Foundational: Zinc Dependency and Biochemical Characterization

References [1], [2], [3]: the primary biochemical characterization literature establishing zinc-dependent activity and the three-dimensional Zn-thymulin epitope.

1. [1] Dardenne M, Pleau JM, Nabarra B, Lefrancier P, Derrien M, Choay J, Bach JF. Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proc Natl Acad Sci USA. 1982;79(17):5370–5373. PMID 6957870 ↗ DOI: 10.1073/pnas.79.17.5370
2. [2] Bach JF, Dardenne M. Thymulin, a zinc-dependent hormone. Med Oncol Tumor Pharmacother. 1989;6(1):25–29. PMID 2657247 ↗ DOI: 10.1007/BF02985220
3. [3] Dardenne M, Savino W, Berrih S, Bach JF. A zinc-dependent epitope on the molecule of thymulin, a thymic hormone. Proc Natl Acad Sci USA. 1985;82(20):7035–7038. PMID 2413455 ↗ DOI: 10.1073/pnas.82.20.7035

T-Cell Differentiation and Human In Vitro

Reference [4]: Incefy et al. (1980) — synthetic FTS induction of T-cell surface markers on human bone marrow precursor cells.

1. [4] Incefy GS, Mertelsmann R, Yata K, Dardenne M, Bach JF, Good RA. Induction of differentiation in human marrow T cell precursors by the synthetic serum thymic factor, FTS. Clin Exp Immunol. 1980;40(3):396–406. PMID 6969145 ↗

Human and Rodent Zinc-Thymulin Studies

References [5], [7], [8], [9], [10]: Prasad et al. (1988) human zinc deficiency study; Mocchegiani et al. (1995, 1999, 2004) rodent and human zinc supplementation, metallothionein, and alpha-2-macroglobulin competition; Haase and Rink (2009) review.

1. [5] Prasad AS, Meftah S, Abdallah J, Kaplan J, Brewer GJ, Bach JF, Dardenne M. Serum thymulin in human zinc deficiency. J Clin Invest. 1988;82(4):1202–1210. PMC442670 ↗ PMID 3262625
2. [7] Mocchegiani E, Santarelli L, Muzzioli M, Fabris N. Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice. Int J Immunopharmacol. 1995;17(9):703–718. PMID 8582782 ↗ DOI: 10.1016/0192-0561(95)00059-b
3. [8] Mocchegiani E, Giacconi R, Cipriano C, Muti E, Gasparini N, Malavolta M. Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing? Immun Ageing. 2004;1:5. PMC544958 ↗ DOI: 10.1186/1742-4933-1-5
4. [9] Haase H, Rink L. The immune system and the impact of zinc during aging. Immun Ageing. 2009;6:9. PMC2702361 ↗ DOI: 10.1186/1742-4933-6-9
5. [10] Mocchegiani E, Ciavattini A, Santarelli L, Tibaldi A, Muzzioli M, Bonazzi P, Giacconi R, Fabris N, Garzetti GG. Role of zinc and alpha-2 macroglobulin on thymic endocrine activity and on peripheral immune efficiency in cervical carcinoma. Br J Cancer. 1999;79(3–4):358–365. PMC2362212 ↗ PMID 9888464

Age-Related Decline and Immunosenescence

1. [6] Consolini R, Legitimo A, Calleri A, Milani M. Distribution of age-related thymulin titres in normal subjects through the course of life. Clin Exp Immunol. 2000;121(3):444–447. PMC1905732 ↗ PMID 10971509

NK Cell Activity

1. [11] Oliver MA, Marsh JA. In vivo thymulin treatments enhance avian lung natural killer cell cytotoxicity in response to infectious bronchitis virus. Int Immunopharmacol. 2003;3(2):241–252. PMID 12538040 ↗ DOI: 10.1016/s1567-5769(02)00236-9

Cytokine Modulation and Anti-Inflammatory Mechanisms

1. [12] Lunin SM, Khrenov MO, Novoselova TV, Parfenyuk SB, Novoselova EG. Thymulin, a thymic peptide, prevents the overproduction of pro-inflammatory cytokines and heat shock protein Hsp70 in inflammation-bearing mice. Immunol Invest. 2008;37(8):858–873. PMID 18991101 ↗ DOI: 10.1080/08820130802447629
2. [13] Novoselova EG, Khrenov MO, Glushkova OV, Lunin SM, Parfenyuk SB, Novoselova TV, Fesenko EE. Anti-Inflammatory Effects of IKK Inhibitor XII, Thymulin, and Fat-Soluble Antioxidants in LPS-Treated Mice. Mediators Inflamm. 2014;2014:724838. PMC4089567 ↗ DOI: 10.1155/2014/724838
3. [18] Lunin SM, Khrenov MO, Novoselova TV, Parfenyuk SB, Glushkova OV, Fesenko EE, Novoselova EG. Modulation of inflammatory response in mice with severe autoimmune disease by thymic peptide thymulin and an inhibitor of NF-kappaB signalling. Int Immunopharmacol. 2015;25(2):368–374. PMID 25662754 ↗ DOI: 10.1016/j.intimp.2015.01.021

Analgesic and Neuroprotective Properties

1. [14] Nasseri B, Zaringhalam J, Daniari S, Manaheji H, Abbasnejad Z, Nazemian V. Thymulin treatment attenuates inflammatory pain by modulating spinal cellular and molecular signaling pathways. Int Immunopharmacol. 2019;70:89–97. PMID 30851702 ↗ DOI: 10.1016/j.intimp.2019.02.042
2. [15] Safieh-Garabedian B, Dardenne M, Pleau JM, Saadé NE. Potent analgesic and anti-inflammatory actions of a novel thymulin-related peptide in the rat. Br J Pharmacol. 2002;136(3):421–428. PMC1573422 ↗ DOI: 10.1038/sj.bjp.0704770
3. [16] Safieh-Garabedian B, Nomikos M, Saadé N. Targeting inflammatory components in neuropathic pain: The analgesic effect of thymulin related peptide. Neurosci Lett. 2019;692:65–70. PMID 30503917 ↗ DOI: 10.1016/j.neulet.2018.11.041
4. [17] Haddad JJ, Hanbali LH. The Anti-Inflammatory and Immunomodulatory Activity of Thymulin Peptide is NF-kappaB-Dependent and Involves the Downregulation of IkappaB-alpha. Am J Med Biol Res. 2013;1(2):35–44. Full text ↗ DOI: 10.12691/ajmbr-1-2-2
5. [25] Dardenne M, Saade N, Safieh-Garabedian B. Role of thymulin or its analogue as a new analgesic molecule. Ann N Y Acad Sci. 2006;1088:153–163. PMID 17192563 ↗ DOI: 10.1196/annals.1366.006

Neuroendocrine-Immune Axis and Pituitary

1. [22] Reggiani PC, Schwerdt JI, Console GM, Roggero EA, Dardenne M, Goya RG. Physiology and therapeutic potential of the thymic peptide thymulin. Curr Pharm Des. 2014;20(29):4690–4696. PMID 24588820 ↗ DOI: 10.2174/1381612820666140130211157
2. [23] Hadley AJ, Rantle CM, Buckingham JC. Thymulin stimulates corticotrophin release and cyclic nucleotide formation in the rat anterior pituitary gland. Neuroimmunomodulation. 1997;4(2):62–69. PMID 9483196 ↗ DOI: 10.1159/000097322
3. [24] Reggiani PC, Morel GR, Console GM, Barbeito CG, Rodriguez SS, Brown OA, Bellini MJ, Pleau JM, Dardenne M, Goya RG. The Thymus-Neuroendocrine Axis: Physiology, Molecular Biology, and Therapeutic Potential of the Thymic Peptide Thymulin. Ann N Y Acad Sci. 2009;1153:98–106. PMC2688715 ↗ DOI: 10.1111/j.1749-6632.2009.04375.x

Gene Therapy and Advanced Delivery

1. [19] Novoselova EG, Lunin SM, Glushkova OV, Khrenov MO, Parfenyuk SB, Zakharova NM, Fesenko EE. Thymulin, free or bound to PBCA nanoparticles, protects mice against chronic septic inflammation. PLoS ONE. 2018;13(5):e0197601. Full text ↗ DOI: 10.1371/journal.pone.0197601
2. [20] Reggiani PC, Barbeito CG, Zuccolilli GO, Console GM, Flamini AM, Dardenne M, Goya RG. Neonatal Thymulin Gene Therapy Prevents Ovarian Dysgenesis and Attenuates Reproductive Derangements in Nude Female Mice. Endocrinology. 2012;153(8):3922–3931. PMC3404341 ↗ PMID 22700775
3. [21] Reggiani PC, Poch B, Console GM, Rimoldi OJ, Schwerdt JI, Tungler V, Garcia-Bravo MM, Dardenne M, Goya RG. Thymulin-Based Gene Therapy and Pituitary Function in Animal Models of Aging. Neuroimmunomodulation. 2011;18(5):279–285. PMC3221262 ↗ PMID 21952687
4. [26] Nanoparticle-based thymulin gene therapy therapeutically reverses key pathology of experimental allergic asthma. Sci Adv. 2020;6(25):eaay7973. PMC7286682 ↗ DOI: 10.1126/sciadv.aay7973
5. [27] Novoselova EG, et al. Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice. Int J Mol Sci. 2019;20(21):5374. PMC6862195 ↗ DOI: 10.3390/ijms20215374