Description of Thymosin Alpha-1

Thymosin Alpha-1, a naturally occurring peptide in the thymus, is recognized for modulating immune functions and responses. It's also been beneficial in reducing morbidity and mortality in sepsis and various infections. Studies suggest its potential to improve outcomes in severely ill COVID-19 patients by repairing lymphocytic immunity damage and preventing excessive T cell activation. Thymosin Aplha-1, and its analogues exhibit immune-modulating properties, inducing cytokine production, lymphocyte differentiation, and enhancing macrophage function. They act via Toll-like receptor activation in dendritic cells, potentially mitigating cytokine storms induced by SARS-CoV-2 infection. Clinical studies support their efficacy in various diseases, including viral infections and cancers. In COVID-19, Thymosin Alpha 1 has shown promise in reducing mortality and restoring immune function. Further research is warranted to explore its potential as a therapeutic agent or adjunctive treatment to mitigate disease severity. Now we would like to bring you closer to the effects of the peptide confirmed in several research studies.

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Research Confirmed Effects

1. Thymosin Alpha-1 In Immune Modulation

Thymosin Alpha-1 (Tα1) is a potent immunomodulator with pleiotropic effects on various immune cell subsets. The thymus is responsible for T-cells, which are the most important parts of the adaptive immune system, and help the immune system remember past infections and improve the function. The peptide works at a fundamental levels of the immune system, and simply activates signaling pathways and stimulates the production of cytokines. Acting through Toll-like receptors in dendritic cells, Thymosin Alpha-1 stimulates the production of immune-related cytokines, making it a potential treatment for immune suppression associated with aging, infection, or cancer. Extensive preclinical and clinical studies have demonstrated Tα1's ability to improve immune system function and its therapeutic potential in diverse diseases.

Combining Thymosin Alpha-1 (Tα1) with bursin-like peptide (BLP) as a recombinant fusion peptide (Tα1-BLP) enhances immune responses against avian influenza. This novel adjuvant boosts antibody titers, increases Th1- and Th2-type cytokine secretion, promotes lymphocyte proliferation, and provides protection against virus replication and lung damage. The study underscores Tα1-BLP's potential as an effective adjuvant for avian influenza vaccines, highlighting its immunopotentiating properties and immune protective effects.

Furthermore, in patients with sepsis, a life-threatening condition characterized by dysregulated immune response to infection, Thymosin Alpha-1 (Tα1) shows promise as an adjunctive therapy. Clinical studies demonstrate that Tα1 treatment, alone or in combination with anti-inflammatory agents, reduces mortality rates, enhances immune function, and lowers the incidence of secondary infections. However, the heterogeneous nature of sepsis poses challenges in generalizing clinical results, and future trials focusing on immunosuppressed individuals may provide further insights into Tα1's efficacy as a therapeutic option for sepsis.

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2. Thymosin Alpha-1 In Nerve Growth

The immune system plays an important role also in CNS nerve growth and development. Thymosin Alpha-1 has been found to significantly impact neurodevelopment in mice by enhancing cognitive function through peripheral administration. Studies suggest that this peptide influences gene expression related to neuron growth and connectivity, fostering an environment conducive to neurological development. Additionally, Thymosin Alpha-1 mitigates inflammation and dysfunction within the nervous system, ultimately improving brain structure and function.

In neonatal mice, administration of Thymosin Alpha-1 (Tα1) enhances cognitive abilities and promotes neurogenesis in the hippocampus. This effect is accompanied by increased levels of neurotrophic factors such as interleukin-4, interferon-gamma, brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor-1, along with a reduction in inflammatory cytokines like IL-6 and tumor necrosis factor-α. Tα1 induces a Th1-polarized immune response and protects against lipopolysaccharide-induced impairment of hippocampal neurogenesis, suggesting potential neuroprotective properties against infections.

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3. Thymosin Alpha-1 and Its Anti-Fungal Properties

Thymosin Alpha-1 (Tα1) emerges as a crucial mediator in activating dendritic cells (DCs) against fungal infections, particularly in response to Aspergillus fumigatus. Dendritic cells are a specific type of cell in the immune system, are important in helping the immune system to recognize fungal infections. Through the p38 mitogen-activated protein kinase/nuclear factor (NF)-kappaB-dependent pathway, Tα1 induces maturation and interleukin-12 production in fungus-pulsed DCs, facilitated by toll-like receptor (TLR) signaling via the myeloid differentiation factor 88 (MyD88)-dependent pathway. This activation primes T-helper (Th) cell 1-dependent antifungal immunity in vivo, leading to accelerated myeloid cell recovery and enhanced protection against aspergillosis, particularly in highly susceptible individuals such as those receiving hematopoietic transplants.

Furthermore, Tα1, initially characterized for its diverse effects on the immune system, is now recognized as a key regulator of inflammation, immunity, and tolerance. Its pivotal role in modulating DC function underscores its potential in inducing various forms of immunity and tolerance. Recent findings reveal Tα1's ability to prime DCs for antifungal Th1 resistance, activate plasmacytoid DCs (pDCs) via TLR9/MyD88-dependent viral recognition, and induce indoleamine 2,3-dioxygenase activity, promoting tolerance towards self and microbial antigens. This intrinsic regulation of immune homeostasis positions Tα1 as a promising candidate for instructive immunotherapy, leveraging DCs and tryptophan catabolism to control inflammation, immunity, and tolerance across diverse clinical contexts.

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4. Thymosin Alpha-1 in Hepatitis

Thymosin Alpha-1 (Tα1), initially utilized for hepatitis B and C treatment, is now gaining recognition for its potential across a spectrum of diseases. Approved in numerous countries, for example currently approved for treatment of hepatitis B and C in over 35 different developing countries, Tα1 is undergoing late-stage clinical trials in the US and Europe for hepatitis C and stage IV melanoma. Recent trials suggest broader applications, including septic shock, acute respiratory distress syndrome, peritonitis, acute cytomegalovirus infection, tuberculosis, severe acute respiratory syndrome, and lung infections in critically ill patients. Additionally, Tα1 shows promise as a chemoprotection agent during chemotherapy, indicating its emerging role in treating life-threatening and chronic diseases.

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5. Thymosin Alpha-1 and HIV

Thymosin Alpha-1 (Tα1) presents a promising avenue for enhancing immune reconstitution in HIV-1-infected individuals undergoing antiretroviral therapy. Despite the benefits of antiretroviral therapy, complete immune restoration remains elusive, often accompanied by persistent inflammation and inadequate cytotoxic T-cell responses. Tα1, known for its ability to restore immune homeostasis in various conditions, including infections and immunodeficiency, holds potential as a multitasking protein depending on the host's inflammatory or immune status. Recent in vitro and in vivo studies have explored Tα1's efficacy in HIV-1 infection, offering insights into its therapeutic implications and future directions for intervention.

Furthermore, Tα1 demonstrates the capacity to enhance the release of antiretroviral soluble factors by CD8(+) cells, contributing to the control or prevention of HIV-1 infection through non-cytolytic mechanisms. Through its specific action on lymphoid cells, Tα1 induces a robust transcriptional response, influencing the release of soluble factors that inhibit HIV-1 infection of monocyte-derived macrophages and peripheral blood mononuclear cells (PBMCs), as well as human T lymphotropic virus 1 (HTLV-1) infection of PBMCs. These findings underscore the potential of Tα1 as an adjunctive therapy alongside innovative treatments and vaccine strategies in the management of HIV-1 infection, offering new avenues for enhancing antiretroviral therapy outcomes.

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6. Thymosin Alpha-1 As An ACE Enzyme Inhibitor

The research investigated the antioxidant properties of thymosin alpha-1 (Tα1) peptide using various methods. New research indicates that Thymosin Alpha-1 blocks angiotensin converting enzyme (ACE) and thus can reduce blood pressure. Tα1 demonstrated significant scavenging activity against DPPH and ABTS radicals, with IC50 values of 20 µM and 85 µM, respectively. Additionally, it exhibited concentration-dependent scavenging of hydroxyl and superoxide radicals, with IC50 values of 82 µM and 20 µM, respectively. Tα1 also reduced cellular reactive oxygen species (ROS) levels in human neural asterocytoma cells. Furthermore, Tα1 displayed inhibitory effects on angiotensin-converting enzyme (ACE), with a mixed inhibition pattern observed in kinetic studies. The IC50 and Ki values of Tα1 were 0.8 µM and 3.33 µM, respectively. Molecular modeling and docking analyses suggested that Tα1 binds to ACE domains, particularly the N-domain, with high affinity, mediated by electrostatic, hydrophobic, and hydrogen forces. Overall, these findings highlight Tα1 as a multifunctional peptide with dual antioxidant and ACE-inhibitory properties, warranting further investigation of its potential benefits both in vitro and in vivo.

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7. Thymosin Alpha-1 in Cancer Treatment

Thymosin Alpha-1 has been tested and is undergoing active testing in a number of different cancers. Thymosin alpha-1 (Thα1) demonstrates anti-proliferative effects on lung adenocarcinoma cells (A549), inhibiting cell growth and migration while enhancing antioxidant enzyme activity and reducing cellular reactive oxygen species (ROS) levels. However, it does not significantly induce apoptosis in these cells. In a large randomized study, combining Thα1 with dacarbazine (DTIC) and interferon alfa (IFN-alpha) in patients with metastatic melanoma showed promising results. Patients receiving the combination therapy exhibited tumor responses and longer duration of response compared to the control group receiving standard therapy alone. Median overall survival (OS) was improved with Thα1 treatment, suggesting its potential as an effective therapy for metastatic melanoma. Clinical trials have provided evidence supporting the use of Thα1 in melanoma treatment, particularly in combination with other agents like DTIC and IFN-alpha, paving the way for further evaluation and clinical applications of Thα1 in melanoma therapy.

Two studies investigated the development and efficacy of a novel long-acting fusion protein called Thymosin Alpha1-Fc (Tα1-Fc) for breast cancer inhibition. The first study focused on generating Tα1-Fc by fusing Tα1 with the Fc domain of human IgG1 to improve its serum half-life. Tα1-Fc demonstrated enhanced potency in inhibiting the growth of 4T1 and MCF-7 breast cancer cells compared to native Tα1. In a murine 4T1 tumor model, Tα1-Fc treatment led to increased levels of CD4 and CD8 cells, interferon-γ, and interleukin-2, indicating enhanced immune response against tumors. Moreover, Tα1-Fc alleviated immunosuppression induced by hydrocortisone, suggesting its potential as an immunomodulatory agent for breast cancer therapy.

In the second study, a recombinant plasmid was constructed to express Tα1-Fc fusion protein, utilizing the Fc domain of human IgG4. The optimized expression conditions yielded high-purity Tα1-Fc protein with a production rate of 160.4 mg/L. Tα1-Fc exhibited a prolonged serum half-life of 25 h in mouse models, approximately 13 times longer than native Tα1. Additionally, Tα1-Fc demonstrated enhanced immune injury repair by increasing lymphocyte numbers. In vivo, Tα1-Fc displayed more effective antitumor activity in 4T1 and B16F10 tumor xenograft models compared to native Tα1. It upregulated CD86 expression, promoted secretion of IFN-γ and IL-2, and increased the number of tumor-infiltrating CD4+ T and CD8+ T cells. These findings highlight the potential of Tα1-Fc as a promising immunotherapeutic agent for breast cancer treatment, providing valuable insights for the development of novel cancer immunotherapies.

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8. Thymosin Alpha-1 in Inflammatory Pain Research

Thymosin Alpha-1 (Tα1) displays anti-inflammatory and neuroprotective properties, but its effects on inflammatory pain remain unclear. However, intraperitoneal administration of Tα1 alleviates pain hypersensitivity induced by Complete Freund's Adjuvant (CFA), a model of peripheral inflammation. This treatment also reduces the up-regulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in both inflamed skin and the spinal cord. Moreover, Tα1 reverses the strong activation of microglia triggered by CFA-induced peripheral inflammation and modulates the expression of vesicular glutamate transporter (VGLUT) and vesicular γ-aminobutyric acid transporter (VGAT) in the spinal cord. These findings suggest that Tα1 has a therapeutic role in inflammatory pain by regulating microglia-induced pro-inflammatory cytokine production and modulating VGLUT and VGAT expression in the spinal cord.

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9. Thymosin Alpha-1 and Damaged Teeth

The review compares interventions for managing traumatised permanent teeth with avulsion injuries, analyzing three randomized controlled trials (RCTs). Study one examined the effect of extra-oral endodontics, showing no significant difference in radiographic resorption compared to intra-oral endodontics provided at week 1 for teeth avulsed for more than 60 minutes dry time. Study two investigated a 10-minute soaking in Thymosin Alpha-1 prior to replantation and reported a strong benefit at 48 months. Study three investigated a 20-minute soaking with gentamycin sulphate prior to replantation and the use of hyperbaric oxygen daily, showing a strong benefit at 12 months. Despite moderate/high risk of bias in these studies, they suggest potential advantages for Thymosin Alpha-1 and gentamycin sulphate followed by hyperbaric oxygen. However, further validation and evidence with low risk of bias are needed.

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10. Synthesis of Thymosin Alpha-1

In the development of Thymosin-α1, an acetylated 28 amino acid long therapeutic peptide, the synthesis via conventional chemical methods is challenging. A fully convergent chemo-enzymatic peptide synthesis (CEPS) process was developed, using a substrate-tailored peptiligase variant called thymoligase. Thymoligase, tailored to recognize 14-mer Thymosin-α1 segments, catalyzes peptide bond formation between segments with high efficiency (>94% yield). The crystal structure of thymoligase was determined, showing good agreement with the engineering model. This combination of solid-phase peptide synthesis (SPPS) of 14-mer segments and thymoligase-catalyzed ligation resulted in a significantly increased overall yield (55%) of Thymosin-α1 compared to existing industrial processes.

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References

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