Modulation Of Immune Response Research Articles

Immune Evasion Mechanism of Neurotropic Viruses.

The persistent challenge posed by viruses that infect the central nervous system lies in their sophisticated ability to evade the host immune system. This review explores into the complex mechanisms of immune evasion employed by these neurotropic viruses, focussing on their modulation of host immune responses, evasion of adaptive immunity, and the cellular and molecular strategies that enable their persistence. Key areas explored include viral latency and reactivation, the inhibition of apoptosis, and antigenic variation, with a detailed examination of viral proteins and their interactions with host cellular processes.

TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer's disease

BackgroundPersistent innate and adaptive immune responses in the brain contribute to the progression of Alzheimer’s disease (AD). APOE4, the most important genetic risk factor for sporadic AD, encodes apolipoprotein E4, which by itself is a potent modulator of immune response. However, little is known about the immune hub that governs the crosstalk between the nervous and the adaptive immune systems. Transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated, nonselective cation channel with Ca2+ permeability, which has been proposed as a neuroprotective target in AD.MethodsUsing Ca2+-sensitive dyes, dynamic changes of Ca2+ in microglia were measured, including exogenous Ca2+ uptake and endoplasmic reticulum Ca2+ release. The mRFP-GFP-tagged LC3 plasmid was expressed in microglia to characterize the role of TRPV1 in the autophagic flux. Transcriptomic analyses and flow cytometry were performed to investigate the effects of APOE4 on brain microglia and T cells from APOE-targeted replacement mice with microglia-specific TRPV1 gene deficiency.ResultsBoth APOE4 microglia derived from induced pluripotent stem cells of AD patients and APOE4-related tauopathy mouse model showed significantly increased cholesterol biosynthesis and accumulation compared to their APOE3 counterparts. Further, cholesterol dysregulation was associated with persistent activation of microglia and elevation of major histocompatibility complex II-dependent antigen presentation in microglia, subsequently accompanied by T cell infiltration. In addition, TRPV1-mediated transient Ca2+ influx mitigated cholesterol biosynthesis in microglia by suppressing the transcriptional activation of sterol regulatory element-binding protein 2, promoted autophagic activity and reduced lysosomal cholesterol accumulation, which were sufficient to resolve excessive immune response and neurodegeneration in APOE4-related tauopathy mouse model. Moreover, microglia-specific deficiency of TRPV1 gene accelerated glial inflammation, T cell response and associated neurodegeneration in an APOE4-related tauopathy mouse model.ConclusionsThe findings provide new perspectives for the treatment of APOE4-dependent neurodegeneration including AD.

Comparative Modulation of Immune Responses and Inflammation by n-6 and n-3 Polyunsaturated Fatty Acids in Oxylipin-Mediated Pathways

Our study investigates the comparative effects of n-6 and n-3 polyunsaturated fatty acids (PUFAs) on immune modulation and inflammation using a fat-1 transgenic mouse model capable of endogenously converting n-6 PUFAs to n-3 PUFAs. The results show that n-6 PUFAs, particularly arachidonic acid (AA), promote a pro-inflammatory environment by increasing the production of inflammatory mediators, including leukotrienes and prostaglandins, while upregulating NFκB signaling and NLRP3 inflammasome activation. In contrast, n-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exhibit anti-inflammatory and pro-resolving properties by enhancing the production of resolvins, protectins, and maresins, and upregulating PPARα expression. Quantitatively, n-3 PUFAs led to a 4-fold increase in resolvin levels compared to the n-6 group (p < 0.001), promoting a resolution of inflammation. This study underscores the critical importance of maintaining an optimal balance between n-6 and n-3 PUFAs in the diet to prevent chronic inflammation and suggests that increasing dietary n-3 PUFAs may mitigate inflammation-driven diseases. The findings highlight the need for further research into the optimal dietary ratios of n-6 and n-3 PUFAs for immune health and disease prevention.

Congenital enteropathies in children: An algorithm for differential diagnosis and therapeutic management. Case report

Infant diarrhea may be caused by infectious, allergic, or surgical diseases. A distinct group comprises congenital enteropathies, a heterogeneous group of genetically determined diseases, including defects in the absorption and transport of nutrients and electrolytes, impaired differentiation of enterocytes and enteroendocrine cells, and defects in the modulation of the intestinal immune response. The final diagnosis of enteropathies is based on the results of molecular genetic tests; however, a detailed assessment of clinical and medical history data and the results of laboratory and instrumental studies enables quick diagnostic search direction and choice of the correct therapeutic tactics. The article considers the algorithm for the differential diagnosis of congenital diarrhea, presents a clinical case of congenital osmotic diarrhea due to disaccharidase insufficiency, and considers the difficulties of the diagnostic search and approaches to diet therapy. The prospective of using a fructose-based formula, Galactomin-19, in the diet therapy of glucose-galactose malabsorption, is presented.

Adrenomedullin as a New Prosperous Biomarker in Infections: Current and Future Perspectives

Adrenomedullin has emerged as a promising biomarker in the field of viral diseases. Numerous studies have demonstrated its potential in assessing disease severity, predicting clinical outcomes, and monitoring treatment response. Adrenomedullin (AM) is a multifaceted peptide implicated in vasodilation, hormone secretion, antimicrobial defense, cellular growth, angiogenesis, and, importantly, chronic pain. AM and related peptides interface with cytoskeletal proteins within neuronal contexts, influencing microtubule dynamics. AM has primarily been utilized in diagnosing diseases of bacterial origin, including sepsis. Nevertheless, there are reports suggesting its utility in diseases of viral origin, and this is the focus of the present study. Furthermore, adrenomedullin has been shown to be elevated in various viral infections, suggesting its role in immune response modulation. Furthermore, AM may contribute to neuronal dysfunction through mechanisms involving immune and inflammatory responses, apoptosis, and disruptions in calcium homeostasis. This review aims to consolidate current knowledge regarding AM and its potential implications in viral diseases, elucidating its diverse roles in neurological pathophysiology. This review highlights the growing importance of adrenomedullin as a biomarker in viral diseases and the need for further functional studies to understand the underlying mechanisms involved.

2-(Benzhydryl sulfinyl)-N-sec-butylacetamide isolated from fig fruits as a potential immune response modulator

2-(Benzhydryl sulfinyl)-N-sec-butylacetamide isolated from fig fruits as a potential immune response modulator

RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is a kinase that plays an essential role in the modulation of innate and adaptive immune responses. As a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs), it is implicated in the signaling triggered by recognition of microbe-associated molecular patterns by NOD1/2 and TLRs. Upon activation of these innate immune receptors, RIPK2 mediates the release of pro-inflammatory factors by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). However, whether RIPK2 is essential for downstream inflammatory signaling following the activation of NOD1/2, TLRs, or both remains controversial. In this study, we examined the role of RIPK2 in NOD2- and TLR4-dependent signaling cascades following stimulation of microglial cells with bacterial muramyl dipeptide (MDP), a NOD2 agonist, or lipopolysaccharide (LPS), a TLR4 agonist. We utilized a highly specific proteolysis targeting chimera (PROTAC) molecule, GSK3728857A, and found dramatic degradation of RIPK2 in a concentration- and time-dependent manner. Importantly, the PROTAC completely abolished MDP-induced increases in iNOS and COX-2 protein levels and pro-inflammatory gene transcription of Nos2 , Ptgs2 , Il-1β , Tnfα , Il6 , Ccl2 , and Mmp9 . However, increases in iNOS and COX-2 proteins and pro-inflammatory gene transcription induced by the TLR4 agonist, LPS, were only slightly attenuated with the GSK3728857A pretreatment. Further findings revealed that the RIPK2 PROTAC completely blocked the phosphorylation and activation of p65 NF-κB and p38 MAPK induced by MDP, but it had no effects on the phosphorylation of these two mediators triggered by LPS. Collectively, our findings strongly suggest that RIPK2 plays an essential role in the inflammatory responses of microglia to bacterial MDP but not to LPS.

Cimicifuga heracleifolia kom. Attenuates ulcerative colitis through the PI3K/AKT/NF-κB signaling pathway

Ethnopharmacological relevanceCimicifuga heracleifolia Kom. (C. heracleifolia) has demonstrated efficacy in treating gastrointestinal disorders, including splenasthenic diarrhea. Ulcerative colitis (UC), a chronic inflammatory bowel disease, shares similarities with splenasthenic diarrhea. However, the pharmacological effects of C. heracleifolia on UC and the underlying mechanisms remain unexplored. Aim of the studyThe present study investigates the therapeutic potential and mechanisms of C. heracleifolia in UC. MethodsInitially, network pharmacology analysis, encompassing ingredient screening, target prediction, protein-protein interaction (PPI) network analysis, and enrichment analysis, was employed to predict the mechanisms of C. heracleifolia. The findings were further validated using transcriptomics and functional assays in a dextran sulfate sodium (DSS)-induced UC model. Additionally, bioactive compounds were identified through surface plasmon resonance (SPR) analysis, molecular docking, and cell-based assays. ResultsA total of 52 ingredients of C. heracleifolia were screened, and 32 key targets were identified within a PPI network comprising 285 potential therapeutic targets. Enrichment analysis indicated that the anti-UC effects of C. heracleifolia are mediated through immune response modulation and the inhibition of inflammatory signaling pathways. In vivo experiments showed that C. heracleifolia mitigated histological damage in the colon, reduced the expression of phosphorylated Akt1, nuclear factor-kappa B (NF-κB) p65, and inhibitor of Kappa B kinase α/β (IKKα/β), suppressed the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and enhanced the expression of tight junction proteins. Moreover, cimigenoside, caffeic acid, and methyl caffeate were identified as the bioactive constituents responsible for the UC treatment effects of C. heracleifolia. ConclusionsIn summary, this study is the first to demonstrate that C. heracleifolia exerts therapeutic effects on UC by enhancing the intestinal mucosal barrier and inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/NF-κB signaling pathway. These findings offer valuable insights into the clinical application of C. heracleifolia for UC management.

Galectins: a potential pharmacological target

Aim. To consider the use of galectin-1 and galectin-3 inhibitors as potential pharmacological targets in antitumor and antifibrotic therapy.The lecture includes the analysis of experimental research and review articles presented in the PubMed database. A brief description of the structure of galectins is given. Their generally accepted classification and features of the structure of the carbohydrate recognition domain in galectin-1 and galectin-3 are presented. The main part of the lecture describes the results of research on the development of carbohydrate-based (β-galactoside derivatives or analogues) and non-carbohydrate-based (peptide-based, carboxamide derivatives) inhibitors capable of interacting with galectin-1 and galectin-3.The results of experiments performed on animal models and tumor cell cultures demonstrate that the antitumor effect of galectin antagonists is realized through the suppression of proliferation and metastasis, activation of tumor cell apoptosis, and modulation of the antitumor immune response. Antagonists of galectin-1 and galectin-3 potentiate the effect of antitumor drugs and have an antifibrotic effect. Some of the compounds discussed in the lecture are undergoing clinical trials. The data presented in the lecture open up opportunities for the development and synthesis of new molecules of potential galectin-1 and 3 inhibitors.

Exploring the Role of Secondary Metabolites from Plants and Microbes as Modulators of Macrophage Differentiation.

Recent research has uncovered that secondary metabolites-biologically active compounds produced by plants, microbes, and other organisms-play a significant role in regulating the differentiation and function of macrophages. Macrophages, key components of the innate immune system, are crucial for a wide range of physiological processes, including immune response modulation, tissue homeostasis, and host defense against pathogens. This research delves into the mechanisms by which secondary metabolites influence macrophage differentiation signaling pathways, with a focus on how specific compounds affect macrophage polarization and functional phenotypes. Understanding these effects can open new avenues for developing therapeutic strategies that target macrophage-mediated immune responses. Secondary metabolites, such as nitrogen (N) and sulfur (S) containing compounds, terpenoids, and phenolic compounds from plants and microbes, can modulate macrophage differentiation by influencing cytokine production and activity. The activation of signaling pathways in macrophages involves multiple receptors and transcription factors, including IFN-γ receptor activation leading to STAT1 activation, TLR4 triggering IRF5, NFκB, and AP1, IL-4 receptor activation leading to STAT6 and IRF4 activation, PPARγ activation via the fatty acid receptor, TLR4 increasing CREB and C/EBP levels. The complex interplay between transcription factors and cytokines is crucial for maintaining the balance between the M1 and M2 states of macrophages. Despite these insights, further research is needed to unravel the specific molecular mechanisms involved and to identify promising secondary metabolites that could be translated into clinical applications.

Protein profile of extracellular vesicles derived from adult Parascaris spp.

BackgroundParascaris spp. represent a significant threat to equine health worldwide, particularly in foals. The long-term survival of parasites in the host necessitates persistent modulation of the host immune response. Intercellular communication achieved through the exchange of molecules via extracellular vesicles (EVs) released from the parasite could be a crucial factor in this regard. This study aimed to isolate and characterize EVs released by adult male and female Parascaris worms and conduct a proteomic analysis to identify sex-specific proteins and potential immunomodulatory factors.MethodsLive adult Parascaris worms were collected, and EVs were isolated from spent culture media using differential ultracentrifugation. Nanoparticle tracking analysis and transmission electron microscopy confirmed the size, concentration, and morphology of the isolated EVs. Proteins within the isolated EVs were analyzed using mass spectrometry-based proteomics (LC–MS/MS).ResultsProteomic analysis revealed a total of 113 proteins in Parascaris EVs, with several proteins showing homology to known helminth exosome proteins and exhibiting immunomodulatory functions. Sex-specific differences in EV protein composition were observed, with a distinct abundance of C-type lectins in female EVs, suggesting potential sex-specific roles or regulation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed metabolic pathways shared between male and female Parascaris EVs, as well as differences in signal transduction, and cell growth and death pathways, indicating sex-specific variations.ConclusionsThese findings imply that Parascaris EVs and their protein cargo are complex. This data potentially opens avenues for discovering innovative approaches to managing and understanding helminth infection.Graphical

From defense to offense: antimicrobial peptides as promising therapeutics for cancer.

Antimicrobial peptides (AMPs), naturally occurring components of innate immunity, are emerging as a promising new class of anticancer agents. This review explores the potential of AMPs as a novel class of anticancer agents. AMPs, naturally occurring peptides with broad-spectrum antimicrobial activity, exhibit several characteristics that make them attractive candidates for cancer therapy, including selectivity for cancer cells, broad-spectrum activity, and immunomodulatory effects. Analysis of a dataset of AMPs with anticancer activity reveals that their effectiveness is influenced by various structural properties, including net charge, length, Boman index, and hydrophobicity. These properties contribute to their ability to target and disrupt cancer cell membranes, interfere with intracellular processes, and modulate the immune response. The review highlights the promising potential of AMPs as a new frontier in cancer treatment, offering hope for more effective and less toxic therapies. AMPs demonstrate promising potential in cancer therapy through multiple mechanisms, including direct cytotoxicity, immune response modulation, and targeting of the tumor microenvironment, as evidenced by extensive preclinical studies in animal models showing tumor regression, metastasis inhibition, and improved survival rates. AMPs show significant potential as cancer therapeutics through their direct cytotoxicity, immune response modulation, and tumor microenvironment targeting, with promising results from preclinical studies and early-phase clinical trials. Future research should focus on optimizing AMP properties, developing novel delivery strategies, and exploring synergistic combination therapies to fully realize their potential as effective cancer treatments, while addressing challenges related to stability, delivery, and potential toxicity.

Lactobacillus rhamnosus ameliorates experimental autoimmune neuritis via modulation of gut microbiota and metabolites

BackgroundGuillain-Barre syndrome (GBS), an autoimmune disease of the peripheral nervous system, is hallmarked by demyelination and immune cellular infiltration. Experimental autoimmune neuritis (EAN), considered a GBS prototype model, has been studied for its potential therapeutic benefits from lactobacilli. This study evaluated the protective role of Lactobacillus rhamnosus GG (GG) for treatment in EAN. T cell ratio, inflammation factors, sciatic nerve pathology, intestinal permeability, and gut inflammation were assessed on day 19 post-immunization to evaluate GG's effect on EAN. Fecal metabolomics and 16s rRNA microbiome analysis were conducted to elucidate its mechanism. ResultsGG dynamically balanced CD4+/CD8+T cell ratio, reduced serum IL-1β and TNF-α expression, improved sciatic nerve demyelination and inflammation, and enhanced neurological scores during peak disease period. Intestinal mucosal damage was evident in EAN rats, with downregulated Occludin and ZO-1 and upregulated IL-1β, TNF-α, and Reg3γ. GG treatment restored intestinal mucosal integrity, upregulated Occludin and ZO-1, and downregulated IL-1, TNF-α, and Reg3γ. GG partially rectified the gut microbiota and metabolite imbalance in EAN rats. ConclusionGG mitigates EAN through immune response modulation and inflammation reduction via the gut microbiota and metabolites.

Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer.

Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast cancer. Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice. HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice. These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast cancer using an anti-PD-L1 antibody.

Using Hybrid Nanoplatforms to Combine Traditional Anti-Inflammatory Drug Delivery with RNA-Based Therapeutics for Macrophage Reprograming.

There is growing evidence on the significant role of prolonged inflammation in triggering and progressing of numerous diseases with substantial health and socioeconomic impacts, such as musculoskeletal, cardiovascular and autoimmune disorders, and cancer. Therefore, there is an urgent need to develop therapies that can overcome the main challenges of currently used approaches, such as non-target action, partial modulation of the complex inflammatory pathways, and short-term effects, to effectively manage and resolve chronic inflammatory states. This work investigates the therapeutic synergy of clinically relevant anti-inflammatory agents approaching naïve and classically activated macrophages owing to their central role in inflammation. Aiming at human therapies, a dual-loading nanoplatform reunites molecules with different physico-chemical properties in a single system, seeking to more effectively and comprehensively regulate macrophage functions for precision cell guidance and greater versatility in disease managing. To build this platform, palmitic acid grafted chitosan, superparamagnetic iron oxide nanoparticles, the clinically approved NSAID celecoxib (also known as Celebrex®), and RNA technologies were combined into superparamagnetic polymeric micelles (SPMs). Our findings demonstrated that traditional anti-inflammatory drugs such as celecoxib and microRNA molecules were efficiently delivered by the SPMs, altering the inflammatory profile of naïve (M0φ) and M1-primed macrophages (M1φ) assessed by gene and protein expression. The impact of the dual-loaded SPMs in naïve Mφ is an interesting finding towards the modulation of the initial immune response, reducing the potential for chronic inflammation and promoting tissue healing. Collectively, these encouraging results demonstrate the promise of multi-nanomedicine strategies to enhance the efficacy of therapeutic interventions by offering a fresh approach to more precisely and carefully regulated nanotherapeutics delivery.

Oral Cavity Microbiome Impact on Respiratory Infections Among Children.

The respiratory system, traditionally considered antiseptic, harbors a diverse and dynamic bacterial microbiome. Recent advancements in microbiome research have revealed its significant influence on both innate and adaptive immunity, particularly in the context of respiratory infections in children. This article also provides an overview of the types of bacteria that commonly affect the respiratory system, including Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae. These bacteria are prevalent in pediatric populations and significantly contribute to the development and severity of respiratory tract infections (RTIs). This review aims to evaluate the impact of the oral cavity and upper respiratory microbiome on the susceptibility and severity of respiratory infections in pediatric populations. We specifically focus on how early colonization patterns of bacteria such as Moraxella and Streptococcus contribute to the development of respiratory tract infections in children from birth through adolescence. A thorough literature review was performed, focusing on studies publishing between 2004 and 2023. The review included research exploring the role of the upper respiratory microbiome in pediatric populations, with a specific focus on children aged birth to 18 years. Emphasis was placed on microbial characterization, the modulation of immune responses in respiratory tract infections, and the potential therapeutic applications of microbiome-targeted interventions. The findings suggest that the composition and disruption of the upper respiratory microbiome significantly influence clinical outcomes in children with respiratory infections. Notably, dysbiosis in the microbiome has been linked to increased susceptibility to repeated infections, highlighting the importance of maintaining microbial balance for optimal respiratory health. Understanding the impact of oral cavity and upper respiratory microbiome could lead to improved management and prevention strategies for respiratory infections in children. This review underscores the potential of microbiome modulation, including the use of probiotics as a therapeutic approach to enhance clinical outcomes in pediatric respiratory infections.

RNA-seq analysis of LPS-induced immune priming in silkworms (Bombyx mori) and the role of cytochrome P450 detoxification system in the process

While immune priming has been identified in many invertebrates, the intricate mechanisms that drive this process in insects continue to be a subject of mystery. In this study, we exposed silkworm larvae to varying doses of lipopolysaccharide (LPS) to induce immune priming and assessed their survival upon challenge with Bacillus thuringiensis (Bt). Transcriptome analysis was performed to identify differentially expressed genes (DEGs) associated with immune priming. The role of CYP450 genes in this process was further explored using RNA interference (RNAi) to knockdown CYP9E2 and CYP6K1, followed by measurements of detoxification enzyme activities and reactive oxygen species (ROS) levels. We found that LPS exposure significantly increased silkworm survival rates upon Bt challenge, indicating the induction of immune priming. Transcriptome analysis revealed 549 DEGs, including a large number involved in detoxification, immunity, and metabolism, suggesting a complex regulatory network that encompasses immune responses and metabolic pathways. Functional enrichment and gene set enrichment analysis (GSEA) highlighted the activation of immune signaling pathways and the involvement of detoxification processes. Knockdown of CYP9E2 and CYP6K1 resulted in increased ROS levels, decreased detoxification enzyme activities, and reduced survival rates post-Bt challenge, implicating the critical role of these genes in immune priming and detoxification. Our findings demonstrate that LPS-induced immune priming in silkworms involves the upregulation of CYP450 genes, which play a critical role in detoxification and immune response modulation. The study provides insights into the molecular mechanisms of immune priming in insects and highlights the potential of CYP9E2 and CYP6K1 as targets for enhancing disease resistance and pest management in insects.

Potential Oncogenic and Immunosuppressive Roles of Multiple EGF-Like Domains 6 (MEGF6) in Colon Cancer: Insights from Bioinformatic Analysis

Multiple epidermal growth factor-like domains protein 6 (MEGF6) is a high molecular weight protein with several EGF-like domains. Although it has been demonstrated to promote metastasis and chemoresistance in colon cancer cells, its specific oncogenic and immunologic functions remain largely unexplored. This study aims to comprehensively analyze publicly available datasets to define the role of MEGF6 in colon cancer development and immune response modulation. The expression of MEGF6 in colon adenocarcinoma (COAD) and normal tissues at both mRNA and protein levels was assessed using the GEPIA2 and HPA databases, respectively. The UALCAN database was employed to examine the association between MEGF6 expression and clinicopathological outcomes in COAD patients, and survival analysis was conducted using the KM plotter database. Functional enrichment analysis of MEGF6-correlated genes was performed using the ShinyGO online tool. Additionally, the correlation of MEGF6 with immune cell infiltration and immunosuppressive molecules was explored through the TIMER and TISIDB databases. Our analysis revealed significantly higher mRNA and protein expressions of MEGF6 in COAD tissues compared to normal tissues, with associations to cancer stage, nodal metastasis status, and histological subtype. High MEGF6 expression was correlated with poorer survival outcomes, and genes correlated with MEGF6 were enriched in biological processes related to cellular component organization, cell adhesion, and extracellular matrix interaction. Furthermore, MEGF6 expression demonstrated a significant correlation with immune cell infiltration and the expression of immunosuppressive molecules, particularly CTLA-4, PD-1, PD-L1, TGF-β, and IL-10. In conclusion, our findings suggest that MEGF6 may play an oncogenic role by influencing cell and extracellular matrix interactions. Its overexpression may indicate immunosuppressive properties within the cancer microenvironment. Therefore, MEGF6 holds promise as a potential biomarker for predicting both prognosis and therapeutic responses in colon cancer. HIGHLIGHTS MEGF6 has been shown to involve colon cancer growth and chemotherapeutic resistance. Bioinformatics confirmed a prognostic significance of MEGF6 in colon cancer. MEGF6 may exert its oncogenic effects by influencing cell-matrix interactions. MEGF6 expression is correlated with immunosuppressive properties of cancers. GRAPHICAL ABSTRACT

The interaction of interferon gamma and gaillardin and the formation of a nanocomplex with improved anti-melanoma effects

This study presents a comprehensive analysis of IFN-γ-Gaillardin nanoparticles (NPs) using a combination of computational, biophysical and cell-based approaches. The molecular docking analysis revealed that both hydrogen and hydrophobic forces are involved in the formation of IFN-γ-Gaillardin complex The interaction between IFN-γ and Gaillardin was further characterized by a pronounced ANS fluorescence spectrum peak and a higher intensity for IFN-γ. The Langmuir, Scatchard, and Hill analyses revealed a higher affinity and lower dissociation constant for IFN-γ NPs compared to IFN-γ alone, suggesting enhanced complex stability. Thermal gravimetric analysis confirmed that the Gaillardin interaction might improve the thermal stability of the NPs. The NPs demonstrated robust stability in various media, highlighting their potential as a delivery system. However, size increase in deionized water suggests the need for formulation optimization. Cell-based assays revealed selective cytotoxicity towards A-375 melanoma cancer cells with minimal impact on non-cancerous HaCaT cells, indicating targeted antitumor effects. Real-time PCR showed gene expression changes consistent with antitumor activity and immune response modulation. The findings suggest that IFN-γ-Gaillardin NPs have potent antitumor properties and the ability to modulate the immune system, warranting further investigation into their therapeutic applications. The development of an IFN-γ-based nanocarrier system for Gaillardin delivery offers a promising approach to melanoma therapy, setting a new direction for NP-based cancer treatment strategies.

Development of fast-dissolving sublingual nanofibers containing allergen and curcumin for immune response modulation in a mouse model of allergic rhinitis.

Curcumin (CUR) has been considered a potential therapeutic agent for allergic reactions due to its antioxidant and anti-inflammatory activities. Nanofibers have attracted increasing attention in drug delivery. The aim of this study was to investigate the combined therapeutic effects of curcumin and allergen in nanofiber-based treatments in order to increase the effectiveness of sublingual immunotherapy (SLIT) efficacy in a mouse model of allergic rhinitis. Nanofibers containing CUR (1.25% and 2.5%) and ovalbumin 2% (OVA) as an allergen were prepared via electrospinning and characterized. BALB/c mice were sensitized with OVA to the induced allergic rhinitis model. SLIT with free and/or nanofibers was carried out. IL-4, INF-γ, and IgE serum levels were measured using ELISA. Splenocyte proliferation was evaluated by the MTT assay. Lung and nasal histological examinations and nasal lavage fluid (NALF) cell counting were carried out. Nanofibers containing 1.25% CUR and 2% OVA were chosen as the optimal formulations. SLIT treatment with the CUR and OVA nanofiber co-administration led to a significantly decreased serum IgE. Nanofiber containing 2.5 µg of CUR/mouse combined with OVA nanofiber showed a significant decrease in IL-4 and an increase in IFN-γ compared to other groups. NALF assessment showed a significant decrease in specific cell and eosinophil counts in the treated nanofiber groups. The histopathological results of NAL in the optimal formulations were near normal, with diminished cellular infiltration and inflammation. Our findings suggest that co-sublingual administration of allergen and CUR nanofibers can be considered as potential immunomodulatory agents.