Semaglutide (GLP-1) Peptide: Hunger Hormone Signaling Regulation and Glycemic Control

Semaglutide (GLP-1) Peptide: Hunger Hormone Signaling Regulation and Glycemic Control

Semaglutide is a synthetic analog of the glucagon-like peptide-1 (GLP-1), an endogenous hormone consisting of 30 amino acids. The primary role of GLP-1 appears to support insulin secretion, lower blood glucose levels, and preserve pancreatic beta cells by stimulating insulin gene transcription. Additionally, it has been posited to delay gastric emptying, leading to appetite suppression. GLP-1 appears to impact several critical organs, including the heart, kidneys, lungs, and liver.

Like the endogenous GLP-1 peptide, Semaglutide, as a GLP-1 receptor agonist, has been researched for its potential to reduce blood glucose levels and decrease appetite.[1] Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced in the intestines, primarily in response to nutrient ingestion. Research suggests that it plays a critical role in the regulation of glucose homeostasis, particularly in postprandial (after caloric intake) conditions. GLP-1 appears to stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner, potentially facilitating cellular glucose uptake and contributing to the reduction of blood glucose levels.

 

Mechanisms of Action

Studies suggest that there are two main ways through which the peptide may function:

Endogenous GLP-1: Endogenous GLP-1 is secreted following food intake. It slows gastric emptying, mitigates hunger hormone signals, and promotes insulin release when blood glucose levels are elevated. This physiological process aids in both glucose and weight regulation by reducing appetite and caloric intake.

GLP-1 Receptor Agonists: Synthetic GLP-1 receptor agonists have been developed in the course of diabetes research. These compounds appear to mimic the impacts of endogenous GLP-1 by activating its receptors on pancreatic beta cells, thereby increasing insulin secretion. They may also suppress glucagon release, further aiding in blood glucose regulation. Additionally, these agonists are considered to delay gastric emptying and mitigate hunger hormone signals, making them relevant to researchers studying the reduction of adipose tissue in laboratory models of type 2 diabetes.

The additional mechanism pathways include:

  • Through binding with the GLP-1 receptors, Semaglutide may promote insulin secretion, i.e., glucose-dependent insulin release.[2]
  • Semaglutide is thought to support pancreatic beta cell function, supporting the proinsulin-to-insulin ratio.[3]
  • By delaying gastric emptying and reducing appetite, the compound may contribute to weight reduction.[4]

 

Scientific and Research Studies

 

Semaglutide (GLP-1) Peptide and the Incretin Effect

Research suggests that the Semaglutide (GLP-1) peptide theoretically displays ‘the incretin effect.’ ‘The Incretin Effect’ is a physiological response mediated by gastrointestinal hormones released post-caloric intake to reduce blood glucose levels.

GLP-1 receptors located on pancreatic beta cells appear to bind with Semaglutide. This is intended to stimulate insulin secretion and aid in glucose control.

According to J.J. Holst, “The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions.”[1] As a GLP-1 receptor agonist, Semaglutide appears to promote incretin hormone activity and, therefore, may have a hand in the regulation of blood sugar levels.

 

Semaglutide (GLP-1) Peptide and Pancreatic Beta Cell Protection

Research suggests that Semaglutide (GLP-1) peptide has the potential to protect pancreatic beta cells, as seen in a study[5] conducted on non-obese diabetic (NOD) mice models. In this experiment, mice were introduced to Semaglutide in combination with lisofylline, an immunomodulatory agent that suppresses autoimmune activity, and exendin-4, a compound regarded for its proposed ability to promote beta cell proliferation. Based on the results, it appeared that Semaglutide might stimulate pancreatic beta-cell growth and mitigate beta-cell apoptosis (cell death).

Furthermore, results also suggested that the mice maintained optimal glucose levels up to 145 days post-introduction, even after discontinuation of the Semaglutide (GLP-1) peptide. Because of these long-lasting impacts, it is speculated that Semaglutide may have enduring relevance to glucose regulation and beta cell preservation.

 

Semaglutide (GLP-1) Peptide and Appetite Suppression

GLP-1 receptor agonists, including Semaglutide, appear to impact appetite regulation through the delay of gastric motility. This potentially leads to a prolonged feeling of fullness, thereby reducing overall food intake.[1] Research[6] suggests that Semaglutide, when introduced in the brain, may reduce the neural drive to consume calories, possibly leading to a decrease in appetite and better-supporting mitigation of hunger hormone signals.

Experimental studies in murine models suggest that Semaglutide’s central action curtails food intake, potentially making it an agent in the reduction of excessive adipose tissue. It is also speculated that over time, Semaglutide may result in gradual weight reduction, possibly contributing to better-supported cardiovascular function and increased energy levels.

 

Semaglutide (GLP-1) Peptide and Neurological Research

Semaglutide, through its action on GLP-1 receptors (GLP-1R), is suggested to possess neuroprotective and cognition-supporting properties. GLP-1 and its receptors are expressed in brain cells, and deficiencies in GLP-1R are associated with seizures, impaired learning, and neuronal damage. Research by Mathew J. During et al. highlights that “Systemic administration of GLP-1 receptor agonists in wild-type animals [may] prevent kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for cognitive-enhancing and neuroprotective agents.”[7]

Additionally, studies[8] have posited that Semaglutide (GLP-1) peptide may protect hippocampal regions of the brain from cellular apoptosis, indicating their potential in addressing neurodegenerative conditions such as Alzheimer’s disease. Furthermore, Semaglutide also appears to reduce beta-amyloid concentrations, which are thought to be linked to the development of Alzheimer’s. Some research posits a possibility that the peptide may contribute to the delay or reversal of some symptoms of neurodegeneration.

 

Semaglutide (GLP-1) Peptide and Cardiovascular Function

Studies suggest that GLP-1 receptors are distributed throughout the cardiovascular system, where their activation appears to play a crucial role in maintaining cardiac function.[9] It appears that Semaglutide, through its theorized action on GLP-1 receptors, may help regulate blood pressure and reduce left ventricular diastolic pressure, both of which are deemed essential in mitigating cardiac hypertrophy and related cardiovascular complications.

Additionally, Semaglutide (GLP-1) peptide is speculated to support glucose uptake in muscle cells specific to muscular tissue in the cardiovascular system, particularly in ischemic or weakened myocardial tissue following a heart attack. Better-supported glucose metabolism appears to further support cardiac function and may aid in reversing the adverse impacts of myocardial infarction.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

  1. Mahapatra MK, Karuppasamy M, Sahoo BM. Semaglutide is a glucagon-like peptide-1 receptor agonist with cardiovascular benefits for the management of type 2 diabetes. Rev Endocr Metab Disord. 2022 Jun;23(3):521-539. doi: 10.1007/s11154-021-09699-1. Epub 2022 Jan 7. PMID: 34993760; PMCID: PMC8736331. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8736331/#:~:text=Semaglutide%20improves%20the%20efficiency%20of,as%20postprandial%20glucose%20%5B26%5D
  2. Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019 Apr 12;10:155. doi: 10.3389/fendo.2019.00155. PMID: 31031702; PMCID: PMC6474072. https://pubmed.ncbi.nlm.nih.gov/31031702/
  3. Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care. 2018 Feb;41(2):258-266. doi: 10.2337/dc17-0417. Epub 2017 Dec 15. PMID: 29246950. https://pubmed.ncbi.nlm.nih.gov/29246950/
  4. Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide is a promising anti-obesity drug. Obes Rev. 2019 Jun;20(6):805-815. doi: 10.1111/obr.12839. Epub 2019 Feb 15. PMID: 30768766. https://pubmed.ncbi.nlm.nih.gov/30768766/
  5. Yang Z, Chen M, Carter JD, Nunemaker CS, Garmey JC, Kimble SD, Nadler JL. Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes. Biochem Biophys Res Commun. 2006 Jun 9;344(3):1017-22. doi: 10.1016/j.bbrc.2006.03.177. Epub 2006 Apr 5. PMID: 16643856. https://pubmed.ncbi.nlm.nih.gov/16643856/
  6. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM. Interim analysis of the effects of exenatide treatment on A1C, weight, and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006 Jul;8(4):436-47. doi: 10.1111/j.1463-1326.2006.00602.x. PMID: 16776751. https://pubmed.ncbi.nlm.nih.gov/16776751/
  7. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. The glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9. doi: 10.1038/nm919. Epub 2003 Aug 17. PMID: 12925848. https://pubmed.ncbi.nlm.nih.gov/12925848/
  8. Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8. doi: 10.1124/jpet.102.037481. PMID: 12183643. https://pubmed.ncbi.nlm.nih.gov/12183643/
  9. Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, Parker TG, Huang Q, Drucker DJ, Husain M. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003 Jun;144(6):2242-52. doi: 10.1210/en.2003-0007. PMID: 12746281. https://pubmed.ncbi.nlm.nih.gov/12746281/
AOD 9604 Research Into Fat Cell Metabolism and Lipolysis

AOD 9604 Research Into Fat Cell Metabolism and Lipolysis

AOD 9604 is described as a synthetic peptide derived from the C-terminal portion of the native growth hormone (GH). It is specifically derived from the last 15 amino acids (residues 177–191) of GH, with an additional tyrosine residue attached at the N-terminus, making it a peptide composed of 16 amino acids. Moreover, the AOD 9604 structure retains a disulfide bridge found between the two cysteine amino acids in the complete GH structure (Cys182 and Cys189), which in the case of AOD 9604 are at the 7th and 14th positions. The presence of a disulfide bridge between these two amino acids, combined with the addition of tyrosine at the N-terminus, is posited to significantly support AOD 9604 stability and bioavailability under conditions of extreme pH and exposure to various digestive enzymes.[1]

AOD 9604 is thought to replicate the lipolytic actions of full-length GH while lacking the ability to influence carbohydrate metabolism, insulin-like growth factor-1 (IGF-1) production, or cellular growth and division. Therefore, the lipolytic activity of AOD 9604 appears to be limited to promoting fatty acid oxidation and increasing the breakdown of fat (lipolysis). Despite these proposed impacts, the exact mechanism through which AOD 9604 exerts its action is still not fully understood. It may not interact with the GH receptor, which suggests it may engage with β3-adrenergic receptors or other unidentified pathways to stimulate energy metabolism and potentially increase energy expenditure.[2]

 

Mechanisms of Action

AOD 9604 peptide seems to activate several mechanisms involved in lipolysis, also referred to as lipolysis. These mechanisms might include both a direct stimulation of lipolysis in adipose cells (adipocytes) and an indirect increase in overall energy expenditure, potentially leading to greater calorie burn. One proposed mechanism is through modulating the expression of β3-adrenergic receptors (β3-AR), which are thought to be important receptors that promote lipolysis in adipose cells. AOD 9604 peptide appears to influence β3-AR mRNA expression, possibly increasing the sensitivity of adipocytes to signals that stimulate lipolysis.

In studies involving obese murine models, AOD 9604 peptide was suggested to increase lipolysis, which seemed to coincide with increased β3-AR mRNA expression. This observation suggests that AOD 9604 peptide might elevate levels of these receptors in adipocytes, potentially supporting the cells’ responsiveness to catecholamines, which are hormones that play a role in promoting lipolysis. In obese murine models, where β3-AR levels are generally reduced compared to lean mice, AOD 9604 appeared to restore β3-AR expression to levels similar to those seen in lean animals.

The role of β3-AR in the actions of AOD 9604 was further explored in studies using murine models lacking β3-AR (β3-AR knockout mice). In these knockout models, AOD 9604 did not result in increased lipolysis, unlike in normal (wild-type) models, which implies that β3-AR might be important for the chronic fat-reducing impacts of AOD 9604 peptide. However, in short-term experiments, AOD 9604 still seemed to increase energy expenditure and fat oxidation in the knockout murine models, although the potential was less pronounced compared to wild-type animals. This suggests that while β3-AR may play a significant role in the long-term lipolytic impacts of AOD 9604, the compound may also activate other β3-AR-independent pathways that influence energy metabolism and utilization of fat stores.[3]

 

Scientific and Research Studies

 

AOD 9604 Peptide and Lipolysis in Adipocytes

AOD 9604 peptide has been suggested to reduce adipose tissue accumulation by more than 50% in laboratory models, possibly by supporting the rate of lipolysis. Research suggests that the peptide may support lipolysis by about 23%.[4] This support is indicated by an increase in glycerol release, which serves as a marker of lipid breakdown. Researchers have linked this impact to the activation of hormone-sensitive lipase (HSL), a crucial enzyme responsible for breaking down stored triglycerides into free fatty acids and glycerol.

This action results in the reduction of adipocyte size. Additionally, it is proposed that AOD 9604 may also inhibit acetyl-CoA carboxylase, an enzyme involved in the synthesis of fatty acids. This suggests that AOD 9604 peptide not only promotes lipolysis but may also mitigate the formation of new fat, thus reducing overall fat storage. The researchers concluded that “The present findings reveal for the first time that the synthetic lipolytic domain [may be] capable of reducing weight gain” in experimental models.

Further research indicates that the impacts of AOD 9604 peptide on HSL and acetyl-CoA carboxylase may be linked to intracellular signaling pathways.[5] Studies have indicated that AOD 9604 induces a biphasic release of diacylglycerol (DAG) in fat cells, similar to the impacts of GH. This suggests that AOD 9604 might share some signaling mechanisms with the growth hormone. The production of DAG is associated with the activation of protein kinase C (PKC), which is believed to regulate both lipolysis and other metabolic processes involved in lipid management.

Another experiment also suggested that AOD 9604 peptide may have been associated with a significant rise in fat oxidation, particularly in obese murine models where a 216% increase in fat oxidation was observed. This suggests that AOD 9604 not only stimulates the breakdown of stored triglycerides and lipolysis but also facilitates the exposure of these liberated fatty acids to cells as an energy source, further decreasing lipid storage in adipocytes.[6]

 

AOD 9604 Peptide and Fat Storage in Adipocytes

As mentioned, AOD 9604 peptide may have anti-lipogenic impacts in isolated adipose tissues. In particular, studies with adipose tissue samples suggest that AOD 9604 may reduce the incorporation of glucose into lipid molecules, thus possibly decreasing the rate of de novo lipogenesis, which is the synthesis of fatty acids from non-lipid sources such as carbohydrates.[5]

In other words, the reduction in adipocytes of various sizes seen with AOD 9604 peptide in lab models may be due to a general suppression of lipid accumulation mechanisms. Specifically, the researchers reported that “A reduction in lipogenesis and a stimulation in lipolysis were observed. These alterations led to decreased rates of lipid storage and increased rates of lipid mobilization from adipose tissue. These changes, in turn, led to the size reduction in adipocyte cell size.” This outcome was reflected by the reduction of the number of large adipocytes and a shift toward smaller adipocytes.

Findings like this one suggest that AOD 9604 peptide may regulate hypertrophy in adipocytes (enlargement) by modulating both anabolic (constructive) and catabolic (destructive) processes of lipid metabolism. This combined action of promoting lipolysis while inhibiting lipogenesis is likely to lead to a net reduction in lipid content within adipocytes, contributing to a decrease in their overall size.

 

AOD 9604 Peptide and Other Research Objectives

Researchers have also explored the potential of AOD 9604 in models of osteoarthritis and its potential actions on tumor cells. For instance, one trial modeled AOD 9604 with and without hyaluronic acid (HA) in a collagenase-induced osteoarthritis model.[7] The morphological and histopathological scores, which indicate the extent of cartilage degeneration, were apparently lower in the AOD 9604 groups. The combination of AOD 9604 and HA indicated potentially synergistic actions. Specifically, the AOD 9604 peptide and HA group suggest reduced signs of cartilage degradation compared to the other groups.

This suggests that AOD 9604 peptide might influence cartilage through mechanisms similar to growth hormone by promoting proteoglycan and collagen production, though in a way that does not involve IGF-1. HA, believed to act as a chondroprotective agent, may also have supported these relevant impacts, possibly supporting the residence time of AOD 9604 in the joint or contributing to its bioactive properties. The study emphasized that while AOD 9604 suggested promise in supporting cartilage regeneration, the exact mechanisms by which it exerts these impacts are not well understood.

AOD 9604 peptide has displayed promising potential in increasing the potential of anti-cancer cell agents like doxorubicin’s ability to bind to critical breast tumor cell receptors such as the progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2).[8] These receptors are pivotal in the progression of these tumor cells, and better-supported binding suggests that doxorubicin may more impactfully target and interfere with cancer cell functions. By loading both AOD 9604 and doxorubicin into Chitosan nanoparticles, the study achieved a delivery system that supports doxorubicin’s potential.

In vitro studies on MCF-7 breast tumor cells indicated that the dual-loaded nanoparticles were more impactful in killing these cells than nanoparticles containing doxorubicin alone, as observed in data that displays comparatively lower IC50 values. The presence of AOD 9604 peptide may support how tumor cells take up doxorubicin or alter how similar agents interact inside the cells, leading to increased tumor cell death. By supporting delivery specifically to tumor cells, AOD 9604 may help reduce the off-target impacts of doxorubicin, minimizing damage to functional cells.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

  1. Isidro ML, Cordido F. Approved and Off-Label Uses of Obesity Medications, and Potential New Pharmacologic Treatment Options. Pharmaceuticals (Basel). 2010 Jan 12;3(1):125-145. doi: 10.3390/ph3010125. PMID: 27713245; PMCID: PMC3991023.
  2. Cox HD, Smeal SJ, Hughes CM, Cox JE, Eichner D. Detection and in vitro metabolism of AOD9604. Drug Test Anal. 2015 Jan;7(1):31-8. doi: 10.1002/dta.1715. Epub 2014 Sep 10. PMID: 25208511.
  3. Heffernan M, Summers RJ, Thorburn A, Ogru E, Gianello R, Jiang WJ, Ng FM. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice. Endocrinology. 2001 Dec;142(12):5182-9. doi: 10.1210/endo.142.12.8522. PMID: 11713213.
  4. Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000;53(6):274-8. doi: 10.1159/000053183. PMID: 11146367.
  5. Ng FM, Jiang WJ, Gianello R, Pitt S, Roupas P. Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats. J Mol Endocrinol. 2000 Dec;25(3):287-98. doi: 10.1677/jme.0.0250287. PMID: 11116208.
  6. Heffernan MA, Thorburn AW, Fam B, Summers R, Conway-Campbell B, Waters MJ, Ng FM. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes Relat Metab Disord. 2001 Oct;25(10):1442-9. doi: 10.1038/sj.ijo.0801740. PMID: 11673763.
  7. Kwon DR, Park GY. Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Ann Clin Lab Sci. 2015 Summer;45(4):426-32. PMID: 26275694.
  8. Habibullah MM, Mohan S, Syed NK, Makeen HA, Jamal QMS, Alothaid H, Bantun F, Alhazmi A, Hakamy A, Kaabi YA, Samlan G, Lohani M, Thangavel N, Al-Kasim MA. Human Growth Hormone Fragment 176-191 Peptide Enhances the Toxicity of Doxorubicin-Loaded Chitosan Nanoparticles Against MCF-7 Breast Cancer Cells. Drug Des Devel Ther. 2022 Jun 27;16:1963-1974. Doi: 10.2147/DDDT.S367586. PMID: 35783198; PMCID: PMC92493
Cardiogen Peptide: Studies on Cardiac Tissues and Cancerous Cells

Cardiogen Peptide: Studies on Cardiac Tissues and Cancerous Cells

Cardiogen (H-Ala-Glu-Asp-Arg-OH)[1] is a short peptide classified as a bioregulator, primarily recognized for its potential influence on fibroblasts—cells responsible for tissue repair and scar formation. While initial research focused on its possible implications within the context of cardiovascular diseases, recent research suggests that Cardiogen’s action may extend beyond the cardiovascular system, indicating potential implications in other tissues.

Research suggests that the peptide may modulate fibroblast activity, which is considered to play a critical role in tissue repair and the extracellular matrix’s structural integrity. In particular, Cardiogen seems to have garnered attention for its ability to influence both collagen and elastin synthesis, two key components required for maintaining tissue integrity.
 

Mechanisms of Action

Cardiogen’s primary mechanism of action appears to involve possible regulatory effects on fibroblasts and cardiomyocytes. By stimulating fibroblast activity, the peptide appears to promote the synthesis of extracellular matrix components such as collagen, thereby believed to facilitate tissue regeneration and repair.[2]
Interestingly, studies suggest that Cardiogen may modulate this fibroblast-driven tissue repair in multiple organs, and not only the cardiovascular system. Additionally, Cardiogen has been observed to possibly stimulate the proliferation of cardiac progenitor cells, leading to the regeneration of damaged myocardium, which may be crucial for restoring cardiac function.
In cardiovascular tissues, Cardiogen appears to support cardiomyocyte proliferation while inhibiting fibroblast-driven scar formation, a process deemed critical for mitigating adverse cardiac remodeling and heart failure in laboratory models. It may also downregulate p53 protein expression, potentially reducing apoptosis rates in cardiac cells and improving long-term outcomes in cardiovascular function.[3]

 

Scientific and Research Studies

 

Cardiogen Peptide and Cardiac Tissue Regeneration

Research indicates that Cardiogen may play a significant role in cardiac tissue regeneration by promoting the proliferation of cardiomyocytes while inhibiting the growth and maturation of fibroblasts. This combination of action may lead to reduced scar formation, potentially improving the long-term prospects for cardiac remodeling and potentially preventing the progression to heart failure.

Furthermore, preliminary data suggests that Cardiogen may suppress the expression of the p53 protein, which is associated with apoptosis, thereby reducing the rate of programmed cell death in myocardial tissue. As indicated by the researchers, “The immunohistochemical study [indicated] a decrease of the p53 protein expression by cardiogen action. This [may] testify that cardiogen inhibits the apoptosis process in the myocard tissue.”[3]

 

Cardiogen Peptide and Tumor Growth

Research suggests that the Cardiogen peptide may have differential effects on apoptosis regulation depending on the cell type. While it has been suggested to reduce apoptosis in cardiac cells by downregulating p53 expression, studies in rat models of M-1 sarcoma indicate that Cardiogen may potentially induce apoptosis in tumor cells. This effect appears to be concentration-dependent, underscoring its potential biological significance.[4]

In particular, research conducted by Drs. Levdik and Knyazkin, affiliated with the St. Petersburg Institute of Bioregulation and Gerontology and the Russian Academy of Medical Sciences, has provided insight into Cardiogen’s influence on tumor growth. Their study on the “tumor-modifying effect of Cardiogen peptide in rats with transplanted M-1 sarcoma” revealed that Cardiogen exposure may have led to a significant increase in apoptosis within tumor cells compared to control groups. The concentration-dependent inhibition of M-1 sarcoma growth was attributed to the development of hemorrhagic necrosis and the stimulation of tumor cell apoptosis.

 

Cardiogen Peptide and Prostate Explorations

In vitro research has indicated that Cardiogen, along with a group of similar peptides, may regulate the expression of key signaling factors in prostate fibroblasts. These signaling factors are considered to be critical in creating a favorable microenvironment within tumors and may play a significant role in the development and progression of prostate cancer. Scientific data indicates that alterations in the synthesis of these markers may occur in cellular aging and senescent fibroblasts, disrupting the paracrine interactions between epithelial and associated stromal fibroblasts. As per the researchers, “These studies represent an important first step towards a mechanistic elucidation of the role of aging in the etiology of benign and malignant prostatic diseases.”[5]

Studies in laboratory models suggest that Cardiogen has the potential to normalize or even support the levels of these signaling molecules in aging fibroblasts, aligning them with those found in youthful cell cultures. As per the study, “all the investigated peptides (including Cardiogen) possess the ability to actively enhance the expression of the above markers, whose synthesis significantly reduced in senescent cultures.”[6]

This finding implies that Cardiogen may not only aid in the prevention of prostate cancer but also in controlling its progression. According to research by O.V. Kheifets and colleagues, these studies pave the way for developing peptide-based studies aimed at exploring age-related dysfunctions of the prostate gland.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

  1. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 11583989, H-Ala-Glu-Asp-Arg-OH. https://pubchem.ncbi.nlm.nih.gov/compound/H-Ala-Glu-Asp-Arg-OH
  2. Khavinson VK, Popovich IG, Linkova NS, Mironova ES, Ilina AR. Peptide Regulation of Gene Expression: A Systematic Review. Molecules. 2021 Nov 22;26(22):7053. doi: 10.3390/molecules26227053. PMID: 34834147; PMCID: PMC8619776. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619776/
  3. Chalisova NI, Lesniak VV, Balykina NA, Urt’eva SA, Urt’eva TA, Sukhonos IuA, Zhekalov AN. [The effect of the amino acids and cardiogen on the development of myocard tissue culture from young and old rats]. Adv Gerontol. 2009;22(3):409-13. Russian. PMID: 20210190. https://pubmed.ncbi.nlm.nih.gov/20210190/
  4. Levdik NV, Knyazkin IV. Tumor-modifying effect of cardiogen peptide on M-1 sarcoma in senescent rats. Bull Exp Biol Med. 2009 Sep;148(3):433-6. English, Russian. doi: 10.1007/s10517-010-0730-9. PMID: 20396706. https://pubmed.ncbi.nlm.nih.gov/20396706/
  5. Begley L, Monteleon C, Shah RB, Macdonald JW, Macoska JA. CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro. Aging Cell. 2005 Dec;4(6):291-8. doi: 10.1111/j.1474-9726.2005.00173.x. PMID: 16300481. https://pubmed.ncbi.nlm.nih.gov/16300481/
  6. Kheĭfets OV, Poliakova VO, Kvetnoĭ IM. [Peptidergic regulation of the expression of signal factors of fibroblast differentiation in the human prostate gland in cell aging]. Adv Gerontol. 2010;23(1):68-70. Russian. PMID: 20586252. https://pubmed.ncbi.nlm.nih.gov/20586252/
Matrixyl Peptide: Potential Impacts on Cellular Aging and Wound Repair

Matrixyl Peptide: Potential Impacts on Cellular Aging and Wound Repair

Matrixyl, chemically recognized as palmitoyl pentapeptide-3 (later renamed palmitoyl pentapeptide-4),[1] is a synthetic lipopeptide composed of a fatty acid conjugated to a short chain of amino acids. Containing 5 amino acids (Lys-Thr-Thr-Lys-Ser-OH or KTTKS-OH), this peptide has a fatty acid portion that is speculated to support its lipid solubility, thereby potentially supporting ability to penetrate the stratum corneum and reach the dermal and epidermal layers.[2]

Matrixyl peptide is suggested to function as an active ingredient in advanced research formulations, particularly the ones synthesized for anti-aging studies. Structurally, it is considered an isomer, meaning that it shares the same molecular formula as other peptides but exhibits distinct atomic arrangements. The primary bioactive component within Matrixyl, often referred to as “Micro-collagen,” is said to mimic the endogenous peptides that signal dermal repair, which has made Matrixyl a significant agent in dermal regeneration research.

Matrixyl has been developed through dermatological investigations focused on two key areas: the acceleration of wound healing and the mechanisms responsible for wrinkle formation.[2] Over time, the dermatological ability to produce collagen, elastin, and fibronectin declines, resulting in a loss of structural integrity, elasticity, and hydration. Matrixyl, through its biochemical interactions, appears to restore these critical components of the stratum corneum, thus potentially contributing to the rejuvenation of the epidermal layer.

 

Mechanisms of Action

Matrixyl’s primary mechanism of action is suggested to be based on its hypothesized ability to promote the synthesis of extracellular matrix components, particularly collagen and fibronectin, within the dermal layer.[2] The peptide interacts with fibroblasts, the key cells responsible for producing and remodeling the extracellular matrix. Research suggests that when exposed to Matrixyl, fibroblasts are stimulated via receptor-mediated signaling pathways, thereby enhancing their capacity to synthesize collagen, glycosaminoglycans (e.g., hyaluronic acid), and other relevant proteins.

The molecular action of Matrixyl is often compared to that of copper peptides, which also are frequently considered to stimulate dermatologic regeneration processes. However, Matrixyl uniquely activates a cascade of signaling events via a receptor-binding process that mimics the endogenous breakdown products of collagen. When collagen degrades, peptides called matrikines are released, which bind to receptors on fibroblasts, triggering the repair and remodeling of the stratum corneum matrix. Matrixyl appears to act similarly to these matrikines, particularly affecting collagen types I and IV. This stimulation may lead to increased production of these collagen types, which play essential roles in maintaining firmness and elasticity.[3]

Moreover, the pentapeptide sequence (KTTKS) in Matrixyl is critical for its biological activity. The attached palmitoyl moiety serves as a lipid delivery system, allowing the peptide to penetrate the stratum corneum more thoroughly than water-soluble peptides. As a result, Matrixyl appears to support collagen synthesis, particularly type I collagen, which is the most abundant in the stratum corneum and provides structural support.[3]

The peptide also appears to stimulate the production of fibronectin, a glycoprotein involved in cell adhesion and wound healing. Thus, it further reinforces the epidermal layer’s extracellular matrix. This comprehensive support of skin structure and function contributes to its wrinkle-reducing impacts.

 

Scientific and Research Studies

 

Matrixyl Peptide and Collagen Synthesis

In vitro studies have highlighted Matrixyl’s potential role in stimulating collagen synthesis.

One key study conducted on cultured fibroblasts revealed a substantial upregulation of collagen production following Matrixyl introduction by transmitting signals to fibroblasts and reportedly stimulating “feedback regulation of new collagen synthesis and ECM proteins.”[4]

This research suggests that Matrixyl may significantly support the dermal layer’s ability to maintain its structural proteins, thereby potentially mitigating the visible impacts of cellular aging that impacts the stratum corneum. Further clinical studies support this data, showing that the implication of Matrixyl-containing formulations on research models led to measurable increases in collagen type I, the principal collagen form responsible for maintaining firmness.[5] Collagen type I contributes to the epidermal layer’s tensile strength, and its synthesis is deemed critical for counteracting the thinning and fragility associated with cellular aging of skin cells.

Research has also indicated Matrixyl’s specific influence on collagen type IV synthesis. Collagen type IV appears to play a vital role in forming the basement membrane, which separates the epidermis from the dermis and supports overall skin structure. In a study evaluating the impacts of Matrixyl on dermal cells, collagen type IV synthesis appeared to increase significantly.

These findings indicate that Matrixyl might be a significant factor in reinforcing the structural layers of the dermis, potentially improving dermal resilience and reducing the depth of wrinkles.

 

Matrixyl Peptide and Wound Healing

Matrixyl’s origin is rooted in wound healing research, where it was initially explored for its potential to accelerate tissue repair.

In the cellular aging process, fibroblasts gradually lose their efficiency in generating new collagen, which may lead to delayed wound closure and compromise the integrity of the stratum corneum. As per the research, Matrixyl peptide “had a larger impact on wound healing compared to that in the positive control group,” suggesting that the peptide stimulates the fibroblast activity, showing potential in promoting the repair of damaged dermal and epidermal cells.[2]

In another study,[6] the potential influence of Matrixyl on fibroblast contractility and its role in scar formation was closely examined. The findings indicated that Matrixyl might functionally downregulate the expression of α-smooth muscle actin (α-SMA) and inhibit the trans-differentiation of fibroblasts into myofibroblasts. α-SMA is a protein predominantly expressed in smooth muscle cells, such as those found in blood vessels and visceral organs like the intestines and bladder. Myofibroblasts, a specialized cell type associated with wound healing and tissue repair, also express it.

In the context of fibrotic scarring, the upregulation of α-SMA in myofibroblasts is associated with increased collagen deposition, leading to the formation of excessive scar tissue. Matrixyl’s hypothetical ability to modulate α-SMA expression suggests its potential to limit myofibroblast differentiation, thereby reducing excessive collagen accumulation. This highlights its promise in attenuating fibrotic scarring and enhancing epidermal healing outcomes.

 

Matrixyl Peptide and Anti-Wrinkle Studies

In a notable clinical trial[7] involving 93 female research models aged 35 to 55, the impacts of Matrixyl-infused moisturizer were compared to a placebo over 12 weeks. Matrixyl was applied to one side of the participants’ faces, while the placebo was applied to the other side. Results observed by researchers indicated that the Matrixyl-introduced group appeared to exhibit a significant reduction in both wrinkles and fine lines compared to the placebo group.

Periorbital wrinkles are a common biomarker associated with cellular aging, often resulting from repetitive movement of muscular tissue and the endogenous loss of elasticity in the stratum corneum. In a clinical study[8] focusing on 21 female research models with visible periorbital creasing, Matrixyl, other peptides, and placebo were introduced exogenously to the periorbital area twice daily for eight weeks. Results suggested that the Matrixyl-introduced group appeared to significantly outperform both the groups introduced with placebo and other peptides.

Another investigation explored Matrixyl’s efficacy in improving overall epidermal smoothness and reducing the depth of periorbital wrinkles. This double-anonymized, randomized, controlled split-face study involved women aged 30 to 70 with moderate to severe periorbital wrinkles. After four weeks, participants in the Matrixyl-introduced group appeared to show more support for a reduction in wrinkle depth.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

  1. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 58942400, Palmitoyl Pentapeptide-4. https://pubchem.ncbi.nlm.nih.gov/compound/Palmitoyl-Pentapeptide-4.
  2. Kachooeian M, Mousivand Z, Sharifikolouei E, Shirangi M, Firoozpour L, Raoufi M, Sharifzadeh M. Matrixyl Patch vs Matrixyl Cream: A Comparative In Vivo Investigation of Matrixyl (MTI) Effect on Wound Healing. ACS Omega. 2022 Jul 11;7(28):24695-24704. doi: 10.1021/acsomega.2c02592. PMID: 35874243; PMCID: PMC9301720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301720/
  3. Jones RR, Castelletto V, Connon CJ, Hamley IW. Collagen stimulating effect of peptide amphiphile C16-KTTKS on human fibroblasts. Mol Pharm. 2013 Mar 4;10(3):1063-9. doi: 10.1021/mp300549d. Epub 2013 Feb 4. PMID: 23320752. https://pubmed.ncbi.nlm.nih.gov/23320752/
  4. Errante, F., Ledwoń, P., Latajka, R., Rovero, P., & Papini, A. M. (2020). Cosmeceutical Peptides in the Framework of Sustainable Wellness Economy. Frontiers in chemistry, 8, 572923. https://doi.org/10.3389/fchem.2020.572923
  5. Robinson LR, Fitzgerald NC, Doughty DG, Dawes NC, Berge CA, Bissett DL. Topical palmitoyl pentapeptide provides an improvement in photoaged human facial skin. Int J Cosmet Sci. 2005 Jun;27(3):155-60. doi: 10.1111/j.1467-2494.2005.00261.x. PMID: 18492182. https://pubmed.ncbi.nlm.nih.gov/18492182/
  6. Park H, An E, Cho Lee AR. Effect of Palmitoyl-Pentapeptide (Pal-KTTKS) on Wound Contractile Process in Relation to Connective Tissue Growth Factor and α-Smooth Muscle Actin Expression. Tissue Eng Regen Med. 2017 Jan 19;14(1):73-80. https://link.springer.com/article/10.1007/s13770-016-0017-y
  7. Robinson, L. R., Fitzgerald, N. C., Doughty, D. G., Dawes, N. C., Berge, C. A., & Bissett, D. L. (2005). Topical palmitoyl pentapeptide provides an improvement in photoaged human facial skin. International journal of cosmetic science, 27(3), 155–160. https://doi.org/10.1111/j.1467-2494.2005.00261.x
  8. Aruan, R. R., Hutabarat, H., Widodo, A. A., Firdiyono, M. T. C. C., Wirawanty, C., & Fransiska, L. (2023). Double-blind, Randomized Trial on the Effectiveness of Acetylhexapeptide-3 Cream and Palmitoyl Pentapeptide-4 Cream for Crow’s Feet. The Journal of clinical and aesthetic dermatology, 16(2), 37–43. https://pubmed.ncbi.nlm.nih.gov/36909866/
  9. Kaczvinsky, J. R., Griffiths, C. E., Schnicker, M. S., & Li, J. (2009). Efficacy of anti-aging products for periorbital wrinkles as measured by 3-D imaging. Journal of cosmetic dermatology, 8(3), 228–233. https://doi.org/10.1111/j.1473-2165.2009.00444.x
Lipopeptide Research in Skin Cells and Extracellular Matrix Components

Lipopeptide Research in Skin Cells and Extracellular Matrix Components

Lipopeptide (aka Palmitoyl hexapeptide-12 or Pal-VGVAPG) is a synthetic peptide derived from a fragment of the protein called elastin. Specifically, its peptide sequence is repeated several times in various forms of elastin, including tropoelastin. The peptide comprises a chain that includes the amino acids valine, glycine, alanine, proline, and glycine in the following sequence: valine-glycine-valine-alanine-proline-glycine (VGVAPG).[1] In addition to this sequence, Lipopeptide is also palmitoylated. The inclusion of palmitic acid within the Lipopeptide structure is thought to support increased penetration to the deeper layers of various structures made of skin cells.

This peptide is posited to play a role in modulating fibroblast activity, possibly by interacting with specific receptors on the fibroblast membrane. Its mechanism is not fully understood, but research suggests it may stimulate the production of collagen and glycosaminoglycans while decreasing the synthesis of elastin, with chemotactic activity and metalloproteinase upregulation properties.[2][3]

 

Mechanisms of Action

Lipopeptide may interact with fibroblasts, which are the primary cells responsible for producing key components of the extracellular matrix, such as elastin, collagen, glycosaminoglycans (like hyaluronan), proteoglycans, fibronectin, and laminin. In particular, Lipopeptide is believed to upregulate the production of collagen while suppressing elastin production.[4] Collagen is a major protein believed to provide strength and resilience in connective tissues such as the skin. The reduction in elastin may be due to negative feedback regulation related to the sequence of Lipopeptide, which is a repetitive sequence found in the structure of elastin fibers like tropoelastin.[2]

Tropoelastin is considered to be a soluble precursor protein to elastin, an essential component of the extracellular matrix that provides elasticity to various tissues, such as skin, lungs, arteries, and ligaments. Further, researchers report that “The present study clearly [indicated] that the hexapeptide VGVAPG stimulated skin fibroblast proliferation.[2] Thus, in addition to possibly regulating the function of fibroblast cells, Lipopeptide is also studied for its potential to upregulate the production of new fibroblast cells. Researchers are also investigating if Lipopeptide may interact with the function of the pigment-producing skin cells called melanocytes and the production of inflammatory molecules by fibroblasts in different conditions.

 

Scientific and Research Studies

 

Lipopeptide and Skin Fibroblasts

Lipopeptide is believed to act as a chemoattractant for fibroblasts, guiding these cells, as well as immune cells such as monocytes, to areas where repair or regeneration may be necessary. Specifically, the VGVAPG sequence is considered to be a key sequence driving the chemotactic activity. Researchers also posit that the interaction of VGVAPG with fibroblasts may not only encourage cell migration but potentially plays a role in tissue remodeling processes. Further, studies suggest that the responsiveness of fibroblasts to VGVAPG is apparently dependent on their differentiation status. Specifically, undifferentiated fibroblasts, which are incapable of producing elastin, do not appear to exhibit chemotaxis toward VGVAPG or other elastin-derived peptides. However, upon exposure to extracellular matrix material and subsequent induction of elastin synthesis, these cells become responsive, indicating that the ability to synthesize elastin might be necessary for fibroblast chemotaxis toward VGVAPG, which allows the peptide to attract only mature and functional cells.[5]

Another study suggests that thanks to its VGVAPG sequence, Lipopeptide appears to potentially stimulate the proliferation of fibroblasts. The mechanism of action is suggested to involve a binding event between VGVAPG and unknown plasmalemmal receptors on the fibroblast cells’ membranes. Although the exact receptor has not been fully characterized, it is hypothesized that this binding initiates a signaling cascade that results in fibroblast proliferation. The study implies that there is a lag phase observed before proliferation which may depend on the initial fibroblast density, suggesting that the response to VGVAPG might be density-dependent. Moreover, when fibroblasts are exposed to VGVAPG, they possibly undergo morphological changes, becoming more elongated. This might imply that VGVAPG not only stimulates proliferation but may also potentially influence the cellular architecture of fibroblasts under these conditions.[6]

 

Lipopeptide and Skin Inflammation Markers

Lipopeptides have been proposed to modulate the production of proinflammatory mediators by skin cells, including interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8), which may, in turn, slow the degradation of the skin’s extracellular matrix.[7] In particular, some in vitro studies suggest that lipopeptides might reduce IL-6 production in keratinocytes, the primary cell type of the epidermis, and in fibroblasts. IL-6 is suggested to be a key regulator of inflammation, a necessary biological response for cell repair following injury or stress. However, excessive or prolonged IL-6 production has been linked to chronic inflammation, which may contribute to the breakdown of the skin’s structural integrity. This is thought to occur through the stimulation of matrix metalloproteinases (MMPs), a group of enzymes that degrade extracellular matrix proteins like collagen and elastin. Overactivation of MMPs, particularly under conditions such as skin cell exposure to ultraviolet (UV) radiation, may lead to diminished skin tissue elasticity, reduced firmness, and other visible signs of skin cell aging. By potentially modulating IL-6 levels, Lipopeptide may influence MMP activity and thus play a role in maintaining the structural integrity of the skin’s extracellular matrix. This reduction in MMP-mediated degradation may hypothetically help preserve collagen and elastin, which are considered essential for skin cell integrity as well as tissue elasticity and resilience.[8][9]

 

Lipopeptide and Skin Pigmentation

Lipopeptide has been posited to interact with melanocytes by modulating melanogenesis-related pathways. A study suggests that Lipopeptide has been “identified as major inhibitors of melanogenesis based on their gene expression profiles.” Specifically, it may downregulate the expression of multiple melanogenic genes in melanocytes. This downregulation may potentially influence critical proteins involved in melanogenesis, such as MITF (microphthalmia-associated transcription factor), tyrosinase, and dopachrome tautomerase. These proteins are essential for the regulation of melanin production, and their inhibition might lead to decreased melanin synthesis.

Additionally, Lipopeptide possibly exerts its actions through the phosphorylation of ERK, which may contribute to the degradation of MITF, leading to reduced melanogenic activity. The gene expression studies in melanocytes showed a notable downregulation of these pathways after exposure to Lipopeptide, suggesting a direct interaction that might decrease melanin production in melanocytes. Furthermore, an in vitro melanogenic model suggested that Lipopeptide apparently resulted in a marked decrease in melanin production, as detailed by absorbance readings indicating reduced melanin content.[10] Interventional studies of Lipopeptide on skin cell aging have also suggested that this peptide may have increased skin structure firmness by 20% and improved epidermal tone by 33 % compared to controls.[9]

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

  1. Resende, D. I. S. P., Ferreira, M. S., Sousa-Lobo, J. M., Sousa, E., & Almeida, I. F. (2021). Usage of Synthetic Peptides in Cosmetics for Sensitive Skin. Pharmaceuticals (Basel, Switzerland), 14(8), 702. https://doi.org/10.3390/ph14080702
  2. Tajima, S., Wachi, H., Uemura, Y., & Okamoto, K. (1997). Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Archives of dermatological research, 289(8), 489–492. https://doi.org/10.1007/s004030050227
  3. Errante, F., Ledwoń, P., Latajka, R., Rovero, P., & Papini, A. M. (2020). Cosmeceutical peptides in the framework of sustainable wellness economy. Frontiers in chemistry, 8, 572923.
  4. Husein El Hadmed, H., & Castillo, R. F. (2016). Cosmeceuticals: peptides, proteins, and growth factors. Journal of cosmetic dermatology, 15(4), 514–519. https://doi.org/10.1111/jocd.12229
  5. Senior, R. M., Griffin, G. L., Mecham, R. P., Wrenn, D. S., Prasad, K. U., & Urry, D. W. (1984). Val-Gly-Val-Ala-Pro-Gly, a repeating peptide in elastin, is chemotactic for fibroblasts and monocytes. The Journal of cell biology, 99(3), 870–874. https://doi.org/10.1083/jcb.99.3.870
  6. Kamoun, A., Landeau, J. M., Godeau, G., Wallach, J., Duchesnay, A., Pellat, B., & Hornebeck, W. (1995). Growth stimulation of human skin fibroblasts by elastin-derived peptides. Cell adhesion and communication, 3(4), 273–281. https://doi.org/10.3109/15419069509081013
  7. Ngoc, L. T. N., Moon, J. Y., & Lee, Y. C. (2023). Insights into bioactive peptides in cosmetics. Cosmetics, 10(4), 111.
  8. Schagen, S. K. (2017). Topical peptide treatments with effective anti-aging results. Cosmetics, 4(2), 16.
  9. Veiga, E., Ferreira, L., Correia, M., Pires, P. C., Hameed, H., Araújo, A. R., … & Paiva-Santos, A. C. (2023). Anti-aging peptides for advanced skincare: focus on nanodelivery systems. Journal of Drug Delivery Science and Technology, 105087.
  10. Widgerow, A., Wang, J., Ziegler, M., Fabi, S., Garruto, J., Robinson, D., & Bell, M. (2022). Advances in Pigmentation Management: A Multipronged Approach. Journal of drugs in dermatology : JDD, 21(11), 1206–1220. https://doi.org/10.36849/JDD.7013
Kisspeptin-10 Peptide: Neuroprotection, Hormonal and Reproductive Regulation

Kisspeptin-10 Peptide: Neuroprotection, Hormonal and Reproductive Regulation

Kisspeptin-10, an endogenously occurring peptide, is derived from the KISS1 gene. The original 145-amino acid polypeptide undergoes proteolytic cleavage to yield a smaller peptide comprised of 54 amino acids. This 54-amino acid peptide is further processed into Kisspeptin 45-54, commonly referred to as Kisspeptin-10.[1,2]

The KISS1 gene has been identified as a potential suppressor of metastasis in melanomas and breast carcinomas. This may suggest potential impacts on the inhibition of abnormal cell proliferation.[1] Initially recognized for its potential in metastasis suppression, subsequent research proposed that Kisspeptin-10 may hypothetically impact the hypothalamus and pituitary gland. This may imply some impact on the regulation of systems related to reproduction. Independent studies conducted in the mid-2000s suggest it may be possible for Kisspeptin-10 to be involved in hypogonadotropic hypogonadism. This may be particularly true in its capacity as a ligand for the G-protein coupled receptor 54 (GPR54).[3]

 

Mechanism of Action

Hypogonadotropic hypogonadism is characterized by inadequate or absent sex hormone production. This may be due to dysfunction in the pituitary gland, hypothalamus, or other parts of the brain. Gonadotropin-releasing hormone (GnRH) is considered to play a pivotal role in stimulating the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are integral to various reproductive functions. Deficiencies in GnRH, FSH, and LH are identified as key contributors to hypogonadotropic hypogonadism.[4]

The GPR54 receptor also referred to as the KISS1 receptor (KISS1R), has been identified as a critical GnRH receptor.[4] Kisspeptin-10 is hypothesized to bind to GPR54 receptors, which may potentially activate the reproductive axis through the stimulation of GnRH and gonadotropin neurons.[5]

Research has isolated smaller peptide fragments, such as Kisspeptin-10, Kisspeptin-13, and Kisspeptin-14, which may exhibit biological activity towards GPR54. These peptides are proposed to bind with low affinity to GPR54 receptors, which may induce calcium mobilization, arachidonic acid release, and extracellular protein kinase phosphorylation. Such events may eventually lead to the depolarization of Kisspeptin-10 neurons and may ultimately contribute to gonadotropin release.

Ongoing research has posited several potential mechanisms of action for Kisspeptin-10. This includes the peptide’s possible role in stimulating GnRH release. The peptide may support endogenous gonadotropin release in animal models with reduced fertility. Also, the peptide may induce desensitization and suppression of the hypothalamus-pituitary-gonadal axis under certain conditions.[6]

 

Scientific and Research Studies

 

Kisspeptin-10 Peptide and Delayed Hormonal Development

The primary aim of this referenced scientific study[7] was to investigate the observed impacts of Kisspeptin-10 peptide in research models with delayed hormonal development.

In this study, researchers hypothesized that Kisspeptin-10 may stimulate gonadal hormone release and modulate reproductive function in laboratory test models. The study involved the random introduction of either Kisspeptin-10 or gonadotropin-releasing hormone (GnRH) to the test models.

Luteinizing hormone (LH) levels were monitored overnight following the introduction. Subsequently, all test models were exposed to GnRH for six days, after which LH levels were re-evaluated. The results observed by researchers indicated that 47% of the experimental group exposed to Kisspeptin-10 exhibited increased LH levels. An additional 6% of the group exhibited an intermediate response, while the remaining 47% indicated no change after exposure to the peptide.

 

Kisspeptin-10 Peptide and Reproductive Regulation

A comprehensive literature review conducted in 2017 examined articles published between 1999 and 2016. This review suggested that experimental data might support the hypothesis that the Kisspeptin-10 system—including the KISS1 gene and its associated GPR54 receptors—might potentially regulate the release of gonadotropin hormones. Researchers suggest that “Kisspeptin or its receptor represents a potential therapeutic target in… [test models] with fertility disorders.”[8]

Studies conducted on experimental animal models suggested that reproductive disorders like HH and PCOS might be linked to abnormalities within the KISS1 and GPR54 systems. The findings of this literature review indicated that Kisspeptin-10 may potentially function as a neuropeptide regulator of GnRH release.

 

Kisspeptin-10 Peptide and Reproductive Hormone Release

The objective of the study[9] was to explore the potential influence of Kisspeptin-10 on the secretion of reproductive hormones. Kisspeptin-10 was introduced to both male and female test models. The findings indicate that in male test models, exposure to the peptide may lead to an elevation in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. In contrast, female test models did not exhibit significant changes in FSH and LH levels throughout the menstrual cycle. Comparatively, there was a notable increase in the hormone levels of observed female test models during the preovulatory phase.

 

Kisspeptin-10 and Its Influence on Food Intake

Kisspeptin-10 appears to be widely distributed across various brain regions, including the hippocampus, cerebellum, posterior hypothalamus, and septum. Its presence in key nuclei involved in food intake regulation, such as the arcuate nucleus (Arc) within the hypothalamus, prompted an investigation into its potential impacts on the feeding behavior of murine test models.

An experiment[10] involving adult male murine models, aged 6 to 8 weeks and maintained under standard conditions, assessed the impact of Kisspeptin-10 on food intake. Following an overnight fast, the murine models were exposed to varying concentrations of Kisspeptin-10 or a placebo alongside a standard rodent diet and water.

Results from this study suggest that Kisspeptin-10 introduction in overnight-fasted mice led to a reduction in caloric intake during the initial 3-to-12-hour period. However, caloric intake reportedly increased during the subsequent 12-to-16-hour period, eventually aligning with levels observed in the placebo group of laboratory test models. This suggests that Kisspeptin-10 may “be a negative central regulator of feeding by increasing satiety.” Scientists observed that exposure to the peptide may lead to increased intervals between periods of calorie consumption without significant change to caloric intake.

Further research[11] has explored Kisspeptin-10’s potential impacts on caloric intake regulation within the central nervous system (CNS). Investigations have suggested that the peptide may influence the expression of genes associated with neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). Additionally, Kisspeptin-10 may affect neurotransmitter concentrations, including dopamine, norepinephrine, serotonin (5-hydroxytryptamine or 5-HT), dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid in hypothalamic cells (specifically Hypo-E22 cells). Observations indicate that Kisspeptin-10 might support NPY gene expression while suppressing BDNF expression.

The peptide also appears to reduce serotonin and dopamine levels, with norepinephrine concentrations remaining stable. Notably, this reduction in dopamine and serotonin was accompanied by increased ratios of their metabolites—dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin—following Kisspeptin-10 exposure. The observed changes in NPY and BDNF expression, coupled with alterations in serotonin activity, may suggest a potential role for Kisspeptin-10 in influencing hunger hormone signaling.

 

Kisspeptin-10 and Emotional Impacts

The study aimed to investigate the impacts of Kisspeptin-10 on limbic brain activity.[12] Neuroimaging and psychometric assessments were employed to analyze the impact of Kisspeptin-10 exposure in research models. The findings suggest that Kisspeptin-10 may have influenced limbic brain function, with data suggesting heightened responsiveness to mating and bonding stimuli.

 

Kisspeptin-10 and Neuroprotection

The accumulation of amyloid-beta (Aβ) and alpha-synuclein (α-syn) in cholinergic neurons is associated with damage and dysfunction in critical central nervous system structures. It is hypothesized that Kisspeptin-10 may bind to extracellular Aβ, potentially mitigating its harmful impacts. Studies[13] indicate that Kisspeptin-10 may counteract the detrimental actions of Aβ, prion protein (PrP), and Islet Amyloid Polypeptide (IAPP) without interference from antagonists of the kisspeptin receptor (GPR-54) or the neuropeptide FF (NPFF) receptor. The similarity between the non-amyloid-β component (NAC) of α-syn and the C-terminus of Aβ raises the possibility that Kisspeptin-10 might also reduce α-syn-induced toxicity in cholinergic neurons.

Research[14] involving cholinergic cells suggests that while high concentrations of Kisspeptin-10 may increase toxicity, lower concentrations might decrease toxicity associated with both wild-type and E46K mutant forms of α-syn. Computational studies support these findings, and some suggest a potentially significant interaction between Kisspeptin-10 and the C-terminal residues of α-syn. Molecular dynamics simulations indicate that the complexes formed between Kisspeptin-10 and α-syn indicate substantial stability.

Further investigation[15] has focused on whether GPR54 activation is crucial for Kisspeptin-10’s ability to bind to the C-terminal regions of α-syn. One study observed choline acetyltransferase (ChAT)-positive SH-SY5Y neurons, genetically modified to express either wild-type or E46K mutant α-syn, to evaluate the impact of Kisspeptin-10 on neuronal damage through flow cytometry and immunocytochemistry.

Some findings suggest that Kisspeptin-10 may reduce both apoptosis and mitochondrial damage in neurons affected by α-syn, with its protective impacts remaining unaffected by the presence of a GPR54 antagonist, kisspeptin-234 (KP-234). This implies that GPR54 activation might not be necessary for Kisspeptin-10’s neuroprotective impacts. Additionally, Kisspeptin-10 appears to lower the levels of α-syn and ChAT in neurons overexpressing both wild-type and E46K mutant α-syn.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

  1. KISS1 KiSS-1 metastasis suppressor [Homo sapiens (humans)]. https://www.ncbi.nlm.nih.gov/gene/3814
  2. Mead EJ, Maguire JJ, Kuc RE, Davenport AP. Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer, and the cardiovascular system. Br J Pharmacol. 2007 Aug;151(8):1143-53. doi: 10.1038/sj.bjp.0707295. Epub 2007 May 21. PMID: 17519946; PMCID: PMC2189831. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189831/
  3. Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1761-6. doi: 10.1073/pnas.0409330102. Epub 2005 Jan 21. PMID: 15665093; PMCID: PMC545088. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545088/
  4. Hypogonadotropic hypogonadism. US National Library of Medicine. https://medlineplus.gov/ency/article/000390.htm
  5. Rønnekleiv OK, Kelly MJ. Kisspeptin excitation of GnRH neurons. Adv Exp Med Biol. 2013;784:113-31. doi: 10.1007/978-1-4614-6199-9_6. PMID: 23550004; PMCID: PMC4019505. target=”_blank” rel=”noopener”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019505/
  6. Prague JK, Dhillo WS. Potential Clinical Use of Kisspeptin. Neuroendocrinology. 2015;102(3):238-45. doi: 10.1159/000439133. Epub 2015 Aug 7. PMID: 26277870. https://pubmed.ncbi.nlm.nih.gov/26277870/
  7. 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
  8. Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The Role of Kisspeptin in Female Reproduction. Int J Endocrinol Metab. 2017 Apr 22;15(3):e44337. doi: 10.5812/ijem.44337. PMID: 29201072; PMCID: PMC5702467. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702467/
  9. Comninos AN, Wall MB, Demetriou L, Shah AJ, Clarke SA, Narayanaswamy S, Nesbitt A, Izzi-Engbeaya C, Prague JK, Abbara A, Ratnasabapathy R, Salem V, Nijher GM, Jayasena CN, Tanner M, Bassett P, Mehta A, Rabiner EA, Hönigsperger C, Silva MR, Brandtzaeg OK, Lundanes E, Wilson SR, Brown RC, Thomas SA, Bloom SR, Dhillo WS. Kisspeptin modulates sexual and emotional brain processing in humans. J Clin Invest. 2017 Feb 1;127(2):709-719. doi: 10.1172/JCI89519. Epub 2017 Jan 23. PMID: 28112678; PMCID: PMC5272173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272173/
  10. 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/
  11. Orlando G, Leone S, Ferrante C, Chiavaroli A, Mollica A, Stefanucci A, Macedonio G, Dimmito MP, Leporini L, Menghini L, Brunetti L, Recinella L. s 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321454/
  12. Chan YM, Lippincott MF, Kusa TO, Seminara SB. Divergent responses to kisspeptin in children with delayed puberty. JCI Insight. 2018 Apr 19;3(8):e99109. doi: 10.1172/jci.insight.99109. PMID: 29669934; PMCID: PMC5931121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931121/
  13. 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. https://pubmed.ncbi.nlm.nih.gov/23019497/
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  16. Image Source: https://pubchem.ncbi.nlm.nih.gov/compound/Kisspeptin-10