TB-500 Fragment (17-23), also called fequesetide or (17) (LKKTETQ) (23), represents the smallest portion of the thymosin beta-4 molecule that retains the larger protein’s active binding domain. Research indicates that this synthetic derivative of thymosin beta-4 is capable of binding to actin, the molecule inside of cells that is responsible for improved cell structure, movement (a.k.a. migration), and replication. By altering the function of actin in cells, TB-500 Fragment (17-23) has been shown to modulate the immune response and alter cell migration patterns. This can lead to large-scale changes in tissue/organ structure and function. In animal models, these changes have been shown to accelerate wound healing, decrease inflammation, promote blood vessel growth, reduce scar formation, improve musculoskeletal function, and help to slow or reverse the course of certain disease conditions.
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TB-500 Fragment (17-23), also called fequesetide or (17) (LKKTETQ) (23), represents the smallest portion of the thymosin beta-4 molecule that retains the larger protein’s active binding domain. Research indicates that this synthetic derivative of thymosin beta-4 is capable of binding to actin, the molecule inside of cells that is responsible for cell structure, movement (a.k.a. migration), and replication. By altering the function of actin in cells, TB-500 Fragment (17-23) has been shown to modulate the immune response and alter cell migration patterns. This, in turn, can lead to large-scale changes in tissue/organ structure and function. In animal models, these changes have been shown to accelerate wound healing, decrease inflammation, promote blood vessel growth, reduce scar formation, improve musculoskeletal function, and even help to slow or reverse the course of certain disease conditions.
Amino Acid Sequence: LEU-LYS-LYS-THR-GLU-THR-GLN (LKKTETQ)
Chemical Structure: C36H66N10O13
Molecular Weight: 846.97 g/mol
PubChem CID: 10169788
CAS No. 476014-70-7
Synonyms: Fequesetide, Thymosin Beta-4(17-23), (17)(LKKTETQ)(23)
To understand how TB-500 fragment (17-23) works, it is necessary to understand the molecule actin. Actin is the most abundant protein in eukaryotic cells (the cells that make up our bodies) and is important in mediating many protein-protein interactions, including cell movement, maintenance of cell shape, vesicle and organelle movement, cell signaling, cell junctions, and regulation of cell division. Actin, along with myosin, is one of the two proteins involved in muscle contraction.
Actin can be found in two forms: monomeric and polymerized. Monomeric actin is the most basic form of the protein and can be thought of as the storage form. Pools of monomeric actin are managed by actin-binding proteins like profilin and thymosin beta-4.
Polymerized actin is often referred to as a microfilament, and this form of the protein is responsible for most of actin’s functions within the cell. The transition from monomeric to polymeric form is controlled by profilin and thymosin beta-4. Profilin ensures that monomeric actin can only bind to one end of the growing filament. Thymosin beta-4 promotes the polymerization of G-actin into F-actin, where F-actin is the version of actin that can form polymeric microfilaments. Thus, thymosin beta-4 acts as both a protector of G-actin in its resting state and helps to promote its elevation to an active state when necessary.
It is not yet clear how thymosin beta-4 promotes actin polymerization, but there is some evidence to suggest that it interacts with another protein complex called Arp2/3. Arp2/3 has been found to be a key orchestrator of cellular response and is responsible for initiating the process of actin polymerization. However, Arp2/3 is a very inefficient nucleator of actin by itself and requires assistance. Several molecules, mainly from the WASP family of proteins, have been shown to play the role of assistant to Arp2/3, but there is speculation that thymosin beta-4 may also play a role, albeit in different settings.
TB-500 fragment (17-23) could provide an excellent tool for further exploring assistants to Arp2/3 and might therefore help to shed some light on an important but still poorly understood aspect of cell physiology [1]. It may play a particularly important role in the establishment of branched actin networks, which are load-sensitive and thereby provide the cell with feedback about its external environment. Such processes underlie vesicle formation and thus play an important role in everything from cell nutrition to the ability of immune cells to ingest and destroy foreign materials.
Arp2/3-dependent actin branching helps cells to respond to environmental forces. Among the main contributors to cell responses against external force loads are branched actin networks generated through Arp2/3-mediated dendritic nucleation. Branched actin networks influence cell motility, genetic stability, and even organelles such as mitochondria.
Thymosin beta-4 is best understood as a biological response modifier and is particularly important in the proper development and differentiation of T-cells. T-cells are crucial types of white blood cells essential to the adaptive immune response, where our bodies memorize invading pathogens to combat them more effectively in the future.
T-cells play a significant role in the inflammatory response, signaling to other cells to either enhance or restrict inflammation. They serve as managers of the immune response, thus influencing everything from tissue regeneration and scar formation to combating infection and even cancer. T-cells are known to regulate the production of inflammatory mediators such as
Research shows that thymosin beta-4, which consists of 43 amino acids and has a molecular weight of 4921 g/mol, possesses a small active domain comprising only a few amino acids. This discovery led to the development of two thymosin beta-4 derivatives, TB-500 and TB-500 fragment (17-23), which retain many properties of thymosin beta-4 but are smaller and thus more bioavailable to receptor sites. Although TB-4 and TB-500 are often used interchangeably, they are distinct molecules. The same applies to TB-500 and TB-500 fragment (17-23). Therefore, to avoid confusion, it is crucial to confirm not only the amino acid sequence but also the chemical formula and molecular weight of the product being utilized.
Both TB-500 and TB-500 fragment (17-23) consist of 7 amino acids from the active domain of thymosin beta-4. The differentiation between TB-500 and TB-500 fragment (17-23) can be perplexing because the two peptides share the exact same amino acid sequence, LKKTETQ. However, upon closer examination, one will notice that while TB-500 has a molecular weight of 889.0 g/mol, TB-500 fragment (17-23) has a molecular weight of 846.97 g/mol. This subtle difference arises from the presence of an aldehyde group on the leucine residue of TB-500, which is absent in TB-500 fragment (17-23). Though seemingly minor, this distinction renders TB-500 fragment (17-23) a more stable molecule. Consequently, it may exhibit not only an extended shelf-life but also increased resistance to modification and degradation within the body therefore extending its half-life. TB-500 fragment (17-23) may demonstrate improved potency and fewer off-target actions. It is soluble in water at concentrations above 60 mg/mL.
For those interested in researching the differences between TB-500 and TB-500 fragment (17-23), it is important to pay close attention to both molecular weight and the chemical formula. TB-500 has the chemical formula C38H68N10O14 whereas TB-500 fragment (17-23) has the chemical formula C36H66N10O13[4].
Perhaps the most fundamental role of thymosin beta-4 and its derivatives is in promoting tissue repair. Careful animal experiments indicate that TB-500 fragments work to promote accelerated tissue repair and wound healing through two processes: fibroblast migration and angiogenesis.
Research clearly indicates that TB-500 fragment (17-23) is important in fibroblast migration. Fibroblasts are the primary cells involved in repairing damaged tissue and are critical to wound healing. As a modulator of actin, TB-500 fragment (17-23) likely affects the ability of fibroblasts to mobilize and reach the areas in which they are needed.
Some studies suggest that another aspect of the ability of TB-500 fragment to alter fibroblast function is mediated through its effects on another molecule called transforming growth factor-beta (TGF-β). TGF-β not only increases the migration of fibroblasts but also enhances their ability to produce collagen. Collagen is essential to the construction of the extracellular matrix, a substance that acts as a kind of scaffolding on which cells can grow. The formation of a robust extracellular matrix is an important early step in wound closure and tissue healing.
Collagen is also an important component of blood vessels, and research shows that TB-500 fragment (17-23) facilitates the growth of blood vessels. This process, called angiogenesis, helps to bring oxygen, nutrients, and immune cells to the site of injury. Thus, angiogenesis is another critical step in the process of tissue repair. TB-500 fragment encourages the migration of endothelial cells, which are the basic cells needed for blood vessel construction. This direct effect is complemented by another indirect effect of TB-500 fragment (17-23), which is to stimulate the release of vascular endothelial growth factor (VEGF) and other growth factors that supercharge the process of angiogenesis [5].
In studies of rats with full-thickness skin wounds, TB-500 has been shown to accelerate wound closure, increase rates of skin growth, and increase rates of collagen deposition. Similar work on damage to the eye has indicated that TB-500 fragment (17-23) can vastly increase rates of corneal healing by not only increasing cell migration but also by reducing cell death (apoptosis) and the impact of pro-inflammatory molecules called cytokines [6]. This latter ability is discussed in more detail in the next section, but it is important to note that TB-500 fragment (17-23) has effects in almost every organ in the body, as far as we have been able to discern. This indicates that it may be a universal promoter of wound healing, regardless of where the injury occurs, and thus, it is intensely researched in everything from burns to neurodegenerative disease research.
One area in which TB-500 fragment (17-23) is likely to have a great deal of benefit is in the growth and regeneration of muscle tissue. In animal models of muscle injury, TB-500 fragment (17-23) activates satellite cells, which are versatile stem cells responsible for muscle repair. TB-500 administration encourages satellite cells to enter the cell cycle and multiply, likely through the Akt pathway discussed later in this article. This heightened satellite cell activity aids in the regeneration of damaged muscle fibers and the formation of new myofibers, thus enhancing muscle repair.
Moreover, TB-500 fragment (17-23) facilitates the migration of satellite cells to the site of muscle injury, where they can participate in the muscle repair process. Early research in muscle repair has suggested that TB-500 fragment (17-23) undergoes chemical modification at the injury site, transforming into a chemoattractant for differentiated myoblasts (muscle cells derived from satellite cells). This encourages migration to the injury site. It is worth noting that satellite cells are not exclusive to muscle tissue but are also found in the central and peripheral nervous systems.
Muscle fibers are made up primarily of actin and myosin filaments. In order for muscle to contract, myosin pulls against the actin filaments and the entire muscle fiber gets shorter. When these fibers are damaged, the muscle itself heals in two ways. The first way in which muscle heals is to repair the damage and add supporting fibers in the area. This is controlled by existing muscle cells. The second way in which muscle heals is via the addition of an entirely separate, new muscle fiber. This second process is controlled by muscle stem cells, called myoblasts or satellite cells.
Muscle growth occurs quite well with existing muscle cells and, in fact, a great deal of performance is gained through the hypertrophy of the fibers that these cells control. There is, however, a limit to how large a muscle fiber can get, however, because it because inefficient for material to move from the muscle cells into the dense fibers that they control. At some point, further increases in performance demand an increase in the number of muscle fibers and thus in the number of cells that support them. This latter process, called hyperplasia, relies entirely on myoblasts.
For myoblasts to have an effect, however, they must migrate through existing muscle tissue to the sites where they can best serve the overall structure of the muscle based on the loads the muscle experiences. Migration can be a slow and inefficient process. Research indicates that Thymosin Beta-4 accelerates this process and thus increases the rate of myoblast chemotaxis (movement) to sites where they can be useful [7], [8]. Of course, for this to work, Thymosin Beta-4 must be present in muscle cells as well and, as a large molecule peptide, it has difficulty diffusing through dense muscle tissue itself.
Fortunately, TB-500 Fragment (17-23) is a short peptide and member of the class of cell-penetrating peptides. Cell-penetrating peptides are able to directly cross cell membranes, without the need for special transport apparatus, and can even penetrate the nuclear membrane [9], [10]. As a cell-penetrating peptide, TB-500 Fragment (17-23) is likely superior as an exogenously administered agent compared to natural Thymosin Beta-4. Its small size and increased bioavailability likely allow it to more easily reach areas where its effects can be most beneficial, thus leading to increased rates of muscle recovery and growth following training, injury, and other muscle-building stimuli. In short, TB-500 Fragment (17-23) likely has a superior effect on muscle performance compared to Thymosin Beta-4. Indeed, TB-500, which is closely related to TB-500 Fragment (17-23), has shown positive effects on functional recovery in animal models [11]. These animals have shown significant improvements in muscle strength, muscle endurance, and motor function compared to control groups [12].
Inflammation is a necessary component of the healing process, but it can often become dysregulated. The difference between regulated and unregulated inflammation is the difference between wound closure and scar formation. While wound closure is necessary and desirable, scar formation can lead to cosmetic and functional problems. For example, scar formation in the heart can lead to arrhythmias or even heart failure.
One might assume that TB-500 fragment (17-23) is a proinflammatory molecule, as it encourages the growth and migration of inflammatory cells in the immune system like T-cells. While this is true, it is best to think of TB-500 fragment as a mediator that strives to strike a balance. It encourages inflammation only up to the point that it is useful, and then TB-500 fragment (17-23) works to downregulate inflammation to prevent damage. TB-500 fragment seeks to modulate a proper balance.
Research indicates that administration of TB-500 fragment (17-23) suppresses the production of TNF-α and interleukin-6 (IL-6). Both cytokines are strongly pro-inflammatory, so suppressing their activity goes a long way toward turning off the inflammatory response. What is interesting about TB-500 fragment is that it works locally to suppress inflammation, rather than globally. This is important because global suppressors of inflammation (e.g., monoclonal antibody drugs like infliximab) tend to suppress the immune system and make a person vulnerable to infections with serious diseases like tuberculosis. The ability of TB-500 fragment (17-23) to work only at the site of injury makes it of great interest to researchers investigating the treatment of conditions like rheumatoid arthritis, inflammatory bowel disease, lupus, and more.
Suppressing the release of proinflammatory cytokines is a good way to turn off the faucet, but what do you do about the inflammation that has already occurred? Research indicates that TB-500 fragment can also promote the release of anti-inflammatory cytokines that work to bring inflammation down to normal levels. In the faucet analogy, this would be like opening the drain so that the water can flow out. These direct effects of TB-500 fragment (17-23) are enhanced by its ability to influence cell signaling pathways to bring in cells that can help clean up the inflammatory site and restore everything to normal.
Cell signaling is the way in which cells send information to one another to coordinate their activities. This signaling is carried out though the release and uptake of chemical messengers at specific places and specific times. Specifically, TB-500 fragment (17-23) modulates activity of the Akt and Bcl-XL pathways.
The Akt pathway is well known for its ability to alter cell survival rates by interfering with the process of apoptosis (programmed cell death). It is worth noting that interfering with apoptosis is not desirable in all settings. In the case of senescence, for instance, inhibiting apoptosis can lead to tissue and organ dysfunction that are the hallmarks of the aging process. Alternatively, inhibiting apoptosis among fibroblasts engaged in wound repair can lead to increased rates of wound healing and better aesthetic outcomes. Thus, it is best to selectively modulate the Akt pathway, which is precisely what TB-500 fragment (17-23) does[8], [9].
The role of Akt in cell survival goes beyond simply inhibiting apoptosis, however. Research shows that Akt promotes the transition from G1 to S phase in the cell cycle. This is a necessary step for DNA synthesis to occur and one of the bottlenecks in the process of cell division. By speeding up this transition, the Akt pathway (and therefore TB-500 fragment (17-23)) increases rates of cell proliferation. In the case of injury and wound healing, this translates into increased proliferation of fibroblasts, endothelial cells, and other cells needed to rebuild tissue[10].
Until recently, most research aimed at neurological restoration following injuries like stroke or traumatic brain injury has focused on neuron-based injury mechanisms. That is to say, most of the focus has been on neurons rather than on the structures and cells that support them. Preclinical studies, however, have indicated that natural processes of neuron restoration involve a diverse assortment of cells and non-cell structures. Thus, researchers have recently started to focus on both stimulating other cells in addition to neurons as well as augmenting natural processes of neuron restoration.
Thymosin beta-4 has long been known to play an important role in the central nervous system, including processes such as axonal pathfinding, neurite formation, neuron survival, and neuron proliferation [11]. In research with mouse models of brain injury, thymosin beta-4 can reduce lesion volume and improve functional recovery when administered via injection.
The benefits of thymosin beta-4 in the brain are like those seen with administration of the protein in other areas of the body. Additionally, it appears that the activity is mediated through the same active domain that constitutes TB-500 fragment (17-23). Thus, it is likely that TB-500 fragment (17-23) has similar benefits in the brain and central nervous system as thymosin beta-4.
Of note, research indicates that the same abilities of TB-500 fragment (17-23) to promote angiogenesis and increase cell proliferation throughout the body are beneficial in the brain as well. Particularly interesting is the ability of the peptide to promote neurogenesis, the production of new neurons. Administration of TB-500 fragment following a stroke shows an increase in markers for a type of cell called oligodendrocytes. These cells support neurons by providing structural support and nutrient supplies. An increase in oligodendrocytes is a strong indicator of increased neuron growth, and while it isn’t clear which of these cell types TB-500 fragment stimulates to grow first, the response is dose-dependent. This is in keeping with a legitimate biological impact [12], [13].
One key feature of TB-500 fragment (17-23) that is thought to be beneficial in the central nervous system is its anti-inflammatory effects. Research indicates that TB-500 fragment increases the expression of microRNA-146a, which is associated with decreased inflammation. Inflammation is inhibitory to neuron growth [14]. Regulating inflammation is therefore a critical first step in repairing injuries to the central nervous system and encouraging neuron growth.
Of note, one area in which the anti-inflammatory effects of TB-500 fragment (17-23) are of particular interest is in the treatment of multiple sclerosis (MS). MS is a disease that impacts the growth of myelin, a protective layer that surrounds the axons of neurons and ensures proper conduction of electrical signals. Damage to myelin is the primary marker of MS. Research indicates that TB-500 fragment (17-23), by thwarting the inflammation associated with MS, may be an effective means of not only treating the disease but also preventing it from recurring, as it so often does [15].
TB-500 and TB-500 Fragment (17-23) are very similar to one another and share many of the same properties. Other peptides appear to be potent anti-inflammatories and encourage the growth, proliferation, and migration of various cells necessary for tissue repair. Their actions seem to be nearly universal, providing increased growth and migration of cells in a range of organs including the skin, muscles, heart, and brain. By reducing inflammation and boosting cell activity, both TB-500 and TB-500 Fragment (17-23) act much like their parent molecule thymosin beta-4 to stimulate the repair of damaged tissue and restore baseline functionality in various tissues.
The chemical structure of TB-500 Fragment (17-23) is slightly modified from TB-500, which itself is heavily modified from thymosin beta-4. These modifications make TB-500 Fragment (17-23) the smallest of the three peptides and provide it with improved shelf-life and increased bioavailability.
The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.
Geoffrey M. Cooper is professor of biology at Boston University. He served as chair of the department of biology for a number of years, and subsequently as associate dean of the faculty for the natural sciences in the university’s college of arts & sciences.
Cooper earned his Ph.D. at the University of Miami in 1973, and was a postdoctoral fellow with nobel laureate, Howard Temin. His work includes cellular growth control, cancer, and signal transduction. More specifically, he focuses on “the roles of proto-oncogene proteins as elements of signal transduction pathways that control proliferation, differentiation, and survival of mammalian cells.”
Geoffrey M. Cooper is being referenced as one of the leading scientists involved in the research and development of TB-500 Fragment (17-23). In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between Peptide Sciences and this doctor. The purpose of citing the doctor is to acknowledge, recognize, and credit the exhaustive research and development efforts conducted by the scientists studying this peptide. Geoffrey M. Cooper is listed in [2] under the referenced citations.
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