Search Results (256)

Alpha-Ketoglutarate (AKG), a central intermediate of the tricarboxylic acid cycle, is a crucial metabolic and signaling molecule that connects mitochondrial function with cellular homeostasis, immunological modulation, epigenetic remodeling, and lifespan. While mitochondrial AKG maintains energy metabolism, the nuclear AKG pool influences chromatin remodeling through DNA and histone modifications, which together control hypoxia responses and shape gene expression patterns. This dual role demonstrates AKG’s significance in mediating metabolic state, gene expression, and long-term cellular adaptability. AKG modulates immunological responses, reduces reactive oxygen species (ROS), promotes the polarization of anti-inflammatory macrophages, and suppresses nuclear factor kappa B (NF-κB) activation, thereby reducing chronic inflammatory processes. AKG restricts pro-inflammatory cytokine production, increases extracellular matrix synthesis, and reduces cartilage degradation in arthritic models, suggesting potential therapeutic benefits in autoimmune diseases and joint degeneration. Additionally, AKG affects lifespan in several model organisms, where supplementation enhances metabolic resilience, lowers age-related inflammation, modifies mTOR signaling, and preserves youthful epigenetic profiles. Additionally, because endogenous AKG levels decrease with age, oral supplementation of AKG, especially with calcium and arginine, has drawn attention to its potential benefits in longevity and metabolic health. Thus, AKG is versatile and has encouraging therapeutic promise for cancer, aging, and inflammatory illnesses. However, a lack of human clinical evidence prompts further research to determine ideal dosage, tissue selectivity, and long-term safety. The goal of this review is to critically examine the current mechanistic knowledge related to AKG biosynthesis and breakdown and its future implications in maintaining cellular homeostasis and controlling chronic inflammation. Full article

Pregnancy represents a dynamic immunological state in which the maternal immune system must balance tolerance toward the semi-allogeneic fetus while maintaining antimicrobial defense. Cytomegalovirus (CMV) infection is highly prevalent worldwide and profoundly shapes immune cell differentiation and long-term activation in adults. However, its interaction with pregnancy-associated immune remodeling remains incompletely defined. In this prospective longitudinal study, we comprehensively analyzed immune profiles of healthy pregnant women across all three trimesters and age-matched nonpregnant controls, stratified by CMV IgG serostatus. Multiparametric flow cytometry characterized T and B cell subsets and cytokine production following in vitro stimulation, while circulating cytokines and adhesion molecules were quantified using multiplex immunoassay. Gestational age was the primary determinant of leukocyte dynamics. Nevertheless, CMV-seropositive pregnant women showed enhanced activation and differentiation of CD4⁺ and, more prominently, CD8⁺ T cell subsets, changes not observed in nonpregnant women. Despite pronounced cellular differences, serum cytokine and adhesion molecule levels were largely comparable between CMV-seropositive and CMV-seronegative participants in both pregnant and nonpregnant groups. Functionally, CMV-seropositive women exhibited enrichment of IFN-γ– and IL-21–producing T cells, whereas B cell responses remained predominantly IL-10–dominated. These findings indicate selective alterations in maternal lymphocyte activation and function during pregnancy in CMV-seropositive women, without evidence of systemic inflammation. Full article

Trogocytosis is the process of engulfment of a portion of a cell’s membrane by another cell. This process is characterized by the transfer of membrane fragments and proteins between adjacent cells without their complete fusion or phagocytosis, which distinguishes it from classical cellular uptake pathways. In the immune system, the initiating signal for trogocytosis is antigen presentation or the interaction of the Fc receptor with an antibody bound to the cell. During trogocytosis, T cells transfer not only the MHC molecule with the antigenic peptide, but also the costimulatory molecules CD80, CD86, OX-40 and others. As a result of trogocytosis, cells can transfer various surface molecules, acquire new immunological properties, and modulate each other’s activity. This review examines the basic mechanisms of trogocytosis, the involvement of T2-mediated immunity components in trogocytosis, and its possible role in allergies. Full article

Background: Immunomodulatory compounds can modify or regulate the immune responses. Given that vaccine-induced immune responses can vary in magnitude and durability depending on antigen properties and adjuvant selection. Immunomodulators that enhance antigen-specific immune responses with low toxicity may complement existing adjuvant systems. Recent studies indicate that adenosine receptor–mediated signaling can modulate dendritic cell (DC) function through mechanisms distinct from classical pathogen-associated molecular pattern (PAMP)-driven Toll-like receptor pathways. Methods: In this context, the present study comparatively evaluates poly-(lactic-co-glycolic acid) (PLGA) microparticle–encapsulated β-L-adenosine (BLA MPs) alongside established FDA-approved adjuvants to assess their immunomodulatory potential under limited-antigen conditions. FDA-approved PLGA was used to encapsulate BLA in combination with multiple viral antigens, including H1N1 influenza, Zika virus, and canine coronavirus, to enable sustained delivery, antigen protection, and efficient uptake by antigen-presenting cells. Results: Physicochemical characterization demonstrated uniform particle size distribution, a low polydispersity index, and a stable negative surface charge. Release studies showed more than 50% payload release within 12 h, with release kinetics best described by the Korsmeyer–Peppas model. Cytotoxicity evaluation using DC2.4 cells confirmed that BLA MPs were non-cytotoxic at concentrations up to 250 μg/mL. Comparative in vitro immunological assessments revealed that BLA MPs induced dendritic cell activation, including upregulation of antigen-presenting and co-stimulatory molecules, at levels largely comparable to those observed with Alum- and MF59-based formulations across multiple antigen groups. Nitric oxide production remained within comparable ranges, indicating balanced immunostimulatory activity without excessive inflammatory signaling. In select conditions, co-formulation of BLA MPs with MF59 further enhanced DC activation, supporting its role as a complementary immunomodulatory component. Conclusion: These findings align with previously reported adenosine-dependent pathways involved in DC maturation and antigen presentation. Overall, this comparative study demonstrates that PLGA-encapsulated β-L-adenosine functions as an effective immunomodulatory agent, with performance comparable to that of established FDA-approved adjuvants across diverse vaccine antigens. Further in vivo studies are warranted to evaluate dose dependency, cytokine profiles, and antibody responses to define its role within combinatorial vaccine adjuvant strategies. Full article

This critical and selective review synthesizes the accumulating body of biological evidence supporting a process we term epigenetic–genetic coupling as a mechanistic basis for Lamarckian inheritance of somatically acquired adaptations. We propose that evolutionary processes in mammals and higher vertebrates can involve deaminase-driven, reverse transcriptase-mediated, RNA-templated targeted homologous recombination. We contrast well-established examples of “Soft”, reversible epigenetic inheritance with historical and contemporary evidence suggestive of stable, DNA-integrated “Hard” Lamarckian transgenerational inheritance. Our analysis indicates that the establishment of “Hard” Lamarckian inheritance may require specific population dynamics, including inbreeding or interbreeding among phenotypically affected offspring, together with sustained and defined environmental stimuli over one or more generations to consolidate the acquired traits at the genomic level. We also present molecular and cellular evidence supporting RNA-to-DNA genetic feedback mechanisms involving targeted genomic integration, primarily mediated by the DNA repair–associated reverse transcriptase activity of DNA polymerase η. Finally, we review diversification mechanisms in molecular and cellular immunology that now routinely employ single-molecule, real-time, long-read genomic sequencing (6–8 kb). We recommend the broader application of these technologies in future breeding and experimental programs across other somatic systems. Their deployment offers a robust strategy for securing definitive “Hard” molecular evidence of Lamarckian acquired inheritance in diverse biological contexts; including somatically acquired immunity, as well as adaptive behavioral and central nervous system phenotypes. This is compatible with our over-arching goal—to provide an experimental road map of conceptual options to drive future experimentation in acquired inheritance breeding programs. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperactivation and excessive autoantibody production. Z-DNA binding protein 1 (ZBP1), an innate immune sensor involved in nucleic acid recognition and cell death signaling, has been implicated in antiviral and inflammatory responses. However, its role in B-cell dysregulation during SLE remains unclear. Methods: Integrative transcriptomic analyses were performed using public datasets (GSE61635, GSE235658, GSE136035, and GSE163497) to determine the expression pattern and biological functions of ZBP1 in SLE. Bulk RNA-seq and single-cell RNA-seq data were used to evaluate ZBP1 expression across B-cell subsets. Correlations between ZBP1 expression, disease activity, and immunological parameters were assessed. RNA-seq data following ZBP1 knockdown were analyzed to explore its potential downstream pathways and molecular networks. In addition, in vitro ZBP1 knockdown experiments were conducted to examine its effects on B-cell activation, plasma cell differentiation, and antibody production. Results: ZBP1 was significantly upregulated in peripheral blood and B cells from SLE patients and was enriched in pathways related to type I interferon signaling and cytokine-mediated immune responses. Single-cell transcriptomic profiling further revealed elevated ZBP1 expression across multiple B-cell subsets, including naïve B cells, memory B cells, age-associated B cells (ABCs), and plasma cells. Clinically, ZBP1 expression in peripheral B cells was positively correlated with CD86 mean fluorescence intensity (MFI), SLE Disease Activity Index (SLEDAI) scores, and serum IgG levels, suggesting a link between ZBP1 and B-cell activation. RNA-seq analysis following ZBP1 silencing demonstrated that ZBP1 regulates genes involved in the cell cycle, DNA replication, and p53 signaling, indicating its potential role in promoting B-cell proliferation and activation. Functionally, ZBP1 silencing impaired B-cell activation, reduced plasma cell differentiation, and decreased immunoglobulin production in vitro. Conclusions: Our study identifies ZBP1 as a molecule upregulated in SLE B cells and associated with B-cell activation and disease activity. Although direct causality remains to be established, the data indicate that ZBP1 may contribute to SLE pathogenesis by modulating cell cycle-related pathways and promoting aberrant B-cell responses, highlighting its potential as a biomarker and a candidate therapeutic target in SLE. Full article

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors with significant biological diversity. Despite significant improvements in diagnostics and a growing range of available therapies, long-term disease control remains difficult in advanced cases. The tumor microenvironment, which in pNENs adopts a predominantly immunosuppressive profile and promotes tumor development, is attracting increasing attention. A complex network of interactions dominates the tumor tissue, including M2 macrophages, regulatory T cells, and numerous pathways that inhibit effector lymphocyte activity. M2 macrophages, through the secretion of anti-inflammatory cytokines and exosome-mediated signaling, support angiogenesis while simultaneously attenuating the cytotoxic response. Simultaneously, receptors and ligands associated with immune checkpoints are overexpressed. In addition to classic molecules such as PD-1/PD-L1 and CTLA-4, the role of B7x and CD276 is increasingly being emphasized, as their presence correlates with rapid disease progression and poor prognosis. To date, attempts to use checkpoint inhibitors as monotherapy have yielded modest clinical benefits. However, approaches based on combination strategies—both in the form of dual immune blockade and in combination with chemotherapy or angiogenesis-targeted therapy—have shown significantly greater activity. Therapies using tyrosine kinase inhibitors, such as sunitinib and newer drugs (lenvatinib, surufatinib, cabozantinib), may partially normalize the tumor’s disrupted vascular architecture and thus increase its susceptibility to immunological interventions. In the coming years, it will be crucial not only to overcome the immunosuppressive nature of the TME but also to identify predictive biomarkers that will allow for more precise patient selection. This approach may open the way to more effective, personalized therapies for pNENs. Full article

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation, organ dysfunction, and potentially death. Despite significant advances in understanding the pathophysiology of sepsis, effective therapeutic options remain limited, and mortality rates remain unacceptably high. Therefore, a deeper understanding of sepsis pathogenesis and the identification of novel therapeutic targets are urgently needed to improve patient outcomes. Recent studies have revealed that RNAs can undergo glycosylation, generating a previously unrecognized class of molecules known as glycosylated RNAs (glycoRNAs), which are localized on the outer surface of cells. GlycoRNAs are highly expressed in immune cells, and accumulating evidence indicates that they play important roles in regulating immune responses, including immune cell adhesion and infiltration, immune cell activation, and immune evasion. In addition, glycoRNAs are abundantly expressed on the epithelial cell surfaces of the respiratory, digestive, urinary, and reproductive systems, suggesting that glycoRNAs may function as a component of epithelial barriers that protect against pathogenic invasion. Collectively, these findings suggest that glycoRNAs may play a critical role in the pathogenesis of sepsis. This review summarizes the expression and functions of glycoRNAs in immune and barrier systems and highlights their potential roles during distinct immunological phases of sepsis. Full article

Due to their therapeutic potential and effects on cells, exosomes derived from bovine colostrum (BCE) and milk (BME) are molecules that have been at the center of recent studies. Their properties include the ability to cross biological barriers, their natural biocompatibility, and their structure, which enable them to act as stable nanocarriers. Exosomes derived from milk and colostrum stand out in cancer prevention and treatment due to these properties. BMEs can be enriched with bioactive peptides, lipids, and nucleic acids. The targeted drug delivery capacity of BMEs can be made more efficient through these enrichment processes. For example, BME enriched with an iRGD peptide and developed using hypoxia-sensitive lipids selectively transported drugs and reduced the survival rate of triple-negative breast cancer (TNBC) cells. ARV-825-CME formulations increased antitumor activity in some cancer types. The anticancer effects of exosomes are supported by these examples. In addition to their anticancer activities, exosomes also exhibit effects that maintain immune balance. BME and BCE can regulate inflammatory responses with their miRNA and protein loads. These effects of BMEs have been demonstrated in studies on colon, breast, liver, and lung cancers. The findings support the safety and scalability of these effects. However, significant challenges remain in terms of their large-scale isolation, load heterogeneity, and regulatory standardization. Consequently, BMEs represent a new generation of biogenic nanoplatforms at the intersection of nutrition, immunology, and oncology, paving the way for innovative therapeutic approaches. Full article

T-cell immunoglobulin and mucin domain 3 (TIM-3), a well-known immune checkpoint molecule, is increasingly recognized for its regulatory functions beyond T cell exhaustion, particularly in macrophages. Recent advances have revealed the important role of this molecule in various pathological and physiological conditions. The demand for a comprehensive study of TIM-3 is increasing, particularly as a result of ongoing clinical trials targeting TIM-3 in oncology. This review is devoted to the role of TIM-3 in macrophage biology, focusing on associations between TIM-3 expression and macrophage polarization states and functional activity, as well as its involvement in the pathogenesis of different diseases and reproductive immunology. The review examines known effects and molecular mechanisms by which TIM-3 regulates macrophage functional phenotype and the contribution of TIM-3-expressing macrophages to cancer, pregnancy, inflammation, infectious and autoimmune diseases, and fibrosis. Findings highlight the controversial role of TIM-3 in the regulatory function of macrophages and suggest that TIM-3 functions differently depending on the context. The review also touches on gaps and unexplored parts of the topic. A summary of current data allows us to conclude that TIM-3 is an important modulator of macrophage functions and can be considered a potential therapeutic target in various pathological conditions. Full article

Infectious diseases remain a persistent global health threat, intensified by the rapid emergence of antibiotic-resistant pathogens. Despite the transformative impact of antibiotics, the escalating resistance crisis underscores the urgent need for alternative therapeutic approaches. Antimicrobial peptides (AMPs) have emerged as promising candidates due to their broad-spectrum antimicrobial and immunomodulatory activities. The present study investigated 82 honey bee antimicrobial peptides (BAMPs) representing seven families: abaecin, apamin, apisimin, apidaecin, defensin, hymenoptaecin, and melittin among eight honey bee species. Immunoinformatics analyses identified five peptides (P15450, A0A2A3EK62, Q86BU7, C7AHW3, and I3RJI9A) with high antigenicity and non-allergenic profiles. Structural modeling, molecular docking with TLR3 and TLR4-MD2, and molecular dynamics simulations revealed stable receptor-peptide interactions and favorable binding energetics, further supported by silico immune simulations. Overall, these findings suggest that the selected BAMPs exhibit strong immunogenic potential and may serve as effective adjuvants or carrier molecules in subunit vaccine design against drug-resistant pathogens; however, further experimental validation is essential to confirm their safety and immunological efficacy. Full article

Background: Tumor-associated neutrophils (TANs) exhibit remarkable functional plasticity within tumor microenvironment (TME), with N1-like subtypes promoting anti-tumor immunity and N2-like subtypes facilitating tumor progression. Despite their critical role in cancer immunology, strategies to selectively modulate TAN polarization remain limited. Methods: We integrated transcriptomic analyses of TAN subtypes to identify potential hub molecules. Molecular docking and experimental assays were used to evaluate DHA’s effect on neutrophil-like cell polarization. Results: Hub genes (TNF, IL1B, PTGS2, BCL2A1, MSR1, ACOD1, CXCL16, CLEC10A, and SOCS3) were identified, with TNF serving as a potential core regulator. Molecular docking indicated that DHA forms stable interactions hub proteins. Experimentally, DHA treatment of neutrophil-like dNB4 cells promoted N1 polarization, evidenced by upregulation of TNF, IL1B, PTGS2, BCL2A1, MSR1, ACOD1, CXCL16, and N1 markers PD-L1 and NOX2, and downregulation of N2 marker CEACAM8 and hub genes CLEC10A and SOCS3. Functional assays demonstrated that DHA-treated cells exhibited increased secretion of TNF, IL1β, ROS, and PD-L1, accompanied by enhanced cytotoxic activity against hepatocellular carcinoma cells in a co-culture system. Conclusions: These findings reveal the molecular mechanisms underlying TAN polarization, and establish DHA as a potent immunomodulatory agent capable of reshaping TANs toward an anti-tumor phenotype. Full article

Per- and Polyfluoroalkyl substances (PFAS) are highly persistent synthetic chemicals increasingly associated with adverse health outcomes. The gastrointestinal tract represents both a major route of exposure and a key target of PFAS toxicity. This review integrates updated evidence on how PFAS compromise intestinal homeostasis through interrelated structural, metabolic, and immunological mechanisms. PFAS disrupt epithelial integrity by down-regulating tight-junction proteins, inducing oxidative stress, and activating inflammasome signaling. Concurrently, metabolic reprogramming and PFAS-driven microbial dysbiosis contribute to barrier dysfunction and altered production of signal/metabolic molecules. These alterations may link environmental exposure to chronic intestinal inflammation and increase susceptibility to inflammatory bowel disease and related metabolic disorders. By synthesizing recent findings, key mechanistic gaps were highlighted also emphasizing the need for integrative experimental and translational studies to refine risk assessment in humans and develop preventive and therapeutic strategies. Full article

In vertebrates, the interleukin-1β molecule (IL-1β) is among the most important proinflammatory cytokines and plays crucial roles in shaping injury progression, immunological challenges, and local and systemic responses to infection. In the current study, a cDNA encoding the IL-1β gene in Asian seabass (Lates calcarifer) (LcIL-1β) was identified at both the nucleotide and protein levels. Its immune responses were investigated in various tissues from diseased and normal fish. Recombinant rLcIL-1β was produced in Escherichia coli. Furthermore, its ability to control two fish pathogenic bacteria, Flavobacterium covae and Streptococcus iniae, was assessed in vitro. Transcriptional expression was quantified by qRT–PCR, which revealed the highest levels in whole blood, followed by the liver, gills and midgut. Immune response analyses of the head kidney, whole blood, liver, gills, spleen and intestines of fish infected with F. covae and S. iniae at concentrations of 1 × 10³, 1 × 10⁴ and 1 × 10⁵ CFU/fish, respectively, revealed significant upregulation of LcIL-1β (p < 0.05) for 6–24 h (h) after induction. Interestingly, compared with the control treatment, the application of 1, 10 and 100 µg of rLcIL-1β greatly increased the phagocytic activity and phagocytic index of phagocytes (p < 0.05). Antibacterial function analyses of F. covae and S. iniae revealed minimal inhibitory concentrations (MICs) of 29.17 and 85.25 μg/mL, respectively. Finally, injection of S. iniae following rLcIL-1β revealed that 50 and 100 µg of the target protein demonstrated significant functional activity in safeguarding Asian seabass from these pathogenic bacteria (p < 0.05). This information revealed that LcIL-1β in Asian seabass significantly drives immune defense mechanisms against pathogenic bacteria, which is important for the development of effective disease prevention methods for Asian seabass aquaculture. Full article

The therapeutic clotting factor VIII (FVIII) is known for its particular immunogenicity, with nearly 30% of hemophilic patients developing neutralizing antibodies against the infused protein. The root cause of this immunogenicity is still not well understood, but intrinsic factors, such as FVIII byproducts, have been linked to the immunological response elicited. Bioengineering of the FVIII molecule has been improving its recombinant (rhFVIII) production in many aspects, mainly enhancing its expression and stability. Assessment of immunogenicity for novel recombinant isoforms is crucial for further development and scaling-up processes, particularly due to the unpredictable antigenic properties and their impact on neutralizing antibody formation. In the present study, we describe a bioengineered human recombinant FVIII (rhFVIII-H6A), which induces lower immunogenicity in a murine model of hemophilia A. The rhFVIII-H6A product is characterized by a B-domain-deleted heavy chain (HCh), with the C-terminal of the B-domain fused to the light chain (BΔ-LCh). Compared to plasma-derived FVIII (pdFVIII) and rhFVIII reference products, treating hemophilic mice with rhFVIII-H6A induced lower levels of anti-FVIII antibody formation, including those with inhibitory neutralizing activity, while no difference was observed in the functional activity of rhFVIII-H6A in reverting the in vivo hemophilia phenotype. In addition, our results indicate that deleting the major part of the B-domain from the HCh might lower the immunogenicity of novel rhFVIII products. Full article