Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells.

Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117+ cells into mature CD28+T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28+, CD4+, CD8+T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28+T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.

Precursors of thymic peptides as stress sensors.

INTRODUCTION: A large volume of data indicates that the known thymic hormones, thymulin, thymopoietin, thymosin-α, thymosin-ß, and thymic humoral factor-y2, exhibit different spectra of activities. Although large in volume, available data are rather fragmented, resulting in a lack of understanding of the role played by thymic hormones in immune homeostasis. AREA COVERED: Existing data compartmentalizes the effect of thymic peptides into 2 categories: influence on immune cells and interconnection with neuroendocrine systems. The current study draws attention to a third aspect of the thymic peptide effect that has not been clarified yet, wherein ubiquitous and highly abundant intranuclear precursors of so called 'thymic peptides' play a fundamental role in all somatic cells. EXPERT OPINION: Our analysis indicated that, under certain stress-related conditions, these precursors are cleaved to form immunologically active peptides that rapidly leave the nucleus and intracellular spaces, to send 'distress signals' to the immune system, thereby acting as stress sensors. We propose that these peptides may form a link between somatic cells and immune as well as neuroendocrine systems. This model may provide a better understanding of the mechanisms underlying immune homeostasis, leading thereby to the development of new therapeutic regimes utilizing the characteristics of thymic peptides.

[Thymus and adaptive changes of bone marrow cell composition in animals of different age].

The influence of thymus removal or administration of thymalin, thymic peptide factor, on number of cells-precursors for colonies of fibroblasts (CFC-F) and for granulocyte-macrophageal colonies (CFC-GM), CD(4+)-cells in bone marrow in CBA mice of different age in some seasons was investigated. It was shown that in adult mice the orientation of influence thymic activity modulation on amount of these types cells is dependent from seasons. It was shown the season possibility of direct effect of thymic stroma supernatant, in which was thymic serum factor (FTS), or the synthetic FTS on the amount of CFC-F and CFC-GM in bone marrow of adult mice; in old mice thymic supernatant increased in vitro the amount of CD(4+)-cells. FTS level in old mice increased after administration of thymalin, the rhythm of CD(4+)-cells number in bone marrow and of corticosterone serum content restored.

[Characteristics of the pineal gland and thymus relationship in aging].

The review presents the interference between thymus and pineal gland during their involution. The research data of thymus peptides influence on pineal gland and pineal peptides on thymus are summarized. Analysis of these data showed that pineal peptides (Epithalamin, Epitalon) had more effective geroprotective effect on thymus involution in comparison with geroprotective effect of thymic peptides (Thymalin, Thymogen) on involution of pineal gland. The key mechanisms of pineal peptides effect on thymus dystrophy is immunoendocrine cooperation, which is realized as transcription's activation of various proteins.

[Mechanisms of the hypothalamic-pituitary and immune system regulation: the role of gonadotropin-releasing hormone and immune mediators].

Different aspects of the reciprocal regulatory influence of systems producing the immune and gonadotropin-releasing hormone (GnRH) in pre- and postnatal ontogeny are discussed in this review. GnRH is a neurohormone synthesized by a small population of neurons located in the anterior hypothalamus, which regulates the secretion of gonadotropines in the anterior lobe of the pituitary gland and they finally regulate the synthesis of sex steroids. Particular attention is given to analysis of the data involving the role of thymus peptides and cytokines in GnRH-system regulation in the normal condition and in the case of inflammation development caused by endotoxines in adult animals. The main prospects of the studies involving the influence of proinflammatory cytokines on GnRH-neuron migration and differentiation in prenatal ontogenesis are also discussed.

Thymus hormones as prospective anti-inflammatory agents.

IMPORTANCE OF THE FIELD: Inflammatory diseases are characterized by severe immune imbalances, leading to excessive or inappropriate release of mediators, which, in turn, result in massive damage to organs and systems. Effective means to control inappropriate immune reactions are often life-critical needs. Available data on the role of thymus-derived hormones in inflammation show their great potential. AREAS COVERED IN THIS REVIEW: The review aims to systematize information for the last two decades on immune system regulation by thymic peptide hormones, with a primary focus on the role of these hormones in the systemic inflammatory response and inflammatory diseases. Anti-inflammatory potential of three thymic hormones - thymulin, thymosin-alpha, and thymopoietin - is discussed, reviewing recently published clinical and experimental studies. WHAT THE READER WILL GAIN: Our analysis revealed the regulation of inflammatory processes via thymic hormones that could be prospective for therapeutic application. This regulation may be mediated through thymic hormone effects on peripheral immune cell activities and bidirectional coupling between thymic hormones and the hypothalamic-pituitary-adrenal axis. TAKE-HOME MESSAGE: In view of the role of thymic hormones in immune and neuroendocrine systems, they could be suitable as therapeutic agents for inflammation.

RNA-binding proteins heterogeneous nuclear ribonucleoprotein A1, E1, and K are involved in post-transcriptional control of collagen I and III synthesis.

Collagen types I and III, coded by COL1A1/COL1A2 and COL3A1 genes, are the major fibrillar collagens produced by fibroblasts, including cardiac fibroblasts of the adult heart. Characteristic for different cardiomyopathies is a remodeling process associated with an upregulation of collagen synthesis, which leads to fibrosis. We report identification of three mRNA-binding proteins, heterogeneous nuclear ribonucleoprote (hnRNP) A1, E1, and K, as positive effectors of collagen synthesis acting at the post-transcriptional level by interaction with the 3'-untranslated regions (3'-UTRs) of COL1A1, 1A2, and 3A1 mRNAs. In vitro, binding experiments (electromobility shift assay and UV cross-linking) reveal significant differences in binding to CU- and AU-rich binding motifs. Reporter gene cell transfection experiments and RNA stability assays show that hnRNPs A1, E1, and K stimulate collagen expression by stabilizing mRNAs. Collagen synthesis is activated via the angiotensin II type 1 (AT1) receptor. We demonstrate that transforming growth factor-beta1, a major product of stimulated AT1 receptor, does not activate solely collagen synthesis but synergistically the synthesis of hnRNP A1, E1, and K as well. Thus, post-transcriptional control of collagen synthesis at the mRNA level may substantially be caused by alteration of the expression of RNA-binding proteins. The pathophysiological impact of this finding was demonstrated by screening the expression of hnRNP E1 and K in cardiovascular diseases. In the heart muscle of patients experiencing aortic stenosis, ischemic cardiomyopathy, or dilatative cardiomyopathy, a significant increase in the expression of hnRNP E1, A1, and K was found between 1.5- and 4.5-fold relative to controls.

New data on the involvement of ectodermal epithelium in extrathymic differentiation of human T-lymphocytes.

Thymalin accumulates only in young cells of the skin ectodermal epithelium and mucosa of the anterior portions of the digestive and respiratory systems. After appearance of keratin the cells no longer accumulate thymalin. Similarly as in the thymus, thymalin content in the ectodermal epithelium of the organs is subjected to age-associated involution.

[The role of thyroid and thymic hormones in regulation of fibrinolytic and pro-coagulant activity of leukocytes in patients with acute destructive appendicitis]. / Rol' tiroidnykh i timicheskikh gormonov v reguliatsii fibrinoliticheskoi i prokoaguliantnoi aktivnosti leikotsitov u bol'nykh s ostrym destruktivnym appenditsitom.

Dynamics of the leukocytes fibrinolytic activity and expression of receptors to thrombin by lymphocytes were studied in patients with an acute destructive appendicitis on background of lowering of the endogenous triiodothyronine synthesis. Misbalance of functional integration of immune system, forming conditions for pronounced disorder of the wound process kinetics, was revealed. Conduction of restoration therapy in the early postoperative period, using thyroid hormones, was substantiated in patients with the triiodothyronine low level syndrome for prophylaxis of complications.

Ubc9 is a novel modulator of the induction properties of glucocorticoid receptors.

The EC(50) of agonists and the partial agonist activity of antagonists are crucial parameters for steroid hormone control of gene expression and endocrine therapies. These parameters have been shown to be modulated by a naturally occurring cis-acting element, called the glucocorticoid modulatory element (GME) that binds two proteins, GMEB-1 and -2. We now present evidence that the GMEBs contact Ubc9, which is the mammalian homolog of a yeast E2 ubiquitin-conjugating enzyme. Ubc9 also binds to glucocorticoid receptors (GRs). Ubc9 displays no intrinsic transactivation activity but modifies both the absolute amount of induced gene product and the fold induction by GR. With high concentrations of GR, added Ubc9 also reduces the EC(50) of agonists and increases the partial agonist activity of antagonists in a manner that is independent of the ability of Ubc9 to transfer SUMO-1 (small ubiquitin-like modifier-1) to proteins. This new activity of Ubc9 requires only the ligand binding domain of GR and part of the hinge region. Interestingly, Ubc9 modulation of full-length GR transcriptional properties can be seen in the absence of a GME. This, though, is consistent with the GME acting by increasing the local concentration of Ubc9, which then activates a previously unobserved target in the transcriptional machinery. With high concentrations of Ubc9 and GR, Ubc9 binding to GR appears to be sufficient to permit Ubc9 to act independently of the GME.

Heterogeneous nuclear ribonucleoprotein A1 and UP1 protect mammalian telomeric repeats and modulate telomere replication in vitro.

The heterogeneous nuclear ribonucleoprotein A1 protein and a shortened derivative (UP1) promote telomere elongation in mammalian cells. To gain insights into the function of A1/UP1 in telomere biogenesis, we have investigated the binding properties of recombinant A1/UP1 and derivatives to single-stranded DNA oligonucleotides. Our results indicate that UP1 prefers to bind to DNA carrying single-stranded telomeric extensions at the 3' terminus. The RNA recognition motif 1 is sufficient for strong and specific binding to oligomers carrying vertebrate telomeric repeats. We find that the binding of A1/UP1 protects telomeric sequences against degradation by endo- and exonucleases. Moreover, A1/UP1 binding prevents extension by telomerase and terminal deoxynucleotidyltransferase and inhibits rNTP-dependent DNA synthesis in vitro. These observations are consistent with the hypothesis that A1/UP1 is a telomere end-binding protein that plays a role in the maintenance of long 3' overhangs.

Role of thymic peptides as transmitters between the neuroendocrine and immune systems.

Thymic peptides, a heterogenous family of polypeptidic hormones synthesized within the thymus, not only exert important regulatory effects within both the immune and neuroendocrine systems but are also themselves subject to control by hormones derived from the hypothalamic-pituitary-adrenal axis (HPA) and other endocrine glands. Regarding thymic hormonal function, thymulin production is up-regulated by several hormones, including prolactin, growth hormone and thyroid hormones. Other aspects of the physiology of thymic epithelial cells can also be modulated by hormones and neuropeptides, particularly cytokeratin expression, cell growth and production of extracellular matrix proteins, thus characterizing the pleiotrophic action of these molecules on the thymic epithelium. Conversely, thymic-derived peptides also regulate hormone release from the HPA axis and may act directly on target endocrine glands of this axis, modulating gonadal tissues. In addition, it has recently been shown that thymulin can modulate some peripheral nervous sensory functions, including those related to sensitivity to pain. According to the dose given, thymulin induces or reduces hyperalgesia related to both mechanical and thermal nociceptors and thus represents an important interface between the immune, endocrine and nervous systems.

The thymus-pituitary axis and its changes during aging.

The pituitary-thymic axis constitutes a bidirectional circuit where the ascending feedback loop is effected by thymic factors of epithelial origin. The aim of the present article is to review the evidence demonstrating that aging brings about a progressive disruption in the integration of this network. In doing so, we briefly review the experimental evidence supporting the view that immune and neuroendocrine aging are interdependent processes. The advantages and limits of the nude mouse as a model of thymus-dependent accelerated aging is also discussed. Next, we review a number of studies which show that the endocrine thymus produces several bioactive molecules, generally called thymic hormones, which in addition to possessing immunoregulatory properties are also active on nervous and endocrine circuits. In particular, the reported activities of thymosin fraction 5 (TF5), thymosin alpha-1 and thymosin beta-4 on beta-endorphin, ACTH, glucocorticoids, LHRH and LH secretion in different animal and cell models are reviewed. The known hypophysiotropic actions of other thymic hormones like thymulin, homeostatic thymus hormone (HTH) and thymus factor are summarized. Aging has a significant impact on pituitary responsiveness to thymic hormones. Thus, it has been reported that TF5 and HTH have thyrotropin-inhibiting activity in young but not in old rats. Furthermore, intravenous administration of HTH was also able to reduce plasma GH and increase corticosterone levels in both young and old rats, although these responses were much weaker in the old animals. Further evidence on this topic is discussed. It is proposed that in addition to its central role in the regulation of the immune function, the thymus gland may extend its influence to nonimmunologic components of the body, including the neuroendocrine system. The early onset of thymus involution might therefore act as a triggering event which would initiate the gradual decline in homeostatic potential that characterizes the aging process.

Suppression of glucocorticoid-induced thymocyte apoptosis by co-culture with thymic epithelial cells.

There are many reports concerning glucocorticoid-induced thymocyte apoptosis, but little is known about the participation of thymic stromal cells, especially the thymic epithelial (TE) cells, in the apoptosis. In this study, we investigated the in vitro effect of TE cells on dexamethasone-induced DNA fragmentation of thymocytes as a parameter for apoptosis. By co-culture of thymocytes with TE cell line, at the condition without cell-cell contact, the DNA fragmentation of thymocytes caused by physiological level of glucocorticoid was significantly suppressed. Same effect was detected when treated the thymocytes with the supernatant from the cultures of TE cell line. These results suggest that the humoral factors released from TE cells rescue the thymocytes from the glucocorticoid-induced apoptosis. Chemical and physico-chemical nature of the factors are discussed.

[Endocrine function of the thymus and ionizing radiation]. / Endokrinnaia funktsiia timusa i ioniziruiushchaia radiatsiia.

It is shown that external as well as incorporated radiation inhibit the endocrine function of the thymus in the result of the direct and indirect effects. Postradiation deficiency of thymic hormones plays a significant role in pathogenesis of functional disorders in the immunity system. Immunocorrection with thymic agents is the most effective method when the mechanism of inhibition of thymic hormonal function are taken into account.

Characterization of the stimulatory actions of thymic factor(s) on basal and gonadotropin-induced steroidogenesis in cultured rat granulosa cells.

Recently, there have been numerous reports that demonstrate the importance of the thymus gland in reproductive physiology. Previously, we have reported that thymic factors (TFs) which are present in thymic cell culture-conditioned medium (TCM) could stimulate basal progesterone and estradiol production from cultured rat granulosa cells. The current study attempts to characterize the stimulatory actions of TFs on both basal and FSH induced steroidogenesis. Thymic epithelial cells from immature female rats were isolated and used for production of TCM. Granulosa cells were obtained from immature diethylstilbestrol (DES)-treated rats. TFs stimulated both basal and FSH-induced progesterone secretions 80 and 17 times, respectively, as compared to the control media. The effects of TFs on basal and FSH-induced 20 alpha-hydroxyprogesterone secretion were comparable to those on progesterone production (40x and 10x, respectively). In addition, TCM stimulated basal and FSH-induced estradiol secretion approximately 4 and 2.5 times, respectively, compared to control. Stimulation of aromatase enzyme activity followed a similar trend as estradiol secretion, and TCM stimulated basal and FSH-stimulated aromatase enzyme activity approximately 15 and 3 times, respectively compared to control. Thus, these results indicate that the observed increases in progesterone and estradiol secretions in TCM-treated rat granulosa cells are likely to be due to elevated activities of specific steroidogenic enzymes. Measurements of total cell protein and DNA synthesis indicate that enhanced steroidogenesis in TCM-treated cells is not due to increased cell growth and/or proliferation. Rather, the enhanced steroidogenesis is probably due to an increased steroid biosynthetic capability of the cells.(ABSTRACT TRUNCATED AT 250 WORDS)