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Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and chronic neuroinflammation. Increasing evidence highlights the interleukin-12 (IL-12) cytokine family-including IL-12, IL-23, IL-27, and IL-35-as central regulators of immune responses in the central nervous system (CNS). IL-12 and IL-23 predominantly promote pro-inflammatory pathways by driving Th1/Th17 activity, microglial activation, and neurotoxicity, whereas IL-27 and IL-35 exert anti-inflammatory and neuroprotective effects through IL-10 induction and expansion of regulatory immune subsets. This review synthesizes disease-specific expression patterns and experimental findings, underscoring the dual pathogenic and protective roles of these cytokines. Therapeutic strategies targeting IL-12 family signaling have shown promise in preclinical and clinical contexts. In AD, blockade of IL-12/IL-23 reduced amyloid burden and improved cognition, while agents such as tadalafil and bergapten enhanced IL-27-mediated neuroprotection via PI3K/Akt, Wnt/β-catenin, and cGMP/PKG pathways. In MS, approaches including p40 blockade (ustekinumab, ABT-874), interferon-β therapy, hematopoietic stem cell transplantation, and B-cell depletion (ocrelizumab) variably suppressed IL-12/IL-23 and augmented IL-27/IL-35, influencing relapse rates and progression. Natural compounds such as curcumin, berberine, and vitamin D further highlight metabolic and dietary opportunities for cytokine modulation. In PD, combinatorial regimens combining herbal formulations with anti-inflammatory agents dampened IL-12-driven macrophage activation and supported dopaminergic neuron survival. Taken together, IL-12 family cytokines emerge as both biomarkers and therapeutic targets in NDs. However, context-dependent activity, blood-brain barrier constraints, and incomplete understanding-particularly of IL-35-pose translational challenges warranting further investigation. Show less

Gut microbiota-derived compounds are pivotal in modulating host immunity by regulating the functions of various key innate and adaptive immune cells. Epstein-Barr virus-induced gene 3 (EBI3) serves as the beta subunit shared by the heterodimeric cytokines interleukin (IL)-27 and IL-35. Both these cytokines have been documented to inhibit the development of T helper 2 (Th2) and T helper 17 (Th17) cells, while enhancing the function of regulatory T cells (Tregs). EBI3, itself, has also been shown to regulate cell-mediated immune responses. Despite their critical roles in maintaining immune homeostasis, there is a significant lack of robust, high-throughput-compatible assays to evaluate the secretion of IL-27, IL-35, or EBI3. In this study, we detail the development of a novel amplified luminescent proximity homogeneous assay (AlphaLISA™) to quantify EBI3 secretion by tolerogenic dendritic cells. We utilized this assay to screen a library of 9739 small proteins derived from the human gut microbiota to identify compounds that could stimulate EBI3 secretion. Our findings revealed the immunoregulatory potential of VAC18, an unknown protein from Fusicatenibacter saccharivorans (Clostridiumcluster XIVa) which significantly induces the secretion of both EBI3 and IL-27. This is the first study to demonstrate the effect of gut microbiota derived peptides on the balanced secretion of EBI3 and IL-27. Show less

Congenital viral infections can have severe consequences for pregnancy and fetal outcomes. Remarkably, the fetal-derived placenta serves as a robust barrier to infection through meticulous regulation by immune effectors and cytokines. Yet, the regulatory roles of many cytokines remain undefined at the maternal-fetal interface, including Interleukin-27 (IL-27). Here, we show that trophoblast organoids derived from human placentas constitutively express both IL-27 and its receptor, and restrict Zika virus infection through IL-27 signaling. Through bulk RNA-sequencing of trophoblast organoids in the absence and presence of IL-27 signaling, we demonstrate IL-27-mediated upregulation of antiviral genes. Finally, we show that IL-27 signaling is critical to restricting placental viral burdens and protecting against pathologic fetal outcomes during murine congenital Zika virus infection. In this work, we demonstrate a novel role for IL-27 in the placenta and establish IL-27 as an innate antiviral defense at the maternal-fetal interface during congenital viral infection. Show less

This study aims to investigate how Bifidobacterium breve BBr60 improves obesity-related metabolic disorders by modulating the gut microbiota-SCFAs axis, thereby affecting inflammatory factors and metabolic hormones. A randomized, double-blind, placebo-controlled trial was conducted. A total of 75 individuals with obesity subjects (BMI ≥ 28) were enrolled and randomly assigned to either the BBr60 intervention group (10 billion CFU daily) and the placebo group. After the 12-week intervention, 65 participants (BBr60: n = 33; placebo: n = 32) completed the study and were included in the primary analysis. All participants received standardized nutritional counseling aimed at a moderate energy intake (~ 1800 kcal/day, including a daily intake of 25 g of dietary fiber.). Every week, we call participants at a fixed time to inquire about their weekly diet and weight changes, and provide dietary suggestions for the following week based on the inquiry results. Participants were instructed to maintain their usual physical activity levels throughout the study. The composition of the gut microbiota was analyzed by 16 S sequencing, fecal SCFAs were detected by GC-MS, and serum levels of IL-27, IL-1β, and metabolic hormones were measured using ELISA technology. Metabolic indicators such as body weight, body fat percentage, and HOMA-IR were also assessed. The BBr60 intervention significantly increased fecal butyrate levels (p < 0.001), accompanied by a decrease in IL-1β levels (p < 0.05) and an upregulation of IL-27 (p < 0.01). In terms of metabolic hormones, leptin (LEP), adiponectin (ADPN), connecting peptide (C-P), pancreatic polypeptide (PP), peptide YY (PYY), Glucose-dependent insulinotropic polypeptide (GIP), and Glucagon-Like Peptide-1 (GLP-1) were all significantly elevated (p < 0.05), while Homeostasis Model Assessment for Insulin Resistance(HOMA-IR) was significantly reduced in the BBr60 group (p < 0.05). In the control group, C-P, PP, and GIP were significantly increased (p < 0.05), whereas LEP, ADPN, PYY, GLP-1, and HOMA-IR showed no difference before and after the 12-week period. Correlation analysis indicated that butyrate levels were significantly positively correlated with GLP-1 and IL-27, and negatively correlated with IL-1β. Bifidobacterium breve BBr60, by remodeling the gut microbiota-SCFAs axis, inhibits the pro-inflammatory factor IL-1β, activates the anti-inflammatory signal IL-27, and synergistically regulates the metabolic hormone network (such as GLP-1, ADPN), significantly improving obesity-related metabolic disorders. This study provides a theoretical basis and intervention targets for the clinical application of probiotics targeting the "microbiota-SCFAs-inflammation/hormone axis," and future research can explore precise probiotic treatment regimens based on individual microbiota characteristics. Show less

Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with dysregulation of the immune response. Current therapeutics are limited to palliative care, i.e., mechanical ventilators, thus highlighting the need to develop targeted therapeutic for ARDS. Interleukin-27 (IL-27) is a multifunctional cytokine with the capability for immune modulation. Our interest lies in exploring the properties of IL-27, particularly as an anti-inflammatory cytokine that functions as an antagonist of IL-6 signaling, as an inducer of anti-viral genes, as a promoter of tissue repair, and as a regulator of both the innate and adaptive immune responses, possessing promising potential as a therapeutic for ARDS. To overcome the challenge of repeated administration due to the short half-life of cytokines, we utilized a cell-based gene therapy approach. An IL-27-expressing plasmid was transfected into adipose mesenchymal stromal cells (ASC) that serve as the gene therapy carriers. For in vitro studies, we treated mono- and co-culture lung lipopolysaccharide (LPS)-induced lung epithelial and monocytes/macrophages cell line with IL-27-expressing ASC (IL-27 ASC) conditioned media (CM) to determine the effects on pro-inflammatory gene expression. For in vivo studies, male C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) and treated either PBS, ASC, or IL-27 ASC (5 × 10 IL-27 ASC CM reduced pro-inflammatory gene expression of lung epithelial and macrophages cultured in both mono- and co-culture systems. Additionally, IL-27 ASC were able to reduce pro-inflammatory markers, decrease cell infiltration into the lungs, promote genes and immune cells involved in tissue repair, and rebalance innate and adaptive immunity in an LPS-induced in vivo model. Collectively, our in vitro and in vivo results show promising potential for IL-27 cell-based gene therapy as a treatment for ARDS. Show less

The early phase of drug development relies on the examination of the efficacy and safety of therapeutic agents in animal models. Due to their close genetic and physiological relation to humans, cynomolgus monkeys ( Show less

Regulatory B cells (Bregs) contribute to immune homeostasis via IL-10-dependent and independent pathways. To dissect additional mediators, we investigated splenic derived GM-CSF/IL-15 fusokine (GIFT15)-induced Bregs in experimental autoimmune encephalomyelitis (EAE) using transcriptomics and functional validation. Bulk RNA-seq of splenic Bregs revealed upregulation of Ccl3, GzmB, and Il27 subunits compared to resting B cells. Functional studies showed that CCL3-deficient Bregs failed to suppress disease, whereas GzmB-deficient Bregs retained efficacy, and IL-27 receptor signaling in recipients was dispensable. Flow cytometry demonstrated that CCL3 expression correlated with FoxP3⁺ Treg and Tr1 expansion, along with CD206⁺ macrophage polarization. In the CNS, transient, tissue-dependent increases in oligodendroglial markers O4 and GalC were detected. Collectively, these findings identify CCL3 as a non-redundant effector of Breg-mediated protection, acting primarily through peripheral T-cell and myeloid remodeling, with secondary CNS impacts. These results highlight the translational potential of CCL3-competent, spleen-derived GIFT15 Bregs for therapeutic modulation of autoimmune demyelination. Show less

In people with HIV (PWH) and suppressed viral replication by antiretroviral therapy persistent T cell activation and inflammation are important contributors of the increased risk of morbidity and mortality. CD8 T cells express checkpoint receptors and are dysfunctional. IL-27, a member of the IL-6/IL-12 family has shown anti-viral properties against various human viruses, including HIV. The role of IL-27 on HIV-specific T cells remains unclear. We hypothesized that IL-27 will enhance the function of HIV-specific T cells. IL-27 effects on T cell function was evaluated by measuring cytokine secretion, proliferation, and cytotoxicity. Our findings show that IL-27 upregulates cytokine secretion and cytotoxic potential, and trafficking of proliferating HIV-specific CD8 T cells expressing checkpoint receptors TIGIT and PD-1. Unbiased clustering analysis showed that IL-27 may have differential effects on distinct populations of HIV-specific T cells. Altogether these results suggest that IL-27 may enhance T cell function in the setting of chronic HIV infection. Show less

Thyroid-associated ophthalmopathy (TAO) is characterized by inflammation and tissue remodeling, including fibrosis and adipogenesis. Here, we identify interleukin-27 (IL-27) as a negative feedback immunomodulator in TAO. Serum IL-27α levels were significantly elevated in patients with TAO compared with healthy and inflammatory disease controls. In orbital fibroblasts (OFs), exogenous IL-27 suppressed IL-1β-induced proinflammatory cytokines and reduced hypoxia-induced NLRP3 inflammasome activation. IL-27 also attenuated TGF-β-driven fibrosis via p38 MAPK signaling in CD90 Show less

GATA2 establishes transcriptomes governing hematopoietic stem/progenitor cell development. In progenitors, GATA2 represses inflammatory genes (Il6st and Il6ra) encoding IL6ST/GP130 and IL6RA receptor subunits mediating IL-6 signaling. While IL6ST heterodimerizes with IL6RA, IL-11, IL-27, oncostatin M, and leukemia inhibitory factor receptors, IL6RA heterodimerizes exclusively with IL6ST to confer IL-6 signaling. As GATA2-dependent repression is not well understood, we devised a multi-omics strategy to elucidate mechanisms underlying repression and applied the approach to the cytokine/chemokine receptor gene family. Identifying accessible distal and intronic chromatin sites in GATA2-deficient (GATA2 Show less

Neonatal necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disease of premature infants, characterized by immune dysregulation and compromised intestinal barrier integrity. Interleukin-27 receptor α (IL-27Ra), a critical component of the JAK-STAT signaling pathway, exhibits dual pro- and anti-inflammatory roles in various inflammatory conditions. However, its role in NEC pathogenesis remains unclear. To elucidate the functional role of IL-27Ra in NEC development and assess its potential as a therapeutic target. A multi-tiered approach was employed, including integrative analysis of clinical NEC specimens by single-cell and bulk RNA sequencing, and a neonatal mouse NEC model. NEC was induced in mice via hyperosmolar formula feeding combined with LPS gavage, intermittent hypoxia, and cold stress. Additional experiments included immunofluorescence staining for IL-27Ra, cytokine profiling (ELISA, quantitative real-time PCR (qPCR)), use of IL-27Ra knockout (IL-27Ra Show less

Coelonin is a dihydrophenanthrene compound derived from the traditional Chinese medicine Bletilla striata (Thunb.) Reichb.f., which exhibits significant anti-inflammatory activity and effectively inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells. Although previous studies have demonstrated the protective effect of Bletilla striata against LPS-induced acute lung injury (ALI), the potential protective role and underlying molecular mechanisms of its major active component, Coelonin, in ALI remain unclear. In this study, an LPS-induced mouse ALI model was established to systematically evaluate the protective effects of Coelonin on ALI. Furthermore, transcriptomic analysis was utilized to investigate the anti-inflammatory mechanisms mediated by Coelonin through the regulation of non-coding RNA (ncRNA)-associated inflammatory pathways. The results indicated that Coelonin significantly ameliorated LPS-induced pathological damage in lung tissues and markedly reduced the levels of inflammatory markers in bronchoalveolar lavage fluid (BALF). In vitro experiments using the murine alveolar macrophages (MH-S) cell line further confirmed the anti-inflammatory activity of Coelonin. Transcriptome analysis revealed that Coelonin markedly upregulates the expression of the ncRNA Gm27505, which was previously found to be downregulated in a mouse model of Alzheimer's disease. To date, there have been no reports on the biological functions of Gm27505. Bioinformatics analysis and real-time quantitative fluorescence PCR (qPCR) confirmed that this ncRNA is primarily localized within the nucleus. Overexpression of Gm27505 in MH-S cells significantly downregulated the expression of inflammation-related genes such as Il6, Tnfα, Il27, and Ccl3 induced by LPS stimulation. Moreover, overexpression of Gm27505 promoted macrophage polarization toward the M2 phenotype while suppressing M1 polarization. These findings suggest that the ncRNA Gm27505 plays an important biological role and is critically involved in the regulation of inflammatory responses. Coelonin may alleviate LPS-induced ALI in mice by up-regulating Gm27505 expression and modulating macrophage polarization. Therefore, Gm27505 may represent a potential target for the prevention and treatment of ALI, providing new research directions for future therapeutic strategies against related diseases. Show less

Atherosclerosis is a progressive arterial disease characterized by chronic inflammation, with interleukin-27 (IL-27) implicated as both a pro- and anti-inflammatory cytokine. This prospective cohort study evaluated association of circulating IL-27 levels in peripheral artery disease patients undergoing elective endovascular revascularization, with major adverse cardiovascular events (MACE) and major adverse limb events (MALE) over a median follow-up of 311 days. Elevated IL-27 levels were significantly associated with increased risk of MACE and MALE in unadjusted analyses. After adjusting for established cardiovascular and PAD risk factors, IL-27 remained an independent predictor of MACE (HR 2.95; Show less

Suicide is a leading global cause of mortality, with major depressive disorder (MDD) contributing significantly. Neuroimmune mechanisms, particularly inflammation, are increasingly recognized in the pathophysiology of depression and suicidal ideation. This study investigated the relationship between inflammatory cytokines and suicidal ideation in patients with MDD. A two sample Mendelian randomization analysis using Genome-Wide Association Study data was performed to evaluate the associations between 16 inflammatory cytokines and suicidal ideation. Then the patients with MDD, stratified by suicidal ideation severity were assessed for peripheral cytokine levels (interleukin [IL])-2, IL-4, IL-6, IL-10, interferon-gamma [IFN-γ], IL-17, IL-12, IL-27, and tumor necrosis factor-α) using flow cytometry and enzyme-linked immunosorbent assay. MR analysis revealed significant associations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and IL-27 with negative and positive effects, respectively. Individuals with high suicide risk exhibited elevated IL-27, IL-12, IFN-γ and IL-4 compared with low suicide risk. There are genetic associations between IL-27 and suicidal ideation, which is biologically corroborated by elevated peripheral IL-27 levels in high-risk suicidal individuals, highlighting its potential as a clinically viable biomarker for assessing suicidal risk in depressive patients. Show less

Chronic lymphocytic leukemia (CLL) is characterized by malignant B lymphocyte accumulation and progressive immune dysfunction. The immune checkpoint molecule TIM-3 and its ligand galectin-9 (Gal-9) contribute to T cell exhaustion, impairing anti-tumour immunity. Interleukin-27 (IL-27) has pleiotropic immunomodulatory properties, but its impact on TIM-3 and Gal-9 expression in CLL remains unclear. Peripheral blood mononuclear cells (PBMCs) from 20 treatment-naive CLL patients were cultured with or without IL-27 (100 ng/mL) for 72 h. Flow cytometry assessed TIM-3 and Gal-9 expression on CD4 IL-27 stimulation significantly increased TIM-3 expression on CD8 IL-27 may enhance immunosuppressive mechanisms in CLL by modulating immune checkpoint expression, potentially contributing to disease progression. These ex vivo findings in PBMCs from CLL patients indicate the IL-27-associated modulation of checkpoint expression under the conditions tested. In the absence of parallel healthy-donor controls, CLL specificity cannot be established in this study. Show less

Adverse pregnancy outcomes represent a global health burden. Bacterial infection and subsequent inflammation in gestational membranes lead to immunological and physiological changes that contribute to adverse pregnancy outcomes. Although animal models of infection during pregnancy are useful to interrogate tissue and cellular level changes in host responses, these models also have numerous drawbacks, including cost, complexity, and ethical considerations. The advent of organ-on-a-chip models provides cutting-edge new approaches to model host-pathogen interactions in multicellular organ and tissue environments. In this work, we employ an organ-on-a-chip model of the maternal-fetal interface as a tool to study immunological responses to infection with the perinatal pathogen, Group B Show less

Lung cancer is the second most common malignancy globally and the leading cause of cancer-related deaths. Interleukin-39 (IL-39), a member of the IL-12 family secreted by B cells, acts as a pro-inflammatory cytokine and induces IL-23p19 expression in endothelial cells. Recent findings suggest reduced IL-39 expression in autoimmune thyroid disorders and breast cancer, indicating its possible role in disease progression. To evaluate the role of IL-39 as an early prognostic biomarker in lung cancer. A case-control study was conducted between February and September 2024, involving 180 individuals aged 45-77. The cohort included 90 lung cancer patients (45 with small-cell carcinoma and 45 with non-small cell carcinoma) and 90 healthy controls. Blood samples were analyzed using ELISA to quantify IL-39 and additional tests, including CBC, liver enzymes (ALT, AST, ALP), and lipid profile (cholesterol, triglycerides). Statistical analysis was performed to assess correlations and diagnostic performance. IL-39 levels were significantly lower in stage IV compared to stage III in both cancer types, with a greater reduction observed in small-cell carcinoma. Significant negative correlations were found between IL-39 and total cholesterol, NLR, ALT, AST, and ALP, while positive correlations were noted with hemoglobin and triglycerides. IL-39 demonstrated excellent diagnostic accuracy in small-cell carcinoma with a cut-off value of 3.26950 pg/mL (sensitivity 100%, specificity 100%, AUC 1.000). In non-small cell carcinoma, the cut-off value was 4.88700 pg/mL (sensitivity 63.5%, specificity 92.6%, AUC 0.689). IL-39 shows promise as a predictive and diagnostic biomarker in lung cancer, particularly in small-cell carcinoma, and may play a protective role in disease modulation through immune-related pathways. Show less

HBsAg incidence in Egypt is at a range of 2 to 7%. Antiviral immunity is linked to interleukin-27 (IL27), a cytokine that is produced by two genes: EBI3 and p28. IL-27 gene SNPs can alter the susceptibility to infection of HVB by impacting the production and/or function of cytokines. The study aimed to examine the impact of the IL-27 SNPs on the progression of HBV infection among Egyptian individuals. This study included a total 112 patients infected with HBV, and 50 healthy individuals served as controls. The link between the IL-27 SNPs (rs181206 T/C and rs17855750 T/G) and HBV was investigated using real-time PCR. There was no significant correlation between fibrosis stages and the distribution of IL-27 rs181206 T/C and rs17855750 T/G genotypes among HBV patients. Results indicated minimal disparity in the distribution of haplotypes among the study groups. No significant difference in the frequency of the CG, CT, TT, TG, and haplotypes between the groups. This study found no correlation between the presence of IL-27 rs1812006 and IL-27 rs17855750 SNPs and the HBV chronicity. Show less

Coronavirus disease 2019 (COVID-19) has been widely associated with intense systemic inflammation, endothelial injury, and a high incidence of thrombotic complications, which together contribute to disease severity and poor clinical outcomes. While endothelial dysfunction, dysregulated cytokine production, and oxidative stress are recognized features of severe COVID-19, the direct impact of circulating factors from infected individuals on endothelial cell behavior remains insufficiently characterized. Here, we examined how serum from patients with severe COVID-19 and from convalescent individuals modulates endothelial activation, inflammatory responses, and oxidative stress using human umbilical vein endothelial cells as an in vitro model. Venous blood samples were collected from individuals with severe COVID-19 (n = 13), convalescent patients (n = 11), and healthy volunteers (n = 7) during the initial phase of the COVID-19 pandemic. Human umbilical vein endothelial cells (HUVEC) were maintained in culture and exposed to 15% serum from each study group after a period of serum deprivation. The expression of genes associated with endothelial activation, thrombosis, inflammation, and oxidative stress was analyzed by quantitative real-time PCR at defined time points. In addition, the endothelial secretory profile was evaluated in cell culture supernatants using multiplex bead-based immunoassays. Statistical analyses were performed using one-way ANOVA followed by appropriate post hoc tests, receiver operating characteristic (ROC) curve analysis to assess the discriminatory capacity of biomarkers, and multivariate linear regression to identify factors associated with disease severity. We investigated the role of the endothelium in modulating the cytokine storm in severe COVID-19. HUVEC were stimulated with serum from patients with severe COVID-19, convalescent individuals, and healthy volunteers. Stimulation with serum from severe cases induces significant increases in These findings suggest that HUVEC serves as a promising biological sensor for detecting inflammatory responses in COVID-19 patients and shows the crucial role of the endothelium in sustaining the cytokine storm that contributes to patient severity and mortality. Show less

DNA methylation plays a pivotal role in the pathogenesis of Acute Lymphocytic Leukemia (ALL), a hematological malignancy marked by abnormal cellular behavior and immune dysregulation. This study aimed to investigate how alterations in DNA methylation affect lysosmal function in pediatric ALL. A total of 50 blood samples were collected from children diagnosed with ALL and analyzed for biochemical markers associated with the disease. Expression levels of key DNA methylation regulators, including DNA methyltransferase 1 (DNMT1) and DNMT3, were evaluated and compared with those from healthy controls. In addition, pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-27 (IL-27), and tumor necrosis factor-alpha (TNF-α), were monitored over a six-day period prior to treatment initiation. The study also assessed the expression of lysosome-associated membrane proteins, LAMP1 and LAMP2, which are essential for lysosomal function and the degradation of autophagosomes. To determine the DNA methylation status of the promoter regions of these genes, genomic DNA underwent sodium bisulfite treatment and digestion with methylation-sensitive and methylation-dependent restriction enzymes, followed by amplification with gene-specific primers. Our results revealed a significant upregulation of DNMT1 and DNMT3 in ALL samples, along with a marked downregulation of TET1 gene expression, which is responsible for DNA demethylation. This suggests that disrupted DNA methylation dynamics may contribute to the pathogenesis of the disease. Furthermore, methylation levels within the CpG islands of the LAMP1 and LAMP2 promoter regions were substantially elevated, showing more than a seven-fold increase in ALL samples compared to healthy control blood samples. In ALL samples, the expression levels of LAMP1 and LAMP2 were significantly reduced, may due to promoter region hypermethylation, which contributes to lysosomal dysfunction. In parallel, the expression of autophagy-related genes such as ATG5 and LC3B, markers of autophagy initiation and maturation, respectively, was markedly increased, suggesting an accumulation of autophagosomes that depend on functional lysosomes for complete degradation. Additionally, elevated levels of pro-inflammatory cytokines IL-6, IL-27, and TNF-α were consistently observed in ALL patients, indicating heightened immune activation that may drive disease progression. Collectively, these findings underscore the pivotal role of DNA methylation in disrupting lysosomal function, leading to autophagosome accumulation and impaired recycling of cytoplasmic components. Show less

Bone remodelling is a physiological process influenced by mechanical stimuli such as those generated during orthodontic treatment. Biochemical markers allow the phases of remodelling to be identified, its progression to be assessed, alterations to be detected and scaffold-based tissue regeneration to be evaluated. This study reviews the main markers involved in bone formation and resorption, highlighting their clinical relevance. A literature search was conducted in biomedical databases, selecting studies that analysed crevicular gingival fluid samples in areas of tension and compression. The markers were classified according to their function and location, and their baseline values, temporal variations and methods of analysis were compiled. Among the markers of bone formation, Osteoprotegerin (OPG), Transforming Growth factor β1 (TGF-β1) and Interleukin 27 (IL-27) stand out; while resorption markers include Receptor Activator of Nuclear Factor appa β Ligand (RANKL), Tumour Necrosis Factor (TNF-α) and Interleukin 1β (IL-1β). The results show different expression patterns depending on the type of force applied and the timing of the follow-up, allowing molecular profiles associated with each phase of remodelling to be established. This characterisation improves our understanding of tooth movement and provides a basis for the development of more precise scaffolds and functional biomaterials in orthodontics. Show less

The integration of serum biomarkers and gene polymorphisms may enhance early prognostic assessment in sepsis. Early and accurate prediction of outcomes is crucial for optimizing treatment strategies and improving survival. However, the clinical utility of combining genetic markers with conventional inflammatory indicators remains insufficiently validated. In this retrospective cohort ( 6 predictors were retained - PCT, CRP, lactate (LAC), lactate clearance rate (LCR), TLR4 rs4986790, and PPARγ rs1801282. The nomogram achieved AUC 0.885 (95% CI 0.812-0.943) with sensitivity 88.6% and specificity 73.9%; calibration was good (H - L χ This integrative biomarker-genotype model demonstrated strong internal performance and potential clinical utility for individualized risk stratification in sepsis. The results support combining genetic susceptibility and inflammatory biomarkers for enhanced prognostic precision, although external and multi-ethnic validation remains warranted before widespread adoption. Show less

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β-cells. Current therapies fail to address the multiple mechanisms driving disease progression. We developed an oral Female non-obese diabetic (NOD) mice were treated with the oral vaccine, GAST-17, or their combination. Blood glucose levels, islet histology, immune cell infiltration, cytokine profiles, and regulatory T cell populations were assessed. Functional assays included antigen-specific stimulation, adoptive transfer, and analysis of immunoregulatory gene expression. Combination therapy demonstrated superior efficacy in both diabetes reversal and prevention. In reversal studies, diabetes remission was achieved in 80% of mice receiving the combination therapy, compared with 63% in the vaccine-only group and 5% in the GAST-17-only group. In prevention studies, diabetes onset was prevented in 80% of mice receiving the combination therapy, compared with 70% in the vaccine-only group and 30% in the GAST-17-only group. Therapeutic effects were associated with increased antigen-specific regulatory T-cells, reduced islet-infiltrating lymphocytes, preserved insulin-positive islet area and β-cell mass, and modulation of cytokine profiles, including elevated IL-10 and TGF-β and reduced IFN-γ, GM-CSF, IL-1α, and IL-12. Upregulation of immune checkpoint molecules (CTLA-4 and PD-L1) and immunoregulatory mediators (AhR, IDO, and IL-27) was observed, suggesting a potential contribution to immune homeostasis. The combination of the oral Show less

Interleukin-27 (IL-27) is a cytokine that belongs to the IL-6/IL-12 cytokine family with diverse influences on the immune response. Elevated levels of IL-27 cytokine during the neonatal period predispose neonatal mice to more severe infection. Neonatal pups deficient in IL-27 signaling exhibit improved survival and bacterial clearance with reduced systemic inflammation. However, the precise molecular mechanisms that regulate bacterial clearance and the overall immune response in IL-27 receptor a-deficient (KO) mice during neonatal sepsis remain incompletely defined. Analysis of the transcriptome of the neonatal spleen during The results uncovered that during infection WT neonatal mice fail to increase expression of CXCR2 but upregulate the cognate ligand CXCL2 significantly. Conversely, IL-27Rα KO neonates increase CXCR2 expression significantly in the spleen during infection but fail to upregulate CXCL2 transcripts. Splenocytes isolated form septic neonatal KO mice migrated with superior efficiency towards the chemokine CXCL2 compared to WT counterparts. Surprisingly, we also found that splenic monocytes but not the neutrophils account for higher CXCR2 gene expression in the IL-27Rα KO neonatal mice. Monocytes isolated from the spleens of both WT and IL-27Rα KO neonatal pups confirmed that the concentration of CXCL2 regulates CXCR2 receptor expression. We further demonstrated that with regulated CXCL2 chemokine expression levels, IL-27Ra-deficient neonatal mice had more CXCR2+ mononuclear cells present at the site of infection. Overall, our findings suggest that during infection in the absence of IL-27 signaling, a differential expression of CXCR2 and CXCL2 promotes increased migration of mononuclear cells consistent with improved bacterial clearance and tissue homeostasis. This study defines mechanisms that improve the host response in the absence of IL-27 signaling during neonatal sepsis and reinforces the potential for antagonizing IL-27 as a host-directed therapy for neonatal sepsis. Show less

The association of mucosal shedding of human simplex virus (HSV)-2, Kaposi's sarcoma-associated herpesvirus (KSHV) and cytomegalovirus (CMV) after antiretroviral therapy (ART) initiation in women-living-with-HIV (WLWH) with systemic inflammation is unclear. We recruited 187 ART-naive adult WLWH in south-central Uganda. HSV-1, HSV-2, CMV, and Varicella Zoster Virus (VZV) in vaginal secretions and Kaposi's sarcoma-associated herpesvirus (KSHV) in oral swabs were quantified by PCR. Plasma biomarkers of systemic inflammation were measured by ELISA or electrochemiluminescence before and after ART initiation (weeks 8, 12, and 24). Participants had a baseline median age of 28 years and CD4 count of 413 cells/μL. Viral shedding rates were similar for all tested viruses between baseline and post-ART timepoints in the overall study population. CMV shedding significantly increased from a baseline rate of 53% to 77% at week 4 visit ( Although ART initiation was not associated with increased herpesvirus shedding overall, CMV shedding increased in women with advanced HIV-1. The association of mucosal shedding of CMV, HSV-2, and KSHV in post-ART timepoints with different baseline biomarkers of systemic inflammation suggest that distinct immunological functions are implicated in the control of their viral replication. Show less

Interleukin-27 (IL-27), an Interleukin-12 (IL-12) family heterodimeric cytokine, plays a central yet complex role in immunoregulation within the intestinal mucosa, where its context-dependent actions can promote both protective and pathogenic outcomes. Although its cellular sources, receptor structure (IL-27Rα/gp130 complex), and involvement in regulating key immune cells (e.g., T-cell subsets, macrophages, neutrophils) and epithelial functions are established, the precise mechanisms underlying its paradoxical effects-balancing homeostasis with inflammation-remain incompletely resolved. This review synthesizes current understanding of IL-27 biology to clarify its multifaceted role. Crucial insights into these dual functions have emerged from preclinical models, including murine colitis (e.g., DSS-, TNBS-induced), enteric infection (e.g., Toxoplasma gondii, Citrobacter rodentium), and colorectal cancer models. These studies demonstrate that IL-27 critically orchestrates gut immunity, maintaining homeostasis through antimicrobial defense and barrier enhancement while suppressing immunopathology. Conversely, its dysregulation drives chronic inflammation and carcinogenesis. Clinically, IL-27 expression correlates with disease activity in inflammatory bowel disease (IBD), colorectal cancer (CRC), and infections, highlighting its biomarker potential. Consequently, targeting the IL-27 pathway presents promising therapeutic avenues: augmenting signaling may mitigate IBD hyperinflammation, while inhibition could bolster antitumor immunity or resolve infection-driven pathology. Future research must prioritize defining context-specific IL-27 functions, optimizing delivery strategies, and integrating IL-27 targeting with existing biologics to translate its immunomodulatory potential into novel therapies for intestinal diseases. Show less

Hyperactivation of cutaneous macrophages promotes the development of chronic pain. Stimulation of nociceptive regions promotes neuroplasticity, which affects pain perception and related physiological responses. However, the specific mechanisms by which cutaneous macrophages sense and elicit nociceptive responses are unknown. Here, we exacerbated the reduction of systemic pain threshold after chronic heart failure (CHF) by silencing follistatin-like 1 (FSTL1), especially the abnormal cutaneous nociceptive sensation at PC6 acupoint, the site associated with cardiac involvement pain. The upregulation of P2Y6 and interleukin-27 expression is intimately linked to the activation of skin macrophages. Hyperactivation of P2Y6 receptor (P2Y6R) may be associated with MHC II M1 Show less

The COVID-19 pandemic has caused over 7 million deaths, but its legacy extends beyond mortality. SARS-CoV-2 infection induces immune alterations that persist post-recovery, manifesting not only in long COVID (LC) but also in healthy individuals. Cytokines serve as critical orchestrators of these processes. The goal of this study is to investigate post-pandemic immune remodeling through cytokine assessment in both patients with LC and healthy donor, and to compare the post-pandemic population with pre-pandemic controls to find changes in the immune responses and cytokine profiles. A panel of 47 immune mediators (cytokines, chemokines, and growth factors) was measured with the MAGPIX multiplex analysis. LC was characterized by an increase in IL-7, IL-8, IL-17F, IL-18, EGF, FGF-2, PDGF-AA, sCD40L, and MCP-3 and a decrease in IL-4, IL-13, IL-22, IL-27, and FLT-3L. Comparing post-pandemic recovered individuals with pre-pandemic healthy cohort, we saw an upregulation of IL-13 and MCP-3 and a downregulation of MDC, M-CSF, IL-12, and IL-17F. While LC is characterized by persistent immune imbalance-particularly in cytokine networks-our data emphasize the critical need to study healthy donors in both pre- and post-pandemic eras when analyzing and interpreting these changes. Show less