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Frontiers in Endocrinology 2023The thymus gland is a central lymphoid organ in which developing T cell precursors, known as thymocytes, undergo differentiation into distinct type of mature T cells,... (Review)
Review
The thymus gland is a central lymphoid organ in which developing T cell precursors, known as thymocytes, undergo differentiation into distinct type of mature T cells, ultimately migrating to the periphery where they exert specialized effector functions and orchestrate the immune responses against tumor cells, pathogens and self-antigens. The mechanisms supporting intrathymic T cell differentiation are pleiotropically regulated by thymic peptide hormones and cytokines produced by stromal cells in the thymic microenvironment and developing thymocytes. Interestingly, in the same way as T cells, thymic hormones (herein exemplified by thymosin, thymulin and thymopoietin), can circulate to impact immune cells and other cellular components in the periphery. Evidence on how thymic function influences tumor cell biology and response of patients with cancer to therapies remains unsatisfactory, although there has been some improvement in the knowledge provided by recent studies. Herein, we summarize research progression in the field of thymus-mediated immunoendocrine control of cancer, providing insights into how manipulation of the thymic microenvironment can influence treatment outcomes, including clinical responses and adverse effects of therapies. We review data obtained from clinical and preclinical cancer research to evidence the complexity of immunoendocrine interactions underpinning anti-tumor immunity.
Topics: Humans; Thymus Gland; T-Lymphocytes; Cytokines; Neoplasms; Peptides; Tumor Microenvironment
PubMed: 37529610
DOI: 10.3389/fendo.2023.1168186 -
Proceedings of the National Academy of... Jun 1987Human thymopoietin and splenin were isolated from human thymus and spleen, respectively, by monitoring tissue fractionation with a bovine thymopoietin RIA cross-reactive...
Human thymopoietin and splenin were isolated from human thymus and spleen, respectively, by monitoring tissue fractionation with a bovine thymopoietin RIA cross-reactive with human thymopoietin and splenin. Bovine thymopoietin and splenin are 49-amino acid polypeptides that differ by only 2 amino acids at positions 34 and 43; the change at position 34 in the active-site region changes the receptor specificities and biological activities. The complete amino acid sequences of purified human thymopoietin and splenin were determined and shown to be 48-amino acid polypeptides differing at four positions. Ten amino acids, constant within each species for thymopoietin and splenin, differ between the human and bovine polypeptides. The pentapeptide active site of thymopoietin (residues 32-36) is constant between the human and bovine thymopoietins, but position 34 in the active site of splenin has changed from glutamic acid in bovine splenin to alanine in human splenin, accounting for the biological activity of the human but not the bovine splenin on the human T-cell line MOLT-4.
Topics: Amino Acid Sequence; Carboxypeptidases; Cyanogen Bromide; Humans; Peptide Fragments; Spleen; Thymopoietins; Thymus Gland; Thymus Hormones; Trypsin
PubMed: 3473468
DOI: 10.1073/pnas.84.11.3545 -
Proceedings of the National Academy of... Mar 1991Thymopoietin, a polypeptide hormone of the thymus that has pleiotropic actions on the immune, endocrine, and nervous systems, potently interacts with the neuromuscular...
Thymopoietin, a polypeptide hormone of the thymus that has pleiotropic actions on the immune, endocrine, and nervous systems, potently interacts with the neuromuscular nicotinic acetylcholine receptor. Thymopoietin binds to the nicotinic alpha-bungarotoxin (alpha-BGT) receptor in muscle and, like alpha-BGT, inhibits cholinergic transmission at this site. Evidence is given that radiolabeled thymopoietin similarly binds to a nicotinic alpha-BGT-binding site within the brain and does so with the characteristics of a specific receptor ligand. Thus specific binding to neuronal membranes was saturable, of high affinity (Kd = 8 nM), linear with increased tissue concentration, and readily reversible; half-time was approximately 5 min for association and 10 min for dissociation. Binding of 125I-labeled thymopoietin was displaced not only by unlabeled thymopoietin but also by alpha-BGT and the nicotinic receptor ligands d-tubocurarine and nicotine; various other receptor ligands (muscarinic, adrenergic, and dopaminergic) did not affect binding of 125I-labeled thymopoietin. Thymopoietin was shown by ELISA to be present in brain extracts, displacement curves of thymus and brain extracts being parallel to the standard thymopoietin curve, and Western (immuno) blot identified in brain and thymus extracts a thymopoietin-immunoreactive polypeptide of the same molecular mass as purified thymopoietin polypeptide. We conclude that thymopoietin and thymopoietin-binding sites are present within the brain and that the receptor for thymopoietin is the previously identified nicotinic alpha-BGT-binding site of neuronal tissue.
Topics: Animals; Binding, Competitive; Brain; Bungarotoxins; Cell Membrane; Female; Humans; Kinetics; Liver; Organ Specificity; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Cholinergic; Receptors, Nicotinic; Receptors, Peptide; Thymopoietins; Thymus Gland; Thyroid Gland; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 1848710
DOI: 10.1073/pnas.88.6.2603 -
Frontiers in Bioscience (Landmark... Jan 2009T-cell development is characterised by a complex series of events in the thymus, which results in the development of self-restricted immunocompetent lymphocytes. We have... (Review)
Review
T-cell development is characterised by a complex series of events in the thymus, which results in the development of self-restricted immunocompetent lymphocytes. We have previously reported the expression of neuropeptides in the thymus of various species, highlighting the evolutionary importance of neuroendocrine interactions in thymocyte development. Despite the many physiological and functional similarities in their immune systems, no study has addressed the importance of neuropeptides and thymic hormones in T-cell development in Xenopus. Immunohistochemical analysis revealed that the neuropeptides substance P, neuropeptide Y, somatostatin, calcitonin gene related peptide, and vasoactive intestinal polypeptide and the thymic hormones thymosin alpha1, thymosin beta4, and thymopoietin are found in the Xenopus thymus. This was further corroborated by RT-PCR. Furthermore, double staining revealed that neuropeptides and thymic hormones are coexpressed within the epithelial cell component of the thymus. These results show that neuropeptides and thymic hormones are expressed in the thymus of Xenopus, and suggest that they are likely to play a role in T-cell development.
Topics: Animals; Neuropeptides; Thymopoietins; Thymosin; Thymus Gland; Xenopus
PubMed: 19273180
DOI: 10.2741/3358 -
The Cochrane Database of Systematic... Feb 2011Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) are thought to enhance the immune system of cancer patients in order to fight the growth of tumour... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) are thought to enhance the immune system of cancer patients in order to fight the growth of tumour cells and to resist infections due to immunosuppression induced by the disease and antineoplastic therapy.
OBJECTIVES
To evaluate the effectiveness of pTE and sTP for the management of cancer.
SEARCH STRATEGY
We searched CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE, EMBASE, AMED, BIOETHICSLINE, BIOSIS, CATLINE, CISCOM, HEALTHSTAR, HTA, SOMED and LILACS (to February 2010).
SELECTION CRITERIA
Randomised trials of pTE or sTP in addition to chemotherapy or radiotherapy, or both, compared to the same regimen with placebo or no additional treatment in adult cancer patients.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data from published trials. We derived odds ratios (OR) from overall survival (OS) and disease-free survival (DFS) rates, tumour response (TR) rates, and rates of adverse effects (AE) related to antineoplastic treatments. We used a random-effects model for meta-analysis.
MAIN RESULTS
We identified 26 trials (2736 patients). Twenty trials investigated pTE (thymostimulin or thymosin fraction 5) and six trials investigated sTP (thymopentin or thymosin α(1)). Twenty-one trials reported results for OS, six for DFS, 14 for TR, nine for AE and 10 for safety of pTE and sTP. Addition of pTE conferred no benefit on OS (RR 1.00, 95% CI 0.79 to 1.25); DFS (RR 0.97, 95% CI 0.82 to 1.16); or TR (RR 1.07, 95% CI 0.92 to 1.25). Heterogeneity was moderate to high for all these outcomes. For thymosin α(1) the pooled RR for OS was 1.21 (95% CI 0.94 to 1.56, P = 0.14), with low heterogeneity; and 3.37 (95% CI 0.66 to 17.30, P = 0.15) for DFS, with moderate heterogeneity. The pTE reduced the risk of severe infectious complications (RR 0.54, 95% CI 0.38 to 0.78, P = 0.0008; I² = 0%). The RR for severe neutropenia in patients treated with thymostimulin was 0.55 (95% CI 0.25 to 1.23, P = 0.15). Tolerability of pTE and sTP was good. Most of the trials had at least a moderate risk of bias.
AUTHORS' CONCLUSIONS
Overall, we found neither evidence that the addition of pTE to antineoplastic treatment reduced the risk of death or disease progression nor that it improved the rate of tumour responses to antineoplastic treatment. For thymosin α(1), there was a trend for a reduced risk of dying and of improved DFS. There was preliminary evidence that pTE lowered the risk of severe infectious complications in patients undergoing chemotherapy or radiotherapy.
Topics: Adjuvants, Immunologic; Adult; Disease-Free Survival; Female; Humans; Immune System; Immunocompromised Host; Male; Neoplasms; Peptides; Thymalfasin; Thymopentin; Thymosin; Thymus Extracts; Thymus Gland
PubMed: 21328265
DOI: 10.1002/14651858.CD003993.pub3 -
International Journal of Molecular... Nov 2022Metabolic alterations that support the supply of biosynthetic molecules necessary for rapid and sustained proliferation are characteristic of cancer. Some cancer cells... (Review)
Review
Metabolic alterations that support the supply of biosynthetic molecules necessary for rapid and sustained proliferation are characteristic of cancer. Some cancer cells rely on glutamine to maintain their energy requirements for growth. Glutamine is an important metabolite in cells because it not only links to the tricarboxylic acid cycle by producing α-ketoglutarate by glutaminase and glutamate dehydrogenase but also supplies other non-essential amino acids, fatty acids, and components of nucleotide synthesis. Altered glutamine metabolism is associated with cancer cell survival, proliferation, metastasis, and aggression. Furthermore, altered glutamine metabolism is known to be involved in therapeutic resistance. In recent studies, lncRNAs were shown to act on amino acid transporters and glutamine-metabolic enzymes, resulting in the regulation of glutamine metabolism. The lncRNAs involved in the expression of the transporters include the abhydrolase domain containing 11 antisense RNA 1, LINC00857, plasmacytoma variant translocation 1, Myc-induced long non-coding RNA, and opa interacting protein 5 antisense RNA 1, all of which play oncogenic roles. When it comes to the regulation of glutamine-metabolic enzymes, several lncRNAs, including nuclear paraspeckle assembly transcript 1, XLOC_006390, urothelial cancer associated 1, and thymopoietin antisense RNA 1, show oncogenic activities, and others such as antisense lncRNA of glutaminase, lincRNA-p21, and ataxin 8 opposite strand serve as tumor suppressors. In addition, glutamine-dependent cancer cells with lncRNA dysregulation promote cell survival, proliferation, and metastasis by increasing chemo- and radio-resistance. Therefore, understanding the roles of lncRNAs in glutamine metabolism will be helpful for the establishment of therapeutic strategies for glutamine-dependent cancer patients.
Topics: Humans; RNA, Long Noncoding; Glutamine; Drug Resistance, Neoplasm; Urinary Bladder Neoplasms; RNA, Antisense
PubMed: 36499136
DOI: 10.3390/ijms232314808 -
Frontiers in Immunology 2021The innate and adaptive immune systems act in concert to protect us from infectious agents and other harmful substances. As a state of temporary or permanent immune...
The innate and adaptive immune systems act in concert to protect us from infectious agents and other harmful substances. As a state of temporary or permanent immune dysfunction, immunosuppression can make an organism more susceptible to infection, organ injury, and cancer due to damage to the immune system. It takes a long time to develop new immunomodulatory agents to prevent and treat immunosuppressive diseases, with slow progress. Toll-like receptor 2 (TLR2) agonists have been reported as potential immunomodulatory candidates due to their effective activation of immune responses. It has been demonstrated that thymopentin (TP5) could modulate immunity by binding to the TLR2 receptor. However, the fairly short half-life of TP5 greatly reduces its pharmacological potential for immunosuppression therapy. Although peptide cathelicidin 2 (CATH2) has a long half-life, it shows poor immunomodulatory activity and severe cytotoxicity, which seriously hampers its clinical development. Peptide hybridization is an effective approach for the design and engineering of novel functional peptides because hybrid peptides combine the advantages and benefits of various native peptides. In this study, to overcome all these challenges faced by the parental peptides, six hybrid peptides (CaTP, CbTP, CcTP, TPCa, TPCb, and TPCc) were designed by combining the full-length TP5 with different active fragments of CATH2. CbTP, the most potent TLR2 agonist among the six hybrid peptides, was effectively screened through in silico analysis and experiments. The CbTP peptide exhibited lower cytotoxicity than either CATH2 or TP5. Furthermore, the immunomodulatory effects of CbTP were confirmed in a CTX-immunosuppressed mouse model, which showed that CbTP has increased immunopotentiating activity and physiological stability compared to the parental peptides. CbTP successfully inhibited immunosuppression and weight loss, increased immune organ indices, and improved CD4/CD8 T lymphocyte subsets. In addition, CbTP significantly increased the production of the cytokine TNF-α and IL-6, and the immunoglobulins IgA, IgM, and IgG. The immunoenhancing effects of CbTP were attributed to its TLR2-binding activity, promoting the formation of the TLR2 cluster, the activation of the TLR2 receptor, and thus activation of the downstream MyD88-NF-кB signaling pathway.
Topics: Animals; Cells, Cultured; Cyclophosphamide; Cytokines; Female; Humans; Immunity; Immunity, Humoral; Immunocompromised Host; Immunomodulation; Mice; Mice, Inbred BALB C; Models, Animal; Peptides; RAW 264.7 Cells; T-Lymphocytes; Thymopentin; Toll-Like Receptor 2
PubMed: 34122400
DOI: 10.3389/fimmu.2021.620494 -
Proceedings of the National Academy of... May 1984Thymopoietin, a 49 amino acid polypeptide hormone of the thymus discovered by its effect on neuromuscular transmission, was later shown to induce T-cell differentiation...
Thymopoietin, a 49 amino acid polypeptide hormone of the thymus discovered by its effect on neuromuscular transmission, was later shown to induce T-cell differentiation and to affect immunoregulatory balance. A radioimmunoassay for thymopoietin revealed a crossreaction with a product found in spleen and lymph node but not other tissues. This product, named splenin, differs from thymopoietin only in position 34, aspartic acid for bovine thymopoietin and glutamic acid for bovine splenin. Synthetic pentapeptides corresponding to residues 32-36, called thymopentin and splenopentin, reproduce biological activities of thymopoietin and splenin, respectively. Thus thymopoietin and thymopentin affect neuromuscular transmission and induce the phenotypic differentiation of T precursor cells in vitro while inhibiting phenotypic differentiation of B cells. Splenin and splenopentin, in contrast, do not affect neuromuscular transmission, and they induce both T- and B-cell precursors.
Topics: Amino Acid Sequence; Animals; Biological Assay; Dose-Response Relationship, Drug; Lymphokines; Mice; Neuromuscular Junction; Spleen; Structure-Activity Relationship; Thymopoietins; Thymus Hormones
PubMed: 6585832
DOI: 10.1073/pnas.81.9.2847 -
Journal of Cancer 2019As one of the deadliest and most common malignancies in the world, gastric cancer (GC) represents a serious health threat. Despite recent advances in the field, the...
As one of the deadliest and most common malignancies in the world, gastric cancer (GC) represents a serious health threat. Despite recent advances in the field, the prognosis of patients with metastatic GC remains poor. In this study, we aimed to investigate the clinical impact of the alpha subunit of the nuclear structural protein thymopoietin (TMPO-α) in GC. The expression of TMPO-α in seven gastric cell lines was detected by immunoblotting. The expression level of TMPO-α levels in gastric tissues collected from 145 GC patients was examined by immunohistochemistry. The correlations between TMPO-α expression level and clinicopathologic parameters, as well as the association of TMPO-α expression with overall survival, were assessed. Immunohistochemistry showed that the expression of TMPO-α was significantly higher in GC tissues and cells in comparison with non-tumor tissues and cells. Furthermore, the overexpression of TMPO-α in gastric tissues (56%) was positively associated with Lauren classification ( = 0.0159), nodal status ( = 0.0265), distant metastasis ( < 0.0001), stage ( = 0.0367), and degree of differentiation ( = 0.0009). Patients with high TMPO-α levels had a significantly poorer overall survival than those with low levels ( = 0.001). Multivariate Cox regression analysis also indicated that TMPO-α was an independent prognostic marker for GC ( = 0.045). In addition, studies conducted in GC cells indicated that knockdown of TMPO-α suppressed cell proliferation and invasion. These findings indicate that TMPO-α overexpression can predict clinicopathologic features and the outcome of patients with GC.
PubMed: 31602262
DOI: 10.7150/jca.30738 -
European Review For Medical and... Sep 2020This study aims to uncover the in vitro influences of lncRNA TMPO-AS1 on the progression of bladder cancer (BLCA) and the underlying mechanism.
OBJECTIVE
This study aims to uncover the in vitro influences of lncRNA TMPO-AS1 on the progression of bladder cancer (BLCA) and the underlying mechanism.
PATIENTS AND METHODS
Expression levels of TMPO-AS1 in BLCA tissues and normal bladder tissues were analyzed in The Cancer Genome Atlas (TCGA) database. Differential expressions of TMPO-AS1 in BLCA tissues and normal bladder epithelial tissues were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Potential influence of TMPO-AS1 on prognosis of BLCA patients was assessed. In vitro influences of TMPO-AS1 on proliferative and migratory abilities in T24 and UMUC-3 cells were evaluated by Cell Counting Kit-8 (CCK-8), transwell, and wound healing assay, respectively. Finally, the correlation between TMPO-AS1 and its sense RNA TMPO was assessed by analyzing TCGA database, clinical samples, and BLCA cell lines.
RESULTS
By analyzing TCGA database and clinical samples, it was found that TMPO-AS1 was upregulated in BLCA tissues compared with that in normal bladder tissues. Worse survival was observed in BLCA patients with high expression of TMPO-AS1. TMPO-AS1 level was correlated to muscle invasiveness and TNM stage of BLCA patients. In T24 and UMUC-3 cells, the knockdown of TMPO-AS1 suppressed proliferative and migratory abilities. TMPO-AS1 level was positively correlated to that of its sense RNA TMPO. Moreover, the knockdown of TMPO-AS1 downregulated mRNA and protein levels of TMPO in BLCA cells.
CONCLUSIONS
TMPO-AS1 is upregulated in BLCA tissue and closely linked to poor prognosis of BLCA patients.
Topics: Cell Line; Cell Movement; Cell Proliferation; Epithelium; Female; Humans; Male; Middle Aged; Nuclear Proteins; Prognosis; RNA, Long Noncoding; Thymopoietins; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 32964962
DOI: 10.26355/eurrev_202009_22812