August 2016

  1. Know about: Thymosin Beta 4 (TB500)

    - Cells containing thymosin beta-4 (Tβ4) co-localize to alpha-smooth muscle actin (alphaSMA), indicating that the protein is active in the presence of fibrosis (induced by experimental chronic liver damage generated by treatment with CCI4). From: Kim J, Wang S, Hyun J, et al. Hepatic Stellate Cells Express Thymosin Beta 4 in Chronically Damaged Liver. PloS one. 2015;10(3):e0122758, reproduced under the terms of the Creative Commons Attribution License

    - Cells containing thymosin beta-4 (Tβ4) co-localize to alpha-smooth muscle actin (alphaSMA), indicating that the protein is active in the presence of fibrosis (induced by experimental chronic liver damage generated by treatment with CCI4). From: Kim J, Wang S, Hyun J, et al. Hepatic Stellate Cells Express Thymosin Beta 4 in Chronically Damaged Liver. PloS one. 2015;10(3):e0122758, reproduced under the terms of the Creative Commons Attribution License

    Thymosin beta-4 is a protein originally discovered as an isolate from the mammalian thymus gland1. It is one of a family of thymosins, which are low-weight acidic molecules that can act as cytopoietics. This means that they can control the movement and/or differentiation of cells by neutralizing the ability of individual actin proteins (or monomers) to polymerize into filaments2. On the other hand, thymosins also aggregate the actin monomers, thus allowing or preventing the formation of subsequent filaments2. At a certain scale, this may promote or prevent the differentiation of a cell such as a pluripotent stem cell into another, such as an osteocyte or a neural cell. Therefore, molecules such as thymosins (of which thymosin beta-4 is the most common in mammals3) may play a significant role in postnatal development or the regeneration of some tissues. The influence of thymosin beta-4 over actin may also control cellular migration and angiogenesis4. It follows, therefore, that the protein also has potential as an agent of wound repair. Thymosin beta-4 is available as a synthetic, laboratory-grade peptide known as TB500­i. Its molecular weight is just over 4.9kDa, and it is supplied as a white solid i. TB500 also has anti-inflammatory properties. It has demonstrated the ability to attenuate the release of NO and prostaglandin E4 in cellular models of reactive oxygen species (ROS) exposure5. However, it may also upregulate pro-inflammatory cytokines such as TNFalpha and several interleukins (e.g. IL-6 and -8) in periodontal cells5. As these molecules are also osteoclastogenic5, it implies an additional role for TB500 in the regulation of bone formation. The peptide also inhibited the activation of NFkappaB in murine macrophages in this study5. TB500 also concerns the release of acSDKP, an anti-inflammatory peptide fragment. This fragment is in fact a breakdown product of TB500, but this metabolism is regulated by a number of interesting factors6. The co-incubation of TB500 with homogenated rodent kidney tissue resulted in a significant increase in the release of acSDKP7. This is controlled by a complex regulatory mechanism which involves peptidases that only cleave molecules of specific fragments, necessitating the hydrolysis of TB500 by meprin-alpha before acSDKP may be cleaved from it7. TB500 may also be of interest to researchers studying the fibrosis of various organs8. One group has recently published results that indicate significant decreases of inflammation in a mouse model of pulmonary fibrosis9. acSDKP has been shown to decrease renal fibrosis in mice, in that treatment with the fragment resulted in the reduced deposition of fibronectin and collagen (i.e. major components of scar tissue) and the reduced migration of macrophages and myofibroblasts to a site of damage6. The up-regulation of thymosin beta-4 is also associated with the activation of hepatic stellate cells, which appear to co-localize to alpha-smooth muscle actin (a marker of chronic liver damage as observed in mouse models of the same)10. In general, TB500 is a peptide involved in complex regulatory and developmental processes in vivo. It appears to be a viable component of the control of tissue regeneration, cell differentiation and inflammation. Therefore, B500 may be applied to models of disorders such as abnormal fibrosis, osteolytic inflammation (e.g. rheumatoid arthritis) and various states of postnatal development.   References:
    1. Goldstein AL, Slater FD, White A. Preparation, assay, and partial purification of a thymic lymphocytopoietic factor (thymosin). Proceedings of the National Academy of Sciences of the United States of America. 1966;56(3):1010-1017.
    2. Huff T, Muller CS, Otto AM, Netzker R, Hannappel E. beta-Thymosins, small acidic peptides with multiple functions. The international journal of biochemistry & cell biology. 2001;33(3):205-220.
    3. Cha HJ, Philp D, Lee SH, Moon HS, Kleinman HK, Nakamura T. Over-expression of thymosin beta 4 promotes abnormal tooth development and stimulation of hair growth. The International journal of developmental biology. 2010;54(1):135-140.
    4. Philp D, Goldstein AL, Kleinman HK. Thymosin beta4 promotes angiogenesis, wound healing, and hair follicle development. Mechanisms of ageing and development. 2004;125(2):113-115.
    5. Lee S-I, Yi J-K, Bae W-J, Lee S, Cha H-J, Kim E-C. Thymosin Beta-4 Suppresses Osteoclastic Differentiation and Inflammatory Responses in Human Periodontal Ligament Cells. PloS one. 2016;11(1):e0146708.
    6. Zuo Y, Chun B, Potthoff SA, et al. Thymosin beta4 and its degradation product, Ac-SDKP, are novel reparative factors in renal fibrosis. Kidney international. 2013;84(6):1166-1175.
    7. Kumar N, Nakagawa P, Janic B, et al. The anti-inflammatory peptide Ac-SDKP is released from thymosin beta4 by renal meprin alpha and prolyl oligopeptidase. American journal of physiology. Renal physiology. 2016:ajprenal.00562.02015.
    8. Peng H, Xu J, Yang XP, et al. Thymosin-beta4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction. American journal of physiology. Heart and circulatory physiology. 2014;307(5):H741-751.
    9. Conte E, Genovese T, Gili E, et al. Protective effects of thymosin beta4 in a mouse model of lung fibrosis. Annals of the New York Academy of Sciences. 2012;1269:69-73.
    10. Kim J, Wang S, Hyun J, et al. Hepatic Stellate Cells Express Thymosin Beta 4 in Chronically Damaged Liver. PloS one. 2015;10(3):e0122758.
    11. TB500 Product Page. Blue Sky Peptide. 2016
  2. What is the difference between a peptide and a protein?

    Tesamorelin, a 44-amino acid peptide that is an analog of full GRP. By Vaccinationist - Egrifta (tesamorelin for injection) for Subcutaneous Use. U.S. Full Prescribing Information. Page 4, Public Domain, https://commons.wikimedia.org/w/index.php?curid=48094028

    Tesamorelin, a 44-amino acid peptide that is an analog of full GRP. By Vaccinationist - Egrifta (tesamorelin for injection) for Subcutaneous Use. U.S. Full Prescribing Information. Page 4, Public Domain, https://commons.wikimedia.org/w/index.php?curid=48094028

    Peptides and proteins are often very discrete terms; however, they refer to biological molecules that often overlap in terms of function and other factors. A peptide is a ‘chain’ of amino acids that is expressed as a result of mRNA translation. This is often thought of as the ‘primary’ dimension of protein structure. Many scientists throughout history may not have thought of a single chain as a complete protein. This is due to the theories of protein structure as composed of multiple chains. In addition, even individual chains may attain additional structural complexity. This complexity is conferred by interactions between the side-chains of the amino acids within the chain. These mainly give rise to alpha-helices or beta-pleated sheets. Shapes such as these are regarded as the secondary degree of protein structures. Complicated chains may then proceed to interact (i.e. ‘interlock’ or form interfaces) with others expressed from the same gene to form certain structures. Common examples of these are known as globular structures and zinc-finger structures. This is known as tertiary protein structures, and also as proteins domains (specific subunits or characteristics). One or more domains may then form interactions or bonds (e.g. sulphide bridges) to form proteins with a quaternary structure. This is the classical view of proteins, which gives rise to their perception as complex molecules that may have a higher weight and three-dimensional size. There are a number of other properties that are also associated with proteins. An example of these is the structure-to-function relationship; essentially how a protein’s structure, once it has been produced as above, defines its role in a living system. However, some peptides present arguments that may dispute these classical characteristics. At the outset of biological research, it may have been thought that proteins required chains with very large numbers of amino acids to carry out the roles increasingly associated with this class of molecule. This is true for some proteins, which require many specific domains in a definitive conformation to interact with their targets. On the other hand, some peptides with relatively short chains may elicit at least some of the functions of larger proteins from which they have been derived1. For example, a twelve-residue peptide fragment may bind to the receptor of the full insulin protein2. Therefore, a peptide may have some protein-like functions. Similarly, IGF-1 is a protein with several domains that has various regulatory functions in the body. Mechano-growth factor (MGF) is a peptide that is an equivalent to just one domain (the E-domain) of IGF-13. Despite its reduced complexity, however, it is active at receptors of its own and is specifically expressed from the IGF1 gene in response to mechanical damage to muscle tissue3. In other words, a typical defining feature of proteins is that it is biologically active, i.e. that it binds a receptor or another protein to affect signaling within a cell. This may require a particularly-shaped protein with at least one domain – i.e. a complex and specific 3D structure. However, GRF is a relatively short peptide that can bind a receptor to enhance growth hormone (GH) release1. In addition, there are even smaller peptides - only six residues long - that may be comparably effective, and are thus known as synthetic GH secretagogues (GHSs)4. This is due to a certain motif, (or specific sequence of amino acids) contained within the six-amino-acid chain, that interacts effectively with the GHS receptor5. Small peptides, containing relevant motifs, also have other advantages over proteins such as increased absorption due to their small size. In general, all proteins may be considered peptide chains, but not all functional peptides need be proteins. References:
    1. Ionescu M, Frohman LA. Pulsatile Secretion of Growth Hormone (GH) Persists during Continuous Stimulation by CJC-1295, a Long-Acting GH-Releasing Hormone Analog. The Journal of Clinical Endocrinology & Metabolism. 2006;91(12):4792-4797.
    2. Wade JD, Ng FM, Bornstein J, Pullin CO, Pearce JS. Effect of C-terminal chain shortening on the insulin-antagonistic activity of human growth hormone 177--191. Acta endocrinologica. 1982;101(1):10-14.
    3. Shioura K, Pena J, Goldspink P. Administration of a Synthetic Peptide Derived from the E-domain Region of Mechano-Growth Factor Delays Decompensation Following Myocardial Infarction. International journal of cardiovascular research. 2014;3(3):1000169.
    4. Cheng K, Chan WW, Barreto A, Jr., Convey EM, Smith RG. The synergistic effects of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on growth hormone (GH)-releasing factor-stimulated GH release and intracellular adenosine 3',5'-monophosphate accumulation in rat primary pituitary cell culture. Endocrinology. 1989;124(6):2791-2798.
    5. Ferro P, Krotov G, Zvereva I, Rodchenkov G, Segura J. Structure-activity relationship for peptidic growth hormone secretagogues. Drug testing and analysis. 2016.

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