivation Therapies Are Created Equal: Leuprolide and the Decreased Risk of Developing Alzheimer's Disease, J. Clin. Oncol., vol 34, no. 23, p.2800, Aug 2016. https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3997 Vesper B, Rohde W, Groot-Wassink T. Ein Beitrag zur klinischen Anwendung von Gonadorelin als Diagnostikum im Einfach- und Doppelbelastungstest [Clinical use of Gonadorelin as a diagnostic agent in one- and two-step tests]. Zentralbl Gynakol. 1986;108(23):1442-52. https://pubmed.ncbi.nlm.nih.gov/3103350/ 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.