Search Results (6)

Aging is characterized by immune decline, mainly due to thymic involution—the age-related shrinkage of the thymus gland. This leads to reduced T-cell production, chronic inflammation, and increased susceptibility to age-related diseases. Thymosin alpha-1 (Tα1), a peptide hormone produced by the thymus, exhibits potent immunomodulatory, anti-inflammatory, and antioxidant properties. It helps restore immune function by stimulating T-cell differentiation, enhancing thymic output, and modulating dendritic cell and macrophage activity. Preclinical and clinical studies show that Tα1 can improve vaccine response in the elderly and mitigate immunosenescence. The hybrid drug Refnot (a fusion of tumor necrosis factor alpha (TNFα) and Tα1) combines Tα1’s immunomodulation with TNF’s antitumor activity but has reduced toxicity. It represents a promising therapeutic approach to counteract age-related immune dysfunction and inflammation, potentially by slowing the aging process. Further research is needed to validate its long-term efficacy and safety in geriatrics. Full article

Resistance and toxicity associated with current treatments for human cytomegalovirus (HCMV) infection highlight the need for alternatives and immunotherapy has emerged as a promising strategy. This study examined the in vitro immunological effects of co-administration of Thymosin-alpha-1 (Tα1) and polyanionic carbosilane dendrimers (PCDs) on peripheral blood mononuclear cells (PBMCs) during HCMV infection. The biocompatibility of PCDs was assessed via MTT and LDH assays. PBMCs were pre-treated with the co-administered compounds and then exposed to HCMV for 48 h. Morphological alterations in PBMCs were observed using optical microscopy and total dendritic cells (tDCs), myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs), along with CD4+/CD8+ T cells and regulatory T cells (Treg), and were characterized using multiparametric flow cytometry. The findings revealed that Tα1 + PCDs treatments increased DC activation and maturation. Furthermore, increased co-receptor expression, intracellular IFNγ production in T cells and elevated Treg functionality and reduced senescence were evident with Tα1 + G2-S24P treatment. Conversely, reduced co-receptor expression, intracellular cytokine production in T cells, lower functionality and higher senescence in Treg were observed with Tα1 + G2S16 treatment. In summary, Tα1 + PCDs treatments demonstrate synergistic effects during early HCMV infection, suggesting their use as an alternative therapeutic for preventing virus infection. Full article

A generally accepted hypothesis for the initial activation of an immune or autoimmune response argues that alarmins are released from injured, dying and/or activated immune cells, and these products complex with receptors that activate signal transduction pathways and recruit immune cells to the site of injury where the recruited cells are stimulated to initiate immune and/or cellular repair responses. While there are multiple diverse families of alarmins such as interleukins (IL), heat-shock proteins (HSP), Toll-like receptors (TLR), plus individual molecular entities such as Galectin-3, Calreticulin, Thymosin, alpha-Defensin-1, RAGE, and Interferon-1, one phylogenetically conserved family are the Annexin proteins known to promote an extensive range of biomolecular and cellular products that can directly and indirectly regulate inflammation and immune activities. For the present report, we examined the temporal expression profiles of the 12 mammalian annexin genes (Anxa1-11 and Anxa13), applying our temporal genome-wide transcriptome analyses of ex vivo salivary and lacrimal glands from our C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren’s Syndrome (SS), a human autoimmune disease characterized primarily by severe dry mouth and dry eye symptoms. Results indicate that annexin genes Anax1-7 and -11 exhibited upregulated expressions and the initial timing for these upregulations occurred as early as 8 weeks of age and prior to any covert signs of a SS-like disease. While the profiles of the two glands were similar, they were not identical, suggesting the possibility that the SS-like disease may not be uniform in the two glands. Nevertheless, this early pre-clinical and concomitant upregulated expression of this specific set of alarmins within the immune-targeted organs represents a potential target for identifying the pre-clinical stage in human SS as well, a fact that would clearly impact future interventions and therapeutic strategies. Full article

Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in Escherichia coli at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance. Full article

The immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a critical factor in the clinical presentation of COVID-19, which may range from asymptomatic to a fatal, multi-organ disease. A dysregulated immune response not only compromises the ability of the host to resolve the viral infection, but may also predispose the individual to secondary bacterial and fungal infections, a risk to which the current therapeutic immunomodulatory approaches significantly contribute. Among the secondary infections that may occur in COVID-19 patients, coronavirus-associated pulmonary aspergillosis (CAPA) is emerging as a potential cause of morbidity and mortality, although many aspects of the disease still remain unresolved. With this opinion, we present the current view of CAPA and discuss how the same mechanisms that underlie the dysregulated immune response in COVID-19 increase susceptibility to Aspergillus infection. Likewise, resorting to endogenous pathways of immunomodulation may not only restore immune homeostasis in COVID-19 patients, but also reduce the risk for aspergillosis. Therefore, CAPA represents the other side of the coin in COVID-19 and our advances in the understanding and treatment of the immune response in COVID-19 should represent the framework for the study of CAPA. Full article

Ependymoma pediatric brain tumor occurs at approximate frequencies of 10–15% in supratentorial and 20–30% in posterior fossa regions. These tumors have an almost selective response to surgery and relative and confirmed resistance to radiotherapy and chemotherapic agents, respectively. Alongside histopathological grading, clinical and treatment evaluation of ependymomas currently consider the tumor localization and the genomic outlined associated molecular subgroups, with the supratentorial and the posterior fossa ependymomas nowadays considered diverse diseases. On these grounds and in trying to better understand the molecular features of these tumors, the present investigation aimed to originally investigate the proteomic profile of pediatric ependymoma tissues of different grade and localization by mass spectrometry platforms to disclose potential distinct protein phenotypes. To this purpose, acid-soluble and acid-insoluble fractions of ependymoma tumor tissues homogenates were analyzed by LC-MS following both the top-down and the shotgun proteomic approaches, respectively, to either investigate the intact proteome or its digested form. The two approaches were complementary in profiling the ependymoma tumor tissues and showed distinguished profiles for supratentorial and posterior fossa ependymomas and for WHO II and III tumor grades. Top-down proteomic analysis revealed statistically significant higher levels of thymosin beta 4, 10 kDa heat shock protein, non-histone chromosomal protein HMG-17, and mono-/uncitrullinated forms ratio of the glial fibrillary acidic protein (GFAP) fragment 388–432 in supratentorial ependymomas—the same GFAP fragment as well as the hemoglobin alpha- and the beta-chain marked grade II with respect to grade III posterior fossa ependymomas. Gene ontology classification of shotgun data of the identified cancer and the non-cancer related proteins disclosed protein elements exclusively marking tumor localization and pathways that were selectively overrepresented. These results, although preliminary, seem consistent with different protein profiles of ependymomas of diverse grade of aggressiveness and brain region development and contributed to enlarging the molecular knowledge of this still enigmatic tumor. Full article