Search Results (1,311)

Background/Objectives: The aim of this study was to investigate the cytotoxic, genotoxic, apoptotic, and anti-inflammatory effects of the antiseptic agent octenidine dihydrochloride (OCT-D) on the RPMI-2650 cell line derived from human nasal mucosa in vitro. Methods: RPMI-2650 cells and Human Umbilical Cord Endothelial Cells (HUVECs) were treated with various concentrations of OCT-D (0.00625–0.4%) for 12 and 24 h. Cell viability was assessed using the WST-1 assay, while DNA damage was assessed using the comet and micronucleus (MN) assays. Apoptotic activity was determined using Annexin V flow cytometry and fluorescence microscopy. Intracellular reactive oxygen species (ROS) levels were measured, and inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The mRNA expression of genes associated with apoptosis, oxidative stress, and inflammation was analyzed using RT-PCR. Results: OCT-D caused dose- and time-dependent cytotoxicity, and RPMI-2650 cells showed greater resistance compared to HUVECs. While a strong apoptotic response was observed in HUVECs, RPMI-2650 cells exhibited limited apoptosis. OCT-D was found to cause dose-dependent DNA damage and an increase in MN in both cell lines. OCT-D significantly reduced cytokine levels and ROS production in both cell types. RT-PCR results supported its anti-inflammatory and antioxidant effects at the molecular level. Conclusions: In conclusion, this study demonstrated that OCT-D exhibited minimal cytotoxic and apoptotic effects in RPMI-2650 cells, but affected vascular structure by inducing apoptosis in endothelial cells. These findings provide important evidence that OCT-D can be used as a potential adjunctive agent in nasal treatments, and these data need to be supported by preclinical and clinical studies. Full article

African swine fever (ASF), caused by the African swine fever virus (ASFV), is an acute, febrile, highly contagious, and lethal disease that poses a severe threat to the global pig farming industry. Currently, no globally recognized, safe, and effective commercial ASF vaccine has been developed, making vaccination a crucial strategy for outbreak control. The ASFV structural proteins p72, p30, and p54 are key targets for vaccine development. In this study, we developed a novel baculovirus vector-based system for surface display of a recombinant protein comprising epitopes from p72, p30, and p54. Upon infection, the recombinant protein was expressed and anchored on the plasma membrane of Sf-9 cells. Purified virus analysis revealed that the Bac-recombinant protein enhanced gene delivery and transgene expression in mammalian cells compared to the Bac-Wild Type (Bac-WT). In a murine model, the Bac-recombinant protein induced significantly higher IFN-γ and IL-4 levels than Bac-p30 and the negative control. However, further evaluation in swine models is required to confirm its protective potential against ASFV. Furthermore, it also elicited a robust antibody response, generating high-titer Bac-recombinant protein-specific antibodies. Therefore, these findings suggest that the ASFV Bac-recombinant protein is a promising candidate for a vector-based vaccine. Full article

The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway, a central innate immune sensor of cytosolic DNA, plays a dual role in immunoregulation within pulmonary diseases. Recent studies demonstrate its critical role in sensing microbial infections and tissue injury in the lung, allowing it to drive the production of type I interferons (IFN-I) and pro-inflammatory cytokines. While this pathway is essential for anti-viral defense and anti-tumor immunity, its dysregulation can exacerbate pathologies such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and lung cancer, mainly through sustained inflammation and fibroblast proliferation. Nowadays, many cGAS-STING agonists and inhibitors are available to treat different diseases. This review comprehensively summarizes the basic mechanism of the cGAS-STING pathway, its diverse roles across various pulmonary diseases, and the current landscape of potential therapeutic strategies targeting this pathway. Notably, the critical role of the cGAS-STING signaling pathway in various lung diseases offers new avenues for therapeutic research. Full article

SARS-CoV-2 infection remains a global health concern, with its impact on host immune responses not fully understood. In a case–control study, we examined how COVID-19 affects DNA methylation patterns in the upper respiratory airway of hospitalized individuals. DNA methylation arrays were performed on nasopharyngeal samples at inclusion/hospitalization and 6 weeks post-inclusion. We found a distinct DNA methylation pattern in COVID-19 patients compared to healthy controls, identifying 510,099 differentially methylated CpGs. Within the transcription start sites (TSSs) and gene body, COVID-19 patients displayed a higher number of genes/CpGs with elevated methylation levels. Enrichment analysis of TSS-methylated genes revealed effects of SARS-CoV-2 on genes associated with type I interferons, anti-viral and inflammatory responses, and immune functions. Some CpG methylations were transient, and normalized at group level by 6 weeks post-inclusion. Several IFN-regulated genes, including OAS1, OAS3, IFIT3, and MX1, were identified. Among the top regulators were IL17A and ERK1/2, both involved in inflammatory processes. Networks nodes included IGF1 and EGF, associated with processes including tissue repair and activation of immune responses. Overall, our data suggests that COVID-19 can impact the upper airway by modifying gene methylation patterns. This could have implications for conditioning of the airways, how individuals respond to future airway infections, and therapeutic interventions. Full article

Background: Lichen planus (LP) is a common inflammatory disease affecting skin, mucous membranes, hairs, and nails, with an unpredictable course involving remissions and relapses. LP is a Type-I-Inflammation disease involving IFN-γ and IL-17 as key inflammatory mediators. Materials and Methods: We searched PubMed/MEDLINE and Google Scholar search engines for studies on the esophageal manifestation of lichen planus over an unlimited time frame. Articles were searched with combinations of Medical Subject Heading (MeSH) terms. Given the limited number of publications, no exclusion criteria were applied. Results: Esophageal lichen planus (ELP) is an underreported manifestation of LP that primarily affects middle-aged women. Its prevalence among LP patients remains to be defined. Though potentially clinically silent, ELP can significantly impact patient wellbeing and serve as a precursor to esophageal squamous cell carcinoma. While dysphagia is the primary symptom, the condition may also remain subclinical. The endoscopic hallmarks of ELP are mucosal denudation and tearing, trachealization, and hyperkeratosis. Chronic disease progression may lead to scarring esophageal stenosis. Histologically, ELP shows mucosal detachment, T-lymphocytic infiltrations, epithelial cell apoptosis (Civatte bodies), dyskeratosis, and hyperkeratosis. Fibrinogen deposits along the basement membrane zone distinguish ELP from various immunological esophageal diseases. There is currently no standardized therapy available. Topical steroids lead to symptomatic and histologic improvements in two-thirds of patients. Severe or refractory cases require immunosuppressive therapy, whereas JAK-inhibitors represent a promising emerging option. Endoscopic dilation helps symptomatic stenosis. Considering ELP’s precancerous potential, timely diagnosis and treatment are crucial in preventing complications, such as stenosis or invasive esophageal squamous cell carcinoma. Conclusions: ELP is an underdiagnosed and underreported manifestation of LP. While it may remain clinically silent, it can nevertheless significantly affect patients’ wellbeing and life expectancy. This narrative review aims to initiate multidisciplinary cooperation among gastroenterologists, dermatologists, oral health professionals, and histopathologists to support clinical diagnosis and management. Full article

Intestinal homeostasis disorders (IHDs), driven by food safety issues, pollution, and drug-resistant pathogens, threaten global health. Key factors in intestinal and metabolic diseases (like IBD, obesity, and liver disease) include barrier dysfunction, gut microbiota imbalance, and excessive immune activation. Transcription factors in intestinal epithelial cells are crucial regulators. ELF4, an ETS family transcription factor, plays vital roles in transcriptional regulation, impacting tumorigenesis, the DNA damage response, and the cell cycle. ELF4 deficiency exacerbates alcoholic liver disease (ALD). Significantly, ELF4 is a novel IFN-I transcription factor with antiviral capabilities. Its regulation of the type I IFN response offers new avenues for developing antiviral and anticancer strategies and managing IFN-induced autoimmune disorders. Thus, ELF4 emerges as a promising target for preventing and treating IHD-related diseases. Mechanistic studies could help identify diets or antimicrobials that activate intestinal ELF4 to combat pathogen/virus-induced intestinal diseases. Full article

Background: The interleukin-10 (IL-10) signaling system, comprising ligands (IL-10s) and receptors (IL-10Rs), plays critical roles in immune regulation, inflammation resolution, and disease pathogenesis. “IL-10 signaling system” here refers to the immunomodulatory signaling system composed of ligands (IL-10s) and receptors (IL-10Rs), which belong to different Protein families in evolution, but achieve functional synergy through the conserved JAK-STAT pathway. Understanding their evolutionary and functional dynamics is essential for elucidating immune mechanisms and therapeutic targeting. Methods: Through phylogenetic reconstruction, homology analysis, and sequence alignment across >400 animal species, we traced the evolutionary trajectory and structural–functional diversification of IL-10s and IL-10Rs. Results and Conclusions: IL-10 signaling components emerged in early vertebrates, with IL-10Rs originating in cartilaginous fishes (~450 Mya) and IL-10s diversifying in bony fishes (~400 Mya). Functional divergence yielded immunosuppressive (IL-10), barrier-protective (IL-20 subfamily), and antiviral (type III IFN) subgroups. Structurally, conserved motifs (e.g., IL-10R1 GYXXQ, IL-22 N54-glycosylation) underpin receptor–ligand binding and JAK/STAT signaling. Evolutionarily invariant residues suggest candidate therapeutic epitopes. This study provides an evolutionary framework highlighting functional conservation and species-specific adaptation within IL-10 signaling, with implications for immunotherapy and animal breeding. Full article

Patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) are at increased risk of severe infections, making effective vaccination strategies essential. While antibody responses to SARS-CoV-2 vaccination have been studied in SLE, less is known about innate immune correlates. Therefore, we evaluated cytokines with a particular emphasis on interferon and chemokine profiles. To fulfill the immunological picture, we also assessed neutralizing antibodies against SARS-CoV-2 variants, lymphocyte subpopulations, and selected gene expression signatures in 33 patients stratified by vaccination status: fully vaccinated (FV, n = 23) and partially vaccinated (PV, n = 10). Serum analyses showed that FV patients exhibited increased type I (IFN-α2, IFN-β) and type III (IFN-λ1, IFN-λ2/3) interferons, as well as elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-12p70) and IL-10, whereas neutralizing antibody (Neut. Ab.) titers against wild-type and variant strains, including Omicron, were comparable between groups. Immunophenotyping demonstrated preserved T- and B-cell subset distributions, except for reduced CD8⁺CD197⁺CD45RA⁻ (central memory) T cells in FV patients. ISG15 gene expression was upregulated in the T cells of FV patients. Correlation analyses linked IL-6 with disease activity and IL-8, GM-CSF, IFN-β, IL-10, and Alpha Neut. Ab. with organ damage. Complement C3 correlated inversely with IFN-α2 and IFN-γ, while C4 correlated positively with Alpha and Omicron Neut. Ab. These findings highlight that vaccination in SLE induces distinct interferon and cytokine signatures without consistent enhancement of neutralizing antibodies against SARS-CoV-2, underscoring the importance of integrated immune correlates in assessing vaccine responses in this population. Full article

Background: Oncolytic virus (OV) therapy couples direct tumor lysis with systemic immune priming, yet clinical benefit remains heterogeneous and the predictive biomarker landscape is poorly defined. We undertook a systematic review and meta-analysis to quantify the efficacy and safety of OV therapy in solid tumors and to synthesize current evidence on response-modulating biomarkers. Methods: Following PRISMA 2020 guidelines, MEDLINE, Embase, Cochrane CENTRAL, ProQuest and Scopus were searched from inception to May 2025. Phase II–III randomized trials of genetically engineered or naturally occurring OV reporting objective response rate (ORR), progression-free survival (PFS), overall survival (OS) or biomarker data were eligible. Hazard ratios (HRs) or odds ratios (OR) were pooled with random-effects models; heterogeneity was assessed with I² statistics. Qualitative synthesis integrated genomic, immunologic and microbiome biomarkers. Results: Thirty-six trials encompassing around 4190 patients across different tumor types met inclusion criteria. Compared with standard therapy, OV-based regimens significantly improved ORR nearly three-fold (pooled OR = 2.77, 95% CI 1.85–4.16), prolonged PFS by 11% (HR = 0.89, 95% CI 0.80–0.99) and reduced mortality by 16% (OS HR = 0.84, 95% CI 0.72–0.97; I² = 59%). Benefits were most pronounced in melanoma (ORR 26–49%; OS HR 0.57–0.79) and in high-dose vaccinia virus for hepatocellular carcinoma (HR = 0.39). Grade ≥ 3 adverse events were not increased versus control (risk ratio 1.05, 95% CI 0.89–1.24); common toxicities were transient flu-like symptoms and injection-site reactions. Biomarker synthesis revealed that high tumor mutational burden, interferon-pathway loss-of-function mutations, baseline CD8⁺ T-cell infiltration, post-OV upregulation of IFN-γ/PD-L1, and favorable gut microbial signatures correlated with response, whereas intact antiviral signaling, immune-excluded microenvironments and myeloid dominance predicted resistance. Conclusions: OV therapy confers clinically meaningful improvements in tumor response, PFS and OS with a favorable safety profile. Integrating composite genomic–immune–microbiome biomarkers into trial design is critical to refine patient selection and realize precision viro-immunotherapy. Future research should prioritize biomarker-enriched, rational combination strategies to overcome resistance and extend benefit beyond melanoma. Full article

Stimulator of interferon genes (STING) is a cytosolic DNA sensor that activates type I interferon (IFN) signaling, which plays a key role in neuroinflammation. Although the role of STING in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), remains debated, its involvement in the development of CNS lesions, particularly within localized pathology, modeled here by targeting the corpus callosum, has yet to be explored. Using a focal EAE model, we compared the induction of lesions in wild-type and STING-deficient (STING^gt/gt) mice. Lesions were analyzed by immunohistochemistry, flow cytometry, and transcriptomics. STING-deficient mice had significantly larger demyelinated lesions, reduced ISG expression, and modified immune cell infiltration. STING signaling limits lesion severity in focal EAE by promoting IFN responses and regulating immune infiltration. These findings position STING as a potential target for MS therapy. Full article

The stimulator of interferon genes (STING) serves as a pivotal signaling hub in innate immunity, orchestrating type I interferon (IFN-I) and pro-inflammatory responses upon detection of cytosolic DNA. While the canonical cyclic GMP-AMP synthase (cGAS)-STING axis has been extensively studied in host defense and sterile inflammation, increasing evidence indicates that STING can also be activated through a variety of both pattern recognition receptors (PRRs)-dependent and PRRs-independent mechanisms. In this review, we comprehensively summarize the molecular pathways through which PRRs—including cGAS, interferon gamma inducible protein 16 (IFI16), DEAD-box helicase 41 (DDX41), and DNA-dependent protein kinase (DNA-PK)—engage and regulate STING activation. Beyond PRRs-triggered pathways, we explore emerging evidence of PRRs-independent STING activation, driven by genetic mutations, endoplasmic reticulum (ER) stress, dysregulated intracellular trafficking, and impaired protein degradation. These mechanisms contribute to the pathogenesis of a broad spectrum of inflammatory and autoimmune disorders affecting multiple organ systems, including the digestive, cardiovascular, renal, pulmonary, and nervous systems. We also highlight the current landscape of pharmacological inhibitors targeting cGAS and STING, categorized according to their mechanisms of action and therapeutic potential. The redundancy and complexity of components within the STING signaling network present challenges in effectively suppressing inflammatory overactivation by targeting a single molecule. Nevertheless, the central role of STING offers multiple opportunities for therapeutic intervention, whether by modulating upstream or downstream signaling elements. This review not only provides a systematic framework for understanding the intricacies of STING signaling, but offers insights into the development of next-generation therapeutics aimed at selectively modulating STING activity in disease contexts. Full article

Background/Objectives: Mitochondrial damage is implicated in metabolic dysfunction and may contribute to inflammation and insulin resistance, key features of type 2 diabetes. This study examined the relationship among inflammatory markers, mtDNA DAMPs, and insulin sensitivity/resistance, and evaluated their response to three dietary interventions in type 2 diabetes. Methods: Data was pooled from two clinical trials involving adults aged 35 to 75 with type 2 diabetes (n = 39). Participants followed one of three 12-week diet interventions aimed at enhancing glucose metabolism without causing weight loss. The sample was 74% female and 64% African American with a mean age of 55.6 ± 7.7 years, and 92.3% (n = 36) had overweight/obesity. Participants were assigned to either a carbohydrate-restricted, low-fat, or fruit-rich Mediterranean diet. Primary outcomes included insulin resistance (HOMA-IR), insulin sensitivity (Matsuda index), mtDNA DAMPs (ND1, ND6), pro/anti-inflammatory cytokines (IFN-γ, IL-10, IL-6, IL-8, TNF-α), CRP, and cortisol. Associations among mtDNA DAMPs, inflammation, and insulin sensitivity/resistance were examined using regression analysis Results: The carbohydrate-restricted diet led to the greatest improvements in insulin sensitivity (72.7%) and reductions in HOMA-IR (41.3%) (p = 0.03). All diets increased mtDNA DAMPs, with most observed in the fruit-rich Mediterranean diet and low-fat diet groups and the smallest in the carbohydrate-restricted group. Total mtDNA DAMPs were associated with lower insulin sensitivity (Matsuda index: β = –0.77; SE = 0.31; p = 0.02), and ND6 mtDNA DAMP levels were associated with greater insulin resistance (HOMA-IR: β = 0.90; SE = 0.40; p = 0.03) and lower insulin sensitivity (Matsuda index: β = –0.86; SE = 0.33; p = 0.01), independent of BMI and race. Proinflammatory cytokines were associated with increased HOMA-IR (β = 0.45; p = 0.007) and reduced Matsuda index (β = –0.43; p = 0.009) and moderated effects of mtDNA DAMPs on insulin sensitivity/resistance. Conclusions: These findings highlight mtDNA DAMPs in metabolic dysfunction in the context of inflammation. Full article

Efficient control of HIV-1 infection relies on highly active antiretroviral therapy (HAART). However, this therapy is not curative and requires continuous drug administration. Application of HIV-1 defective interfering particles (DIPs), engineered with ablations in key viral protein expressions (e.g., Tat, Rev, Vpu, and Env), suggests a therapeutic potential transforming them into Therapeutic Interfering Particles (TIPs). A recent animal HIV model study in non-human primates reports a substantial reduction in viral load after a single intravenous injection of TIPs. In contrast, human clinical trials demonstrate no beneficial effect of defective interfering particles (DIPs) in people living with HIV-1. This discrepancy highlights the importance of further investigation of HIV-TIP interactions. A quantitative view of intracellular replication for HIV-1 in the presence of TIPs is still missing. Here, we develop a high-resolution mathematical model to study various aspects of the interference of a specific engineered TIP-2 particle characterized by a 2.5-kb deletion in the HIV pol-vpr region with HIV-1 replication within infected CD4+ T cells. We define the conditions in terms of the number of homozygous HIV-1 virions and TIP-2 particles that enable the reduction of the wild-type virus replication number to the value of about one. The deterministic model predicts that at a ratio of 1 HIV-1 to 10 TIP-2 particles, the infected cell still produces some viruses, although in a minor quantity, i.e., about two virions per cycle. Pre-activation of the interferon type I (IFN-I) system results in a complete block of HIV-1 production by TIP-2 co-infected cells. Overall, the modelling results suggest that to improve the effectiveness of TIPs in reducing HIV infection, their combination with other types of antiviral protection should be considered. Our results can be used in the development of combination therapy aimed at treating HIV-1 infection. Full article

Chlamydia invades multiple mucosal tissues in humans and animals. The body’s first line of defense against chlamydial infection is provided by innate immunity, whereas adaptive immunity plays a crucial role in managing the infection’s progression and preparing the immune system to combat reinfection. Host resistance to chlamydial infection necessitates a coordinated effort between innate and adaptive immune cells. Numerous cell types are capable of producing interferon gamma (IFN-γ) as a defense mechanism against chlamydial infection, thereby effectively mediating the clearance of infection. However, the distinct roles of various immune cell populations in responding to chlamydial infection, as well as their functions during infection progression, remain poorly understood. Therefore, we will discuss the various roles of IFN-γ released by different immune cells in chlamydial infection, focusing primarily on experimental animal models and a review of available data from in vivo cellular immunological studies in humans. Full article

Excessive production of type I interferons (IFNs) underlies the immunopathogenesis of autoimmune disorders, including systemic lupus erythematosus and autoimmune pancreatitis. Whether type I IFNs play pathogenic or protective roles in the development of inflammatory bowel diseases (IBD) has been a matter of debate. The production of type I IFNs is tightly regulated by the conjugation and removal of polyubiquitin chains on or from intracellular signaling molecules. OTU deubiquitinases 3 (OTUD3) and 5 (OTUD5) are enzymes that cleave various polyubiquitin chains from target proteins. OTUD3 and OTUD5 deubiquitinate key critical intracellular molecules of the type I IFN signaling pathways, stimulator of interferon genes (STING), and TNF receptor-associated factor 3 (TRAF3), respectively, and thus regulate the production of type I IFNs by innate immune cells. Recent studies provided evidence that the impaired function of OTUD3 and OTUD5 increases susceptibility to human and experimental IBD owing to the excessive production of type I IFNs caused by the activation of STING and TRAF3, respectively. Collectively, OTUD3 and OTUD5 play protective rather than pathogenic roles in the development of IBD through the negative regulation of type I IFN-mediated signaling pathways. In this review article, we discuss the association between the development of IBD and impaired function of OTUD3 or OTUD5 by focusing on their deubiquitinase activity and type I IFN responses. Full article