Analogous to adenosine monophosphate (AMP), a fundamental nucleotide pivotal in cellular energy metabolism, AICAR (short for 5-aminoimidazole-4-carboxamide ribonucleotide)^[1] has garnered attention for its potential in various realms of scientific inquiry.

A significant aspect of AICAR’s potential lies in its ability to potentially reduce reperfusion injury following tissue ischemia and to potentially improve metabolic disorders. The key to how it works seems to lie in its activation of AMP-activated protein kinase (AMPK), an enzyme that plays a vital role in many metabolic processes inside cells. AMPK’s job involves bringing the cell’s energy back into balance by controlling processes that either use up energy (like making proteins and fats) or produce energy (like breaking down glucose and fats).^[1] By slowing down energy-consuming processes and speeding up energy-producing ones, AMPK is considered to help cells generate more ATP, the energy currency of cells.

Moreover, the influence of AMPK extends beyond mere energy regulation, encompassing pivotal cellular processes including autophagy, mitochondrial biogenesis, and inflammatory modulation. Due to its potential to activate AMPK, AICAR peptide offers possible pathways to increase the uptake of glucose in skeletal muscle, improve sensitivity to insulin, and enhance tolerance to glucose. Additionally, scientists are considering its anti-inflammatory potential and the possibility of improving physical performance in certain experimental conditions. As such, the interplay between AICAR peptide and AMPK unveils several possibilities, requiring further investigation into its multifaceted roles.

AICAR Peptide and Organ Protection

Researchers suggest peptide may exhibit promise in conferring organ-protective impacts, particularly concerning ischemia and reperfusion injury. Initial investigations suggest that AICAR may attenuate myocardial infarction size and enhance cardiac function in an animal model subjected to myocardial ischemia-reperfusion injury.^[2]

Notably, a meta-analysis encompassing data from five randomized, placebo-controlled, double-blind studies^[3] further explored AICAR’s potential in cardiovascular contexts. The analysis indicated that peptide exposure may have been associated with reductions in myocardial tissue infarction size and cardiac cell death, potentially leading to improved overall outcomes. This protective potential of peptide is suggested by researchers to stem from its influence on cellular metabolism, possibly rendering cells more resilient to hypoxic conditions by upregulating energy availability, notably myocardial glucose. Experimental data from murine models suggests that AICAR, through AMPK activation, “may participate in the control of glycogen metabolism.” Furthermore, AICAR exposure was correlated with elevated levels of 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranotide (ZMP), its active intracellular form. Although AICAR did not appear to notably impact the activity of glycogen synthase (GS) or glycogen phosphorylase (GP) in tissue homogenates, it seemingly facilitated glycogenolysis through allosteric activation of GP, potentially providing an alternative energy substrate during cellular stress.^[4]

Beyond its cardioprotective potential, research suggests that peptide “appears to protect the liver from fatty changes associated with chronic alcohol [exposure]” as observed in experimental murine models. Chronic ethanol exposure typically induces histological and biochemical changes indicative of fatty liver. However, AICAR intervention appeared to have attenuated these alterations, potentially by downregulating hepatic sterol regulatory element-binding protein 1c (SREBP-1c) expression and reducing fatty acid synthase (FAS) enzyme activity. SREBP-1c, a key regulator of lipid metabolism primarily in hepatic tissues, is considered by scientists to modulate the expression of genes involved in cholesterol, fatty acid, and triglyceride synthesis. Consequently, the observed decrease in SREBP-1c levels following peptide exposure likely contributes to diminished fatty acid synthesis. Meanwhile, FAS, a pivotal enzyme in fatty acid biosynthesis, appears to be regulated by SREBP-1c, further implicating AICAR in attenuating hepatic lipid accumulation.^[5]

AICAR and Physical Activity

AICAR peptide has garnered considerable attention by researchers in studies in the realm of physical endurance, with researchers hypothesizing its potential to activate key metabolic pathways to improve and increase activity. Specifically, studies suggest that AICAR may activate enzymes such as AMPK, glycogen phosphorylase, and fructose-1,6-bisphosphatase, leading to potential enhancements in oxidative metabolism and the creation of new mitochondria, a process known as mitochondrial biogenesis.^[6] The augmentation of mitochondrial quantity and function is suggested to confer benefits to muscle endurance. For instance, experimental data indicates that AICAR exposure in sedentary murine models appeared to have resulted in a substantial improvement in running endurance, potentially attributable to the induction of metabolic genes. These findings imply that peptides may modulate the AMPK-PPARδ pathway to facilitate training adaptations or augment endurance capacity without the need for physical exercise.^[7]

PPARδ, short for Peroxisome Proliferator-Activated Receptor Delta, represents a class of nuclear receptors implicated in the regulation of genes associated with energy metabolism. It is hypothesized that PPARδ may influence processes such as lipid oxidation and mitochondrial biogenesis. The AMPK-PPARδ pathway is proposed as a conduit between the energy-sensing function of AMPK and the gene regulatory role of PPARδ. Activation of this pathway potentially induces adaptations in muscle cells akin to those induced by prolonged physical activity, including heightened mitochondrial content and a shift in muscle fiber composition towards endurance-oriented fibers, thereby potentially augmenting endurance capacity.

Further experiments in murine models have provided additional insights into the potential of peptide in augmenting endurance.^[8] Notably, the introduction of an AMP-activated protein kinase agonist appeared to have resulted in increased endurance compared to controls. Additionally, in a murine model of Duchenne muscular dystrophy, AICAR appeared to have the potential to enhance the effects of physical activity and muscle function, possibly through the stimulation of autophagy.

Moreover, investigations into the vascular effects of peptide have revealed intriguing findings. Infusion of AICA-riboside, a precursor of AICAR, was associated with correlated increases in forearm blood flow, potentially mediated by nitric oxide. This suggests a potential dual role for AICAR in improving muscle blood flow and acting as a nitric oxide booster, both of which are critical factors in prolonged physical activity.^[9]

AICAR Peptide and Insulin Sensitivity

Research suggests that AICAR may enhance the insulin sensitivity of various tissues by activating AMPK within cells, thereby facilitating glucose uptake. In an experimental model focusing on equine skeletal muscle, AICAR exposure appeared to lead to a decrease in glucose levels and an increase in insulin concentration, while lactate concentration remained unaffected. Notably, AICAR potentially augmented the ratio of phosphorylated to total AMPK in skeletal muscle and may have upregulated GLUT8 protein expression. The observed elevation in GLUT8 protein expression could potentially enhance glucose transport into cells, consequently improving insulin sensitivity.

Moreover, a study^[10] investigating AICAR’s impact on muscle glucose uptake alongside physical activity revealed a potential increase in glucose uptake in muscle tissue. This effect might extend beyond muscle tissue, potentially enhancing peripheral and overall insulin sensitivity. Researchers also proposed that peptide might elevate the phosphorylation of extracellular signal-regulated kinase 1/2, enzymes crucial in the MAP kinase/ERK pathway, which regulates cellular processes like division, differentiation, and stress response.

Furthermore, investigations suggest that AICAR may potentially decrease hepatic glucose output, lower glucose concentrations, promote hepatic fatty acid oxidation, and inhibit lipolysis, consequently reducing plasma-free fatty acid availability.^[11] Although no increase in AMPK phosphorylation was reported in skeletal muscle, a significant rise in acetyl-CoA carboxylase phosphorylation was observed. This enzyme is considered to play a pivotal role in fatty acid metabolism, catalyzing the conversion of acetyl-CoA to malonyl-CoA, a critical step in fatty acid synthesis. The apparent inactivation of acetyl-CoA carboxylase is speculated to stimulate “hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.”

AICAR Peptide and Cellular Apoptosis

Data from research studies suggests that peptide may instigate programmed cell death, known as apoptosis, in test models of B-cell chronic lymphocytic leukemia (B-CLL).

Specifically, one study^[12] posits that this phenomenon might entail the activation of specific enzymes involved in apoptosis, including caspase-3, -8, and -9, alongside the release of cytochrome C. Furthermore, the incubation of B-CLL cells with AICAR appears to stimulate the phosphorylation of AMP-activated protein kinase (AMPK), indicating the potential of peptide in activating this protein. Investigation into the cellular mechanisms underlying AICAR-induced apoptosis explored the necessity of AICAR’s entry into the cell and its subsequent conversion to AICA ribotide (ZMP). This inquiry employed various inhibitors, such as Nitrobenzylthioinosine (NBTI), 5-iodotubercidin, and adenosine, which were hypothesized to impede AICAR-induced apoptosis and AMPK phosphorylation. Interestingly, inhibitors targeting protein kinase A and mitogen-activated protein kinases did not seem to hinder AICAR-induced apoptosis in B-CLL cells.

Moreover, the study observed that peptide did not appear to have significantly impacted the levels or phosphorylation of p53, suggesting a mechanism of apoptosis independent of p53 activation in B-CLL cells. A comparative analysis of the sensitivity of normal B lymphocytes, T cells, and B-CLL cells to AICAR-induced apoptosis appeared to reveal similar susceptibility between normal B lymphocytes and B-CLL cells, with T cells from B-CLL subjects displaying only marginal sensitivity. Notably, the phosphorylation of AMPK was not observed in T cells exposed to AICAR. Furthermore, upon AICAR exposure, B-CLL cells appeared to have exhibited higher intracellular levels of ZMP compared to T cells, implying that the accumulation of ZMP may play a pivotal role in activating AMPK and prompting apoptosis in these 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. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 65110, AICA ribonucleotide https://pubchem.ncbi.nlm.nih.gov/compound/AICA-ribonucleotide.
2. 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
3. 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
4. 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
5. 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
6. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185962/
7. 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
8. Goodyear, L. J. (2008). The exercise pill—too good to be true? New England Journal of Medicine, 359(17), 1842-1844. https://www.nejm.org/doi/abs/10.1056/NEJMcibr0806723
9. 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
10. 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
11. 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
12. 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

Growth Hormone Releasing Peptide-2 (GHRP-2), also known as pralmorelin, stands as a synthetic peptide reportedly designed to mimic the actions of ghrelin,^[1] an endogenous peptide considered to be crucial in various physiological processes. Ghrelin, initially discovered in stomach tissues and comprised of 28 amino acids, is considered by scientists to play pivotal roles in regulating food intake, growth hormone release, and wound healing.^[2]

GHRP-2, the pioneer among growth hormone secretagogues, has been suggested by researchers to operate by binding to the ghrelin/growth hormone secretagogues receptor, thereby triggering the secretion of growth hormone.

Additionally, studies conducted in bovine models have indicated potential multifaceted impacts of GHRP-2, suggesting its involvement in stimulating growth hormone secretion via interactions with growth hormone release factor receptors, calcium channels, and signaling pathways like the cAMP pathway and protein kinase C activation.^[3]

These mechanisms are speculated to collectively contribute to the elevation of growth hormone levels, implicating GHRP-2 as a promising agent in various physiological contexts.

GHRP-2 Peptide and Growth Hormone (GH) Deficiency

Existing conventional procedures to identify growth hormone (GH) deficiency may involve testing insulin tolerance; however, they may potentiate adverse effects and contradictions. To address these limitations, one investigation^[4] sought to evaluate the utility of Growth Hormone Releasing Peptide-2 (GHRP-2) as an alternative diagnostic for GH deficiency in laboratory settings.

The researchers conducted initial testing of the research model via ITT. Blood samples were collected and analyzed after a 2-hour interval. Results indicated a consistent peak in GH levels one hour post-GHRP-2 exposure. However, a marginal decrease in efficacy was observed in certain models of obesity or advanced age. The study results suggest the diagnostic potential of GHRP-2 in severe GH deficiency research, acknowledging minor influences from age and adiposity levels.

In a separate study^[3], the diagnostic efficacy of GHRP-2 compared to conventional compounds often studied in conjunction with growth hormone deficiency (GHD) was explored. Research models of GHD, having undergone exposure with at least one conventional medication, were subjects of this study. The researchers suggested that additional exposure to GHRP-2 may have acted as a reliable predictor of the pituitary gland’s capacity to release GH, a feature not reported with the conventional compounds in isolation.

GHRP-2 Peptide and Caloric Intake

In a controlled experimental setting,^[6] researchers attempted to investigate the impact of Growth Hormone Releasing Peptide-2 (GHRP-2) on food consumption. An experimental research model group was exposed to GHRP-2, compared to a separate control group exposed to saline over a 4.5-hour period. Subsequently, researchers monitored food intake. Results indicated a notable increase in food consumption among the GHRP-2 group, exhibiting a mean increase of approximately 36% compared to the saline group.

These findings suggest the possible action of GHRP-2 in stimulating appetite, as indicated by the substantial increase in food consumption observed in the experimental group. Moreover, the concurrent rise in GH levels further underlies the hypothetical physiological action of GHRP-2 in regulating appetite and metabolism.

General Action

Numerous investigations^[5] conducted on animals elucidate the potential impacts of GHRP-2 peptide. In both rabbits and guinea pigs, the exposure of GHRP-2 appears to exhibit no discernible effects on the central nervous system. Notably, apart from a modest increase in the motility of the isolated rabbit ileum and enhanced contraction of the isolated guinea pig ileum at higher GHRP-2 concentrations, no other significant effects were observed. Moreover, GHRP-2 exposure reportedly may not elicit alterations in the respiratory, digestive, renal, and circulatory systems. As per the researchers, the peptide “has no serious general [effects] at [concentration] levels showing GH-releasing activity in the experimental animals,” and the peptide is speculated to support the diagnosis of “serious GH deficiency and short stature.”^[5]

Combination Studies with TRH and GnRH

A research study^[7] aimed to assess the effects of GHRP-2, Thyrotropin Releasing Hormone (TRH), and Gonadotropin Releasing Hormone (GnRH) alone and in various combinations on research models of prolonged hyposomatotropism, hypogonadism, or hypothyroid complications.

Over the course of five days, the researchers evaluated the action of three compounds: placebo, GHRP-2 alone every hour, GHRP-2 and TRH every hour, and GHRP-2, TRH, and GnRH every 90 minutes. Serum samples were collected on the first and last nights of the study period for analysis.

Analysis of the results suggests that the combination of GHRP-2, GnRH, and TRH elicited the most pronounced activation of growth hormone, thyroid stimulating hormone, and luteinizing hormone axes, accompanied by potential metabolic effects. Conversely, the effects observed with GHRP-2 alone were reported to be minimal, and even the combination of GHRP-2 and TRH appeared to only partially induce similar effects compared to the triple combination regimen.

These findings underscore the potential synergistic action of GHRP-2 with GnRH and TRH in eliciting robust hormonal responses in experimental settings.

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. Garcia JM, Merriam GR, Kargi AY. Growth Hormone in Aging. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext. South Dartmouth (MA): MDText.com. https://www.ncbi.nlm.nih.gov/books/NBK279163/
2. GHRP 2, GPA 748, Growth Hormone-Releasing Peptide 2, KP-102 D, KP-102 LN, KP-102D, KP-102 LN. https://link.springer.com/article/10.2165/00126839-200405040-00011#
3. Asad Rahim, Stephen M. Shalet, in Growth Hormone Secretagogues, 1999. Does desensitization to growth hormone secretagogues occur? https://www.sciencedirect.com/topics/medicine-and-dentistry/pralmorelin
4. Roh SG, He ML, Matsunaga N, Hidaka S, Hidari H. Mechanisms of action of growth hormone-releasing peptide-2 in bovine pituitary cells. J Anim Sci. 1997 Oct;75(10):2744-8. doi: 10.2527/1997.75102744x. PMID: 9331879. https://pubmed.ncbi.nlm.nih.gov/9331879/
5. Furuta S, Shimada O, Doi N, Ukai K, Nakagawa T, Watanabe J, Imaizumi M. General pharmacology of KP-102 (GHRP-2), a potent growth hormone-releasing peptide. Arzneimittelforschung. 2004;54(12):868-80. doi: 10.1055/s-0031-1297042. PMID: 15646371. https://pubmed.ncbi.nlm.nih.gov/15646371/
6. Laferrère, Blandine et al. Growth hormone releasing peptide-2 (GHRP-2), like ghrelin, increases food intake in healthy men. The Journal of clinical endocrinology and metabolism vol. 90,2 (2005): 611-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824650/
7. Van den Berghe G, Baxter RC, Weekers F, Wouters P, Bowers CY, Iranmanesh A, Veldhuis JD, Bouillon R. The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone. Clin Endocrinol (Oxf). 2002 May;56(5):655-69. doi: 10.1046/j.1365-2265.2002.01255.x. PMID: 12030918. https://pubmed.ncbi.nlm.nih.gov/12030918/
8. Image source: National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 6918245, Pralmorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Pralmorelin.

Comprising the amino acids arginine, lysine, methionine, phenylalanine, proline, tryptophan, and valine, Nonapeptide-1 first emerged in the 1990s as a subject of scientific inquiry, primarily for its proposed capacity to impede melanin synthesis. Melanin is a primary pigment in mammals governing skin, fur, hair, and ocular coloration. Despite initial interest, the understanding of Nonapeptide-1 remains rudimentary, with many aspects of its mechanisms and potential yet to be elucidated.

Research on Nonapeptide-1 has concentrated on its putative role in melanin production inhibition by disrupting the signaling cascade intrinsic to melanogenesis. Specifically, investigations suggest that Nonapeptide-1 may interfere with melanocortin-1 receptor function, potentially impeding the action of melanocyte-stimulating hormones and hindering the activation of tyrosinase, an essential enzyme in melanin synthesis. Preliminary animal studies indicate a possible attenuation of hyperpigmentation and modulation of skin tone with Nonapeptide-1 exposure. However, comprehensive investigations are imperative to grasp the peptide’s complete potential.

Mechanism of Action

Nonapeptide-1, at a technical level, appears to exhibit capacity as a melanin synthesis inhibitor, reportedly achieved through interference with the action of tyrosinase. Tyrosinase, the principal enzyme governing melanin synthesis within specialized cells termed melanocytes, is considered crucial for pigment production. Nonapeptide-1’s apparent interference with tyrosinase function appears to impede melanocyte pigment production.^[2,3]

Consequently, through this mechanism, researchers suggest that Nonapeptide-1 may demonstrate potential in animal studies to diminish skin pigmentation, thereby ameliorating hyperpigmented areas caused by sun exposure and certain pathologies.

Emerging scientific data also suggests that Nonapeptide-1 may exert its effects by modulating the activity of melanocyte-stimulating hormone (MSH). MSH levels elevate during specific physiological states such as pregnancy, certain disorders (e.g., diabetes, Addison’s disease), and excessive sun exposure. MSH, derived from adrenocorticotropic hormone, is considered to play a pivotal role in skin pigmentation regulation. Synthetic analogs of MSH, like melanotan II, has been proposed to mimic its effects and induce skin darkening. Intriguingly, the responsiveness to MSH appears to vary; with some research models exhibiting apparent diminished responsiveness due to genetic variations in MSH receptors, resulting in inadequate MSH-mediated effects on melanocytes.

Nonapeptide-1 and Dermal Pigmentation

Research into the potential effects of Nonapeptide-1 has been conducted in both clinical and laboratory environments. In a particular in vitro investigation, keratinocyte cell line (HaCaT) cells and epidermal melanocytes (HEM) were subjected to UVA exposure and then introduced with varying concentrations of the acetate salt of Nonapeptide-1.^[4]

Examinations of cell viability, melanin content, and tyrosinase activity were carried out. The findings suggested that Nonapeptide-1 exhibited the capability to downregulate melanocortin 1 receptor expression without impacting α-MSH levels. Moreover, it appeared to significantly diminish the expression of tyrosinase, TRP1 (tyrosinase-related protein-1), TRP2 (tyrosinase-related protein-2), and MITF (microphthalmia-associated transcription factor), both in the presence and absence of concurrent UVA radiation. Additionally, the researchers proposed that cells exposed to Nonapeptide-1 displayed potential to resist melanin production.

Recent investigations into Nonapeptide-1 hypothesize a noticeable skin lightening effect, estimated to be at least 33%, with indications of continued lightening over time.^[5]

The sole clinical trial on this subject was a prospective double-blinded parallel-group randomized controlled pilot study spanning eight months and comprising three phases.^[6] Researchers reported an observable amelioration in severity scores of melasma and mean melanin index. As per the researchers, “The melasma area and severity index score showed a consistent reduction in the case group, whereas it increased in the control group from baseline.”

Nonapeptide-1 Future Research

In addition to melanocytes, Nonapeptide-1 may potentially target melanocortin-1 receptors expressed in various cell types, including nerve and immune cells. Specifically, these receptors have been identified in the periaqueductal gray matter, a region pivotal in nociception.^[7]

Experiments conducted on mice with heightened expression of an endogenous melanocortin 1 receptor antagonist, in comparison to control mice, shed light on their responses to both painful and non-painful stimuli, as well as their reactions to inflammatory and neuropathic pain. Furthermore, their aversion to capsaicin, which activates the TRPV1 noxious heat receptor, was assessed using a paired preference paradigm.

Mice exhibiting elevated levels of the melanocortin 1 receptor antagonist showcased a diminished inflammatory pain response, slower onset of inflammation-induced hypersensitivity and allodynia, and reduced aversion to moderate capsaicin concentrations. Notably, these effects were discernible solely in female mice, with no “effect of mutant genotype on neuropathic pain” on mice of either sex.^[8]

Moreover, investigations suggest a potential involvement of melanocortin 1 receptors in the proliferation and survival of melanoma tumor cells.^[9] Melanoma may exhibit alterations in risk associated with mutations in the melanocortin 1 receptor gene. In a pertinent study, researchers inhibited melanocortin 1 receptors utilizing natural inhibitors, resulting in diminished melanin synthesis and morphological heterogeneity in murine B16-F10 melanoma cells. Notably, this inhibition correlated with decelerated tumor cell growth and enhanced uniformity in tumor size and morphology.

The findings underscore the potential significance of melanocortin 1 receptors in governing melanoma growth and morphology, suggesting that sustained inhibition of these receptors might impede the growth rate of tumor cells expressing them. It is noteworthy that Nonapeptide-1’s impact on melanoma tumor cells remains unexplored.

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. Ishihara Y, Oka M, Tsunakawa M, Tomita K, Hatori M, Yamamoto H, Kamei H, Miyaki T, Konishi M, Oki T. Melanostatin, a new melanin synthesis inhibitor. Production, isolation, chemical properties, structure and biological activity. J Antibiot (Tokyo). 1991 Jan;44(1):25-32. doi: 10.7164/antibiotics.44.25. PMID: 1672125. https://pubmed.ncbi.nlm.nih.gov/1672125/
2. MelanostatineTM 5 – Lucas Meyer Cosmetics – datasheet. Available at: http://cosmetics.specialchem.com/product/i-lucas-meyer-cosmetics-melanostatine-5
3. Abu Ubeid A, Zhao L, Wang Y, Hantash BM. Short-sequence oligopeptides with inhibitory activity against mushroom and human tyrosinase. J Invest Dermatol. 2009 Sep;129(9):2242-9. doi: 10.1038/jid.2009.124. Epub 2009 May 14. PMID: 19440221. https://pubmed.ncbi.nlm.nih.gov/19440221/
4. Chen, J., Li, H., Liang, B., & Zhu, H. (2022). Effects of tea polyphenols on UVA-induced melanogenesis via inhibition of α-MSH-MC1R signalling pathway. Postepy dermatologii i alergologii, 39(2), 327–335. https://doi.org/10.5114/ada.2022.115890
5. Mohammed, Y. H., Moghimi, H. R., Yousef, S. A., Chandrasekaran, N. C., Bibi, C. R., Sukumar, S. C., Grice, J. E., Sakran, W., & Roberts, M. S. (2017). Efficacy, Safety and Targets in Transdermal Active and Excipient Delivery. Percutaneous Penetration Enhancers Drug Penetration Into/Through the Skin: Methodology and General Considerations, 369–391. https://doi.org/10.1007/978-3-662-53270-6_23
6. Chatterjee, M., Neema, S., & Rajput, G. R. (2021). A randomized controlled pilot study of a proprietary combination versus sunscreen in melasma maintenance. Indian journal of dermatology, venereology and leprology, 88(1), 51–58. https://doi.org/10.25259/IJDVL_976_18
7. Xia Y, Wikberg JE, Chhajlani V. Expression of melanocortin 1 receptor in periaqueductal gray matter. Neuroreport. 1995 Nov 13;6(16):2193-6. doi: 10.1097/00001756-199511000-00022. PMID: 8595200. https://pubmed.ncbi.nlm.nih.gov/8595200/
8. Delaney, A., Keighren, M., Fleetwood-Walker, S. M., & Jackson, I. J. (2010). Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin. PloS one, 5(9), e12498. https://doi.org/10.1371/journal.pone.0012498
9. Kansal, R. G., McCravy, M. S., Basham, J. H., Earl, J. A., McMurray, S. L., Starner, C. J., Whitt, M. A., & Albritton, L. M. (2016). Inhibition of melanocortin 1 receptor slows melanoma growth, reduces tumor heterogeneity and increases survival. Oncotarget, 7(18), 26331–26345. https://doi.org/10.18632/oncotarget.8372

Both Ipamorelin and CJC-1295 peptides are grouped within this category, investigated for their supposed similar physiological effects, although they appear to differ primarily in their half-life and pharmacokinetic properties.

CJC-1295 Peptide

CJC-1295 peptide represents a tetra-substituted derivative of growth hormone-releasing hormone (GHRH) 1-29, devised to mimic the shortest functional sequence of GHRH. GHRH 1-29 encompasses the initial 29 amino acids of the native GHRH peptide and holds the potential to stimulate growth hormone production within somatotrophs, the pituitary gland cells. The peptide undergoes four amino acid substitutions, strategically positioned within its structure, which researchers hypothesize may bolster its activity and resilience against proteolytic degradation. Specifically, the substitutions are situated at the 2nd, 8th, 15th, and 27th amino acid positions.

These alterations potentially enable the peptide to covalently bind to blood albumin, with incidental interactions possibly occurring with fibrinogen and immunoglobulin G (IgG). Consequently, the reported half-life of the peptide may possibly extend from 10 minutes to approximately 30 minutes.^[3] This elongated half-life may culminate in heightened levels of plasma growth hormone and insulin-like growth factor 1 (IGF-1).

Furthermore, CJC-1295 is speculated to incorporate a “drug affinity complex” (DAC) component, which may associate with plasma proteins. Specifically, the DAC element within CJC-1295 pertains to the attachment of N-epsilon-3-maleimidopropionamide derivative of lysine at the C-terminal end. By amalgamating the tetra-substituted amino acid chain with the DAC element, CJC-1295 may exhibit improved pharmacokinetic properties while preserving a comparable affinity to the GHRH receptors within the pituitary gland, akin to endogenous GHRH.^[4]

Ipamorelin Peptide

Ipamorelin is a synthetically engineered pentapeptide believed to interact with the growth hormone secretagogues receptor (GHS-R1a) situated in pituitary gland cells. These receptors, primarily localized in the hypothalamus, are commonly referred to as ghrelin receptors due to the apparent affinity of ghrelin as their primary endogenous ligand. Ipamorelin distinguishes itself among other growth hormone secretagogues (GHSs) as a potentially more selective compound. It is hypothesized to selectively stimulate the release of growth hormone (GH) levels from somatotroph cells without concomitant elevation of other hormones produced by the anterior pituitary gland, such as prolactin.

When the peptide blend, also denoted as the peptide stack, is introduced in combination, studies indicate that Ipamorelin typically initiates first action, purported exhibiting discernible impact within the initial two hours of exposure. Subsequently, as the Ipamorelin effect diminishes, the CJC-1295 peptide may progressively contribute to the alleged physiological actions.^[5]

CJC-1295 & Ipamorelin Peptide Blend and Growth Hormone Levels

In a clinical trial^[6] conducted in the early 2000s, research subjects were allocated into two groups: one receiving a placebo and the other exposed to CJC-1295 peptide. Blood samples taken before and after the peptide exposure revealed a substantial increase, approximately 7.5-fold, in growth hormone pulsatility levels in the CJC-1295 group compared to the placebo group. Additionally, beyond its apparent influence on growth hormone synthesis, CJC-1295 reportedly “caused an increase in total pituitary RNA and GH mRNA, suggesting that proliferation of somatotroph cells had occurred, as [noted] by immunohistochemistry images.”

The underlying mechanisms of CJC-1295’s potential reportedly involve its interaction with specific binding sites on the growth hormone-releasing hormone (GHRH) receptor protein, possibly triggering conformational changes and initiating intracellular signaling cascades.^[7] This interaction is speculated to activate G-proteins, which, in turn, may lead to the generation of secondary messengers like cyclic adenosine monophosphate (cAMP) or inositol trisphosphate (IP3). These messengers further modulate cellular activities through protein kinases, ultimately influencing gene expression associated with growth hormone production.

Conversely, researchers suggest that Ipamorelin interacts with the N-terminus of the growth hormone secretagogue receptor (GHS-R1a) in anterior pituitary gland cells, forming non-permanent attachments through intermolecular forces such as hydrogen bonds and van der Waals forces. This interaction may potentially induce conformational changes in the receptor, initiating cell signaling pathways primarily involving G-proteins, notably Gαq/11.^[8] Activation of GHS-R1a may potentially trigger the activation of phospholipase C (PLC), leading to the production of secondary messengers like IP3 and diacylglycerol (DAG). IP3 release may lead to calcium ion (Ca2+) release from the endoplasmic reticulum, while DAG activates protein kinase C (PKC), ultimately facilitating the release of growth hormone from pituitary gland cells.^[9]

These findings suggest the intricate molecular mechanisms through which CJC-1295 and Ipamorelin may potentially modulate growth hormone secretion, providing valuable insights into their possible physiological effects.

Comparative Mechanisms of Action

Research investigations have been undertaken to ascertain the half-life and individual mechanistic actions of the two peptides – Ipamorelin and CJC-1295.

In a 1990s study^[5] with a concentration-escalation design, the levels of growth hormones were systematically monitored following each presentation of the peptides. The study’s findings suggested a singular episode of growth hormone release, reaching its zenith at 0.67 hours, followed by an exponential decline, supposedly due to negligible concentrations. This investigation concluded that Ipamorelin appears to exhibit a short half-life of approximately 2 hours, with potential actions tapering off thereafter.

In contrast, CJC-1295 was suggested to host a notably protracted half-life. Researchers noted that a single introduction of the peptide appeared to have led to sustained upregulation of growth hormone production by somatotrophs, purportedly contributing to an overall increase in growth hormone secretion by 46%. Another publication reported potential increases in growth hormone concentrations by “2- to 10-fold” and estimated the half-life of CJC-1295 to range between 5.8 to 8.1 days.^[11]

Ipamorelin & CJC-1295 Peptide Blend and Lean Mass

The interaction between CJC-1295 and Ipamorelin in stimulating growth hormone production by somatotroph cells in the anterior pituitary gland appears to yield a synergistic effect, potentially resulting in a positive nitrogen balance and increased lean mass in experimental models. A study^[11] aimed to elucidate the metabolic potential of Ipamorelin focused on hepatic markers associated with alpha-amino-nitrogen processing during artificially-induced catabolism.

Researchers investigated the liver’s capacity to produce urea-N (CUNS), serving as an indicator of nitrogen processing within the organ. They assessed the mRNA levels associated with enzymes of the urea cycle, evaluated overall nitrogen equilibrium, and estimated nitrogen distribution across various organs. Ipamorelin exposure was hypothesized to lead to a notable 20% reduction in CUNS compared to the catabolic state induced experimentally. Additionally, it was suggested that Ipamorelin might decrease the expression of urea cycle enzymes, restore nitrogen equilibrium, and potentially modulate nitrogen levels in organs.

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. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998 Nov;139(5):552-61. doi: 10.1530/eje.0.1390552. PMID: 9849822. https://pubmed.ncbi.nlm.nih.gov/9849822/
2. Lucie Jette et al, hGRF1-29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long Lasting GRF Analog, ResearchGate, January 2005. https://www.researchgate.net/publication/228484039
3. The Discovery of Growth Hormone-Releasing Hormone: An Update https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2826.2008.01740.x
4. Jetté, L., Léger, R., Thibaudeau, K., Benquet, C., Robitaille, M., Pellerin, I., Paradis, V., van Wyk, P., Pham, K., & Bridon, D. P. (2005). Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology, 146(7), 3052–3058. https://doi.org/10.1210/en.2004-1286
5. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999 Sep;16(9):1412-6. doi: 10.1023/a:1018955126402. PMID: 10496658. https://pubmed.ncbi.nlm.nih.gov/10496658/
6. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. doi: 10.1210/jc.2006-1702. Epub 2006 Oct 3. PMID: 17018654. https://pubmed.ncbi.nlm.nih.gov/17018654/
7. Martin, B., Lopez de Maturana, R., Brenneman, R., Walent, T., Mattson, M. P., & Maudsley, S. (2005). Class II G protein-coupled receptors and their ligands in neuronal function and protection. Neuromolecular medicine, 7(1-2), 3–36. https://doi.org/10.1385/nmm:7:1-2:003
8. Yin, Y., Li, Y., & Zhang, W. (2014). The growth hormone secretagogue receptor: its intracellular signaling and regulation. International journal of molecular sciences, 15(3), 4837–4855. https://doi.org/10.3390/ijms15034837
9. Bill, C. A., & Vines, C. M. (2020). Phospholipase C. Advances in experimental medicine and biology, 1131, 215–242. https://doi.org/10.1007/978-3-030-12457-1_9
10. Martin, B., Lopez de Maturana, R., Brenneman, R., Walent, T., Mattson, M. P., & Maudsley, S. (2005). Class II G protein-coupled receptors and their ligands in neuronal function and protection. Neuromolecular medicine, 7(1-2), 3–36. https://doi.org/10.1385/nmm:7:1-2:003
11. Aagaard, N. K., Grøfte, T., Greisen, J., Malmlöf, K., Johansen, P. B., Grønbaek, H., Ørskov, H., Tygstrup, N., & Vilstrup, H. (2009). Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 19(5), 426–431. https://doi.org/10.1016/j.ghir.2009.01.001

Protirelin Essential Functions

Researchers suggested that Protirelin may mimic the characteristics of naturally-occurring thyrotropin-releasing hormone (TRH). TRH is considered the first well-characterized hypothalamic peptide and has been studied as a neuroendocrine element. This peptide appears to be widely distributed in different brain regions, alluding to its analogs’ potential within the context of conditions such as brain and spinal injuries, as well as CNS disorders like schizophrenia, Alzheimer’s disease, epilepsy, amyotrophic lateral sclerosis, Parkinson’s disease, depression, shock, and ischemia.

Protirelin appears to stimulate the release of thyroid-stimulating hormone from the anterior pituitary. Additionally, it may potentially also increase prolactin release. The peptide has been suggested to increase TSH levels rapidly, peaking, then proceeding to decline more slowly, returning to baseline levels after about three hours.

Scientific Studies on Protirelin

Research teams have evaluated the potential impacts of Protirelin in the context of spinocerebellar degeneration (SCD). This disease is manifested as a group of progressive neurodegenerative disorders affecting the spinal cord and cerebellum, vital central nervous system components. Research models of SCD ultimately exhibit a decline in motor function. The potential efficacy of the peptide within the context of SCD was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Data from both these scoring matrices may indicate the effectiveness of Protirelin in ameliorating SCD.^[1]

Thyrotropin releasing hormone (TRH), the smallest peptide hormone, is considered to exhibit central effects beyond its endocrine potential by acting on the pituitary-thyroid axis. It has been suggested to hold potential within the context of various neurological disorders, including intractable epilepsy. Research has been conducted to evaluate this peptide within the context of conditions like West syndrome, Lennox-Gastaut syndrome, and myoclonic epilepsy. Protirelin’s hypothetically prolonged action suggests a unique anticonvulsant mechanism, potentially influencing the seizure network’s plasticity.^[2]

Case Studies of Protirelin

In a randomized, single-blind, placebo-controlled study, research models of chronic upper motoneuron syndrome due to ischemic cerebrovascular lesions were exposed to a Protirelin tartrate. A semiquantitative assessment was used to identify a homogenous sample population, focusing on weakness and spasticity and neurophysiological evaluations (F-waves, magnetic motor evoked potentials). Results suggested a statistically significant absolute improvement in spasticity and muscular strength following the Protirelin tartrate, particularly in the lower limbs. The compound also exhibited supposedly favorable modifications in the response of the biceps femoris muscle to transcranial magnetic stimulation, including reappearance, increased amplitude, and a reduction in the motor-evoked potential threshold.^[3]

Exposure of L-pyroglutamyl-L-histidyl-L-prolinamide (protirelin) to research models of amyotrophic lateral sclerosis (ALS), appeared to result in an improvement in functions associated with a deficiency in both lower motor neurons (weakness) and upper motor neurons (spasticity). This improvement appeared to be sustained during the infusion and persisted for about 1 hour post-infusion, with occasional slight improvements even 20 hours later. The mechanism by which Protirelin may produce this action, whether by replacing an ALS-associated deficiency or acting as a symptomatic supplement, remains uncertain. This study suggests the potential of further TRH study within the context of ALS, and offers insights into its potential pathogenesis, opening avenues for further exploring this biomolecule.^[4]

Researchers hypothesize that Protirelin is also involved in elevating prolactin plasma levels, which may potentially influence sexual drive and function. As such, elevation in prolactin with Protirelin may contribute to modulating central nervous system centers regulating sexual drive and behavior.^[7]

Conclusions

Protirelin is a synthetic analog of the TRH neuropeptide. As outlined above, researchers speculate that the peptide’s impact may be diverse, the most prominent being neuroprotective potential in several neurodegenerative diseases. This peptide appears to be widely distributed in the hypothalamus region and may potentially manifest mitigatory action in refractory epilepsy, amyotrophic lateral sclerosis, motoneuron syndrome, and spinocerebellar degeneration.^[8]

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. Yoshida A, Yamanishi Y, Tada S, Miyaue N, Ando R, Nagai M. Comparison of therapeutic effectiveness with SARA and iCARS using protirelin for spinocerebellar degeneration’s patients. Neurological Therapeutics. 2022;39(5):803-807. doi:10.15082/jsnt.39.5_803
2. Takeuchi Y. Thyrotropin-Releasing Hormone (Protirelin). CNS Drugs. 1996;6:341–350. https://doi.org/10.2165/00023210-199606050-00001
3. Civardi C, Naldi P, Cantello R, Gianelli M, Mutani R. Protirelin tartrate (TRH-T) in upper motoneuron syndrome: a controlled neurophysiological and clinical study. Ital J Neurol Sci. Nov 1994;15(8):395-406. doi:10.1007/BF02339903, PMID: 7875957, https://pubmed.ncbi.nlm.nih.gov/7875957/
4. Engel WK, Siddique T, Nicoloff JT. Effect on weakness and spasticity in amyotrophic lateral sclerosis of thyrotropin-releasing hormone. Lancet. Jul 9 1983;2(8341):73-5. doi:10.1016/s0140-6736(83)90060-0, PMID: 6134961, https://pubmed.ncbi.nlm.nih.gov/6134961/
5. Eandi M, Signorile F, Rubinetto MP, Genazzani E. [Evaluation of the efficacy and tolerability of protirelin. Results of a multicenter study in Italy]. Ann Ital Med Int. Jul-Sep 1990;5(3 Pt 2):270-8. Valutazione dell’efficacia e tollerabilita della protirelina. Risultati di uno studio policentrico in Italia. PMID: 2127689, https://pubmed.ncbi.nlm.nih.gov/2127689/
6. Marangell LB, George MS, Callahan AM, Ketter TA, Pazzaglia PJ, L’Herrou TA, Leverich GS, Post RM. Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients. Arch Gen Psychiatry. Mar 1997;54(3):214-22. doi:10.1001/archpsyc.1997.01830150034007, PMID: 9075462, https://pubmed.ncbi.nlm.nih.gov/9075462/
7. Kruger TH, Haake P, Haverkamp J, Kramer M, Exton MS, Saller B, Leygraf N, Hartmann U, Schedlowski M. Effects of acute prolactin manipulation on sexual drive and function in males. J Endocrinol. Dec 2003;179(3):357-65. doi:10.1677/joe.0.1790357, PMID: 14656205, https://pubmed.ncbi.nlm.nih.gov/14656205/
8. Alvarez-Salas E, Garcia-Luna C, de Gortari P. New Efforts to Demonstrate the Successful Use of TRH as a Therapeutic Agent. Int J Mol Sci. Jul 4, 2023;24(13) doi:10.3390/ijms241311047, PMID: 37446225 PMCID: PMC10341491, https://pubmed.ncbi.nlm.nih.gov/37446225/

Regarding the isolation, purification, and preparation of Thymosin Alpha 1, it was initially isolated from the calf thymus in 1977. However, a solid-phase synthesis technique in which molecules are covalently bound to a solid material is predominantly used for its commercial production. With the arrival of molecular expression methods, Ta1 is also being produced through prokaryotic and eukaryotic expression methodologies.

Thymosin Alpha 1 Overview

The synthetic analog of Thymosin Alpha 1, namely Thymalfasin, is primarily studied in research models of hepatitis B and C infection. It has the following amino acid sequence:

Ac–S–D–A–A–V–Asp–T–S–S–E–I–T–T–K–D–L–K–E–K–K–E–V–V–E–E–A–E–N–OH.

As described above and shown in the sequence, the peptide is N-terminally acetylated, has a net positive charge, and lacks stable conformation.

Several research institutions and teams have aimed to explore the breadth of the peptide’s potential. However, the mechanisms by which this peptide exerts its effects are an active area of investigation. Scientists believe that Thymosin Alpha 1’s potential in overcoming infections, cancer, immunodeficiency, and cell aging, may be through pleiotropic action. A recent study suggested that Thymosin Alpha 1 interactions with an oligosaccharide binding protein, Galectin -1 (Gal-1), are necessary to activate its potential ^[1].

The immunostimulatory effects of Thymosin Alpha-1 peptide are supposed to be mediated through Toll-like receptors (TLRs). It has been observed that Thymosin Alpha 1, through its binding with TLR3/4/9, appears to stimulate interferon regulatory factor (IRF3) and NF-kB signaling pathways. The ultimate effect is reflected in the immune-enhancing potential for both innate and adaptive immune system machinery. The immunomodulation against viral infections also appears to be mediated through activating T cells, B cells, macrophages, and Natural Killer cells ^[2].

The molecular mechanisms underlying the potential of Ta1 in controlling cellular proliferation through inducing apoptosis of cancerous cells are also being evaluated. Scientific studies suggest that the hypothetical anti-cancer action of Thymosin Alpha 1 may be mediated through the PI3K/Akt/mTOR signaling pathway. Furthermore, PTEN appears to mediate apoptosis through Thymosin Alpha 1 ^[3]. The specificity of this is yet to be deciphered through further studies.

It is clear from the above-described studies that researchers general assert that Thymosin Alpha 1 appears to exert action through differential molecular and cellular mechanisms that should be investigated in further detail.

Thymosin Alpha 1 Peptide Research

Scientific studies have provided ample data to support its hypothetical consequence within the context of various ailments.

The primary objectives of several ongoing research studies are to evaluate this peptide’s potential individually or in combination with other compounds. Mainly, its action as a sole agent in the research of immune reconstitution disorders, hepatocellular carcinoma, osteoporotic pain, rheumatic heart disease, sepsis, and viral infections, is an active area of scientific investigation. The peptide, in combination with other compounds, is being evaluated for advanced refractory solid tumors, esophageal cancer, rectal carcinoma, malignant melanoma, and non-small cell lung cancer (NSCLC).

Besides prospective well-designed studies, several retrospective evaluations hypothesize the relevance of this peptide in various avenues of scientific research. Particularly in sepsis, organ dysfunction is a major focus. A study compared the benefits of Thymosin Alpha 1 with a placebo. The outcome revealed that Ta1 reduces organ damage among research models of sepsis ^[4].

Another study evaluated the potential of Thymosin Alpha 1 on long-term survival in margin-free (R0)-resected stage IA–IIIA with non-small cell lung cancer (NSCLC) models. Findings suggested that Thymosin Alpha 1 exposure appeared to have improved disease-free survival after R0 resection. The period of the study spanned 24 months ^[5].

The United States Patent Application Publication US 2010/0004174 A1 published in the year 2010 claimed that Thymosin Alpha 1 may exhibit potential benefits in cases of multiple sclerosis, inflammatory bowel disease, Crohn’s disease/ulcerative colitis.

Conclusion

Thymosin Alpha 1 is an endogenous peptide, whose synthetic analog, Thymalfasin, is widely researched as a prospective agent in various ailments. Most prominent theorized actions of Thymosin Alpha 1 are speculated to encompass tumor growth and cancer suppression, boosting immune cell functions, mitigating bacterial, viral, and fungal infections, acting as an anti-inflammatory agent, and augmenting vaccine activity. The most plausible explanation for its diverse potential is that Thymosin Alpha 1 may mediate homeostasis within different organs and systems. However, diverse mechanisms operate to control different diseases. Though a broader profile, this peptide molecular mechanism still needs to be elucidated for each proposed indication.

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. Matteucci C, Nepravishta R, Argaw-Denboba A, Mandaliti W, Giovinazzo A, Petrone V, Balestrieri E, Sinibaldi-Vallebona P, Pica F, Paci M, Garaci E. Thymosin alpha1 interacts with Galectin-1 modulating the beta-galactosides affinity and inducing alteration in the biological activity. Int Immunopharmacol. May 2023;118:110113. doi:10.1016/j.intimp.2023.110113. PMID: 37028279. https://pubmed.ncbi.nlm.nih.gov/37028279/
2. Tao N, Xu X, Ying Y, Hu S, Sun Q, Lv G, Gao J. Thymosin alpha1 and Its Role in Viral Infectious Diseases: The Mechanism and Clinical Application. Molecules. Apr 17 2023;28(8)doi:10.3390/molecules28083539. PMID: 37110771; PMCID: PMC10144173. https://pubmed.ncbi.nlm.nih.gov/37110771/
3. Guo Y, Chang H, Li J, Xu XY, Shen L, Yu ZB, Liu WC. Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K/Akt/mTOR signaling pathway. Apoptosis. Aug 2015;20(8):1109-21. doi:10.1007/s10495-015-1138-9. PMID: 26002438. https://pubmed.ncbi.nlm.nih.gov/26002438/
4. Cao M, Wang G, Xie J. Immune dysregulation in sepsis: experiences, lessons and perspectives. Cell Death Discov. Dec 19 2023;9(1):465. doi:10.1038/s41420-023-01766-7. PMID: 38114466; PMCID: PMC10730904. https://pubmed.ncbi.nlm.nih.gov/38114466/
5. Guo CL, Mei JD, Jia YL, Gan FY, Tang YD, Liu CW, Zeng Z, Yang ZY, Deng SY, Sun X, Liu LX. Impact of thymosin alpha1 as an immunomodulatory therapy on long-term survival of non-small cell lung cancer patients after R0 resection: a propensity score-matched analysis. Chin Med J (Engl). Nov 3 2021;134(22):2700-2709. doi:10.1097/CM9.0000000000001819. PMID: 34732663; PMCID: PMC8631386. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631386/