Search Results (1,864)

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

Hypertension affects over 1.39 billion people globally, causing 9.4 million deaths annually. This paper examines the intricate relationship between the immune system and hypertension, highlighting the contributions of both innate and adaptive immune responses. The innate response, involving natural killer (NK) cells, macrophages, toll-like receptors (TLRs), and dendritic cells, contributes to organ damage and inflammatory responses, exacerbating hypertension. Adaptive immunity, particularly T cells, further exacerbates vascular and renal dysfunction through the release of cytokines such as IFN-γ, IL-17A, and TNF-α, ultimately leading to multisystem damage. Therapeutic strategies targeting these immune responses are being explored, including immunosuppressants such as mycophenolate mofetil (MMF) and methotrexate (MTX), as well as monoclonal antibodies against IL-1β and TNF-α. While these strategies show promise, further research is needed to evaluate their efficacy and safety. Furthermore, this paper highlights the potential benefits of immunological approaches in managing the root causes of hypertension, offering an alternative to conventional therapies focused on the renin–angiotensin–aldosterone system. In conclusion, this work highlights the immune mechanisms in the hypertension pathogenesis, identifying them as potential therapeutic targets for enhanced management and improved patient outcomes. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM. Full article

Rabies, a zoonotic infectious disease causing central nervous system inflammation, remains a threat to public health in regions with limited medical resources. Vaccination effectively reduces rabies incidence and mortality, underscoring the need for vaccines that are cost-effective, immunogenic, protective, and safe. This study constructed a recombinant rabies virus (rRABV)-overexpressing glucocorticoid-induced tumor necrosis factor receptor ligand (GitrL), named rLBNSE-GitrL, using a reverse genetic operating system. rLBNSE-GitrL exhibited similar in vitro phenotypic characteristics and immune safety as the parent RABV (rLBNSE). This recombinant virus stimulated the production of a greater number of activated dendritic cells (DCs) compared to rLBNSE. The enhanced innate immune response induced by rLBNSE-GitrL may be mediated through the activation of innate immune-related signaling pathways, such as the tumor necrosis factor (TNF), and chemokine signaling pathways, and the upregulation of a series of innate immune-related genes, including MMP2, IL-6, CXCL9, TIMP1, IL-17d, and TNF-α. Consequently, rLBNSE-GitrL elicited significantly higher levels of RABV vaccine-induced virus-neutralizing antibodies (VNA), IgG, and IgM compared to rLBNSE as early as 3 days post-immunization (dpi), thereby improving the protective effect in mice. Collectively, the overexpression of GitrL facilitated the induction of early and potent antibody responses following RABV immunization. Full article

Background/Objectives: The expanding focus on novel therapeutic pathways for long-term pain relief has directed interest toward compounds obtained from Cannabis sativa. This study evaluated the antinociceptive potential of cannabigerol-enriched extract (CBG) in models of acute and chronic hypernociception, along with morphological outcomes. Methods: Formalin and hot plate tests were used on male Swiss mice to assess acute oral antinociception. To the chronic pain model, 8-week-old male Wistar rats underwent spinal nerve ligation (SNL), and CBG was administered orally by gavage once daily for 14 days. Results: CBG reduced nociceptive responses in the formalin test and hot plate tests, mainly at a dose of 30 mg/kg, showing antinociceptive activity. CBG attenuated SNL-induced thermal and mechanical hypersensitivity, accompanied by reduced microglial density and spinal morphological changes. Importantly, cannabinoid receptor type 2 (CB2R) signaling contributed to the antinociceptive effects of orally administered CBG, whereas cannabinoid receptor type 1 (CB1R), Brain-Derived Neurotrophic Factor (BDNF), and Tumor Necrosis Factor (TNF) did not appear to play major roles under our experimental conditions. Conclusions: Collectively, these findings support CBG as a promising alternative for chronic pain management. Full article

Over the past two decades, immune–inflammatory dysregulation has emerged as a central paradigm in the biology of mood disorders. Patients with major depression (MDD) and bipolar disorder (BD) frequently display low-grade systemic inflammation. Elevated C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) identify clinically relevant subgroups of patients characterized by greater severity, cognitive impairment, and poor treatment response. Changes in the gut microbiota and disruptions of the blood–brain barrier (BBB) act as important gateways through which systemic immune activity can influence the brain. At the intracellular level, pattern-recognition receptors activate convergent hubs including NF-κB, JAK/STAT, and MAPK cascades, while the NLRP3 inflammasome integrates mitochondrial dysfunction and oxidative stress with IL-1β release and pyroptosis. These pathways converge on glial dysregulation, impaired BDNF/TrkB signaling, and kynurenine pathway (KP) alterations, fostering excitotoxicity and synaptic deficits. Translational studies demonstrate that elevated CRP and IL-6 predict poor antidepressant outcomes. Anti-inflammatory agents such as infliximab and celecoxib show efficacy in specific subgroups of patients. Emerging multi-omics approaches identify immuno-metabolic biotypes, supporting the rationale for biomarker-guided stratification. These findings define an ‘inflammatory biotype’ of mood disorders and highlight the need for biomarkers and precision-based trials to guide treatment. Full article

Porcine epidemic diarrhea virus (PEDV), a member of the genus Alpha coronavirus, is one of the main pathogens causing piglet diarrhea. PEDV can enhance its replication by regulating host protein function. The tyrosine phosphatase src homology 2 domain-containing PTP (SHP-1) acts as a host natural immune protein capable of influencing viral replication, but there are no studies on the regulation of virus replication by pig SHP-1. In this study, we expressed porcine SHP-1 protein and examined its interaction with PEDV as well as its potential role in PEDV infection. The results showed that SHP-1 overexpression in porcine kidney cells (PK15) significantly increased the mRNA level of viral S protein in a dose-dependent manner. In contrast, SHP-1 knockdown reduced S gene expression, indicating that SHP-1 promoted PEDV replication. Overexpression of SHP-1 had an inhibitory effect on IFN-β, TNF-α, ISG15, and CXCL10, while this inhibition was reduced as SHP-1 expression decreased. Furthermore, we found that SHP-1 interacted with TNF receptor-associated factor 3 (TRAF3) and inhibited its K63-linked ubiquitination, suppressing the expression of IFN-β and ISGs and facilitating PEDV replication. The study provided new insights for the prevention and control of porcine epidemic diarrhea. Full article

Dendrobium officinale (Orchidaceae) is a commonly used medicinal and edible herb. Although its anti-ageing properties have been demonstrated, the underlying mechanisms remain unclear. We employed network pharmacology and molecular biology techniques to systematically explore its anti-ageing mechanisms. An ageing model was established using D-galactose-induced Kunming mice. D. officinale significantly ameliorated ageing-related symptoms, including behavioural impairment and organ index reduction. It enhanced antioxidant capacity by increasing serum T-AOC levels and restoring renal activities of key antioxidant enzymes (SOD, GSH-Px, CAT) while reducing MDA; it suppressed serum TNF-α levels, indicating anti-inflammatory effects. Histopathological examination revealed that D. officinale alleviated D-galactose-induced renal damage, including tubular cell swelling and glomerular capsule widening. Network pharmacology identified 8 core active compounds (e.g., 5,7-dihydroxyflavone, naringenin) and 10 key targets (e.g., HSP90AA1, EGFR, MAPK3). KEGG analysis highlighted pathways including neuroactive ligand–receptor interaction, cAMP signalling, and calcium signalling. Molecular docking confirmed strong binding affinities between core compounds and key targets. Western blotting and immunohistochemistry validated that D. officinale upregulated EGFR, HSP90AA1, ERK, and GAPDH expression in renal tissues. In summary, D. officinale exerts anti-ageing effects by modulating oxidative stress, suppressing inflammation, and regulating multiple signalling pathways. Our findings provide a scientific rationale for its application in anti-ageing interventions. Full article

Sleeplessness (insomnia) is a significant symptom associated with stress-induced depression/anxiety. In the present study, we selected Bifidobacterium longum P77, which increased serotonin production in corticosterone-stimulated SH-SY5Y cells, from the fecal bacteria collection of healthy volunteers and examined the effects of B. longum on depression, anxiety, and sleeplessness induced by immobilization stress or by transplantation of cultured fecal microbiota (cFM) from patients with depression. Orally administered B. longum P77 decreased depression/anxiety- and sleeplessness-like behaviors in immobilization stress-exposed mice. B. longum P77 reduced immobilization stress-induced corticosterone, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 expression and the cell population of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)⁺ in the prefrontal cortex, while the expression levels of immobilization stress-suppressed IL-10, γ-aminobutyric acid (GABA), its receptor GABA_ARα1, serotonin, and its receptor 5-HT_1AR increased. B. longum P77 also alleviated immobilization stress-induced colitis: it decreased TNF-α and IL-6 expression and increased IL-10 expression in the colon. Furthermore, B. longum P77, Lactiplantibacillus plantarum P72, and their combination decreased cFM- or immobilization stress-induced depression-, anxiety-, and sleeplessness-like behaviors. They also decreased cFM-induced, corticosterone, TNF-α, and IL-6 expression levels in the prefrontal cortex and colon, while increasing cFM- or immobilization stress-suppressed GABA, GABA_ARα1, serotonin, and 5-HT_1AR expression levels in the prefrontal cortex. In particular, the combination of B. longum P77 and L. plantarum P72 (P7277) additively or synergistically alleviated depression-, anxiety-, and sleeplessness-like behaviors, along with their associated biomarkers. Heat-killed P7277 also alleviated immobilization stress-induced depression/anxiety- and sleeplessness-like symptoms. These results imply that L. plantarum P72 and/or B. longum P77 can mitigate depression/anxiety and sleeplessness by upregulating GABAergic and serotonergic systems, along with the suppression of NF-κB activation. Full article

Cancer-induced cardiac dysfunction has become a major clinical challenge as advances in cancer therapies continue to extend patient survival. Once regarded as a secondary concern, cardiotoxicity is now recognized as a leading contributor to morbidity and mortality among cancer patients and survivors. Its pathophysiology is multifactorial, involving systemic inflammation (e.g., TNF-α, IL-6), oxidative stress driven by reactive oxygen species (ROS), neurohormonal imbalances (e.g., angiotensin II, endothelin-1), and metabolic disturbances. These mechanisms collectively promote cardiomyocyte apoptosis, atrophy, mitochondrial dysfunction, and impaired cardiac output. Cardiac complications may arise directly from cancer itself or as adverse effects of oncologic therapies such as anthracyclines, trastuzumab, and immune checkpoint inhibitors. These agents have been linked to heart failure (HF), systolic dysfunction, and cardiac atrophy, often progressing insidiously and underscoring the importance of early detection and careful monitoring. Current preventive and therapeutic strategies include pharmacological interventions such as ACE inhibitors, beta-blockers, statins, dexrazoxane, and endothelin receptor antagonists like atrasentan. Emerging compounds, particularly Withaferin A (WFA), have shown potential through their anti-inflammatory and cardiac protective properties. In addition, antioxidants and lifestyle modifications may provide supplementary cardioprotective benefits, while interventional cardiology procedures are increasingly considered in selected patients. Despite encouraging progress, standardized treatment protocols and robust long-term outcome data remain limited. Given the heterogeneity of cancer types and cardiovascular responses, a personalized and multidisciplinary approach is essential. Continued research and close collaboration between oncologists, cardiologists, and basic scientists will be the key to advancing care, reducing treatment-related morbidity, and ensuring that improvements in cancer survival are matched by preservation of cardiovascular health. Full article

Periodontitis has been associated with adverse pregnancy outcomes, but the effect of oral pathogens on placental tissue and local immunity remains unclear. In this study, we investigated the response of human placental explants (HPEs) to lysates of Porphyromonas (P.) gingivalis, a keystone periodontal pathogen. Exposure to P. gingivalis induced significant histological damage and extracellular matrix degradation in placental tissue. The lysate activated the canonical NF-κB pathway, as demonstrated by increased phosphorylation of IκBα, particularly in the trophoblast. This activation was predominantly mediated by Toll-like receptor 2 (TLR-2), with partial contribution from TLR-4. Notably, TLR-2 protein levels decreased upon stimulation, while soluble (s) TLR-2 was markedly elevated in culture supernatants, suggesting receptor cleavage as a regulatory mechanism. P. gingivalis also triggered a robust proinflammatory cytokine secretion, including IL-1β, IL-6, IL-8, and TNF-α, with variable dependence on TLR-2 and TLR-4 signaling. These findings reveal that P. gingivalis components elicit a complex innate immune response in the placenta, driven by TLR-mediated NF-κB activation and modulated by sTLR-2. This study provides mechanistic insight into how periodontitis may contribute to placental inflammation and highlights potential pathways linking maternal oral health to pregnancy complications. Full article

Tumor necrosis factor receptor-associated factors (TRAFs) are a family of adaptor proteins that transmit signals from immunoregulatory receptors—such as TNF receptors, Toll-like receptors, and interleukin receptors—to coordinate immune and inflammatory responses. Among them, TRAF5 is highly expressed in lymphocytes and implicated in obesity-associated inflammation, but its role in secondary lymphoid organs during chronic low-grade inflammation remains unclear. We examined splenic B and T cell phenotypes in wild-type (WT) and Traf5-deficient (KO) mice fed a high-fat diet (HFD). Although lymphocyte composition was broadly comparable, KO mice showed reduced spontaneous immunoglobulin G2c (IgG2c) production ex vivo—about 1.5-fold lower than WT. Notably, despite elevated TNF-α and CD40 ligand (CD40L) expression in HFD-fed KO splenocytes, IgG2c production remained diminished—about 1.9-fold lower than WT—upon soluble CD40L stimulation, indicating impaired CD40-mediated class-switch recombination (CSR). Consistently, B cells from KO mice on a normal diet exhibited reduced activation-induced cytidine deaminase (AID) expression—about 4.4-fold lower than WT—after CD40L stimulation, and decreased IgG2c secretion—about 6.6-fold lower—upon CD40L and IFN-γ co-stimulation in vitro. Collectively, these findings suggest that TRAF5 is involved in CD40-dependent CSR in B cells under inflammatory conditions and may contribute to sustaining adaptive immune responses during obesity-associated chronic inflammation. Full article

Toll-like receptor 3 (TLR3) initiates antiviral and inflammatory responses exclusively through the adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β). In contrast, MyD88 (myeloid differentiation primary response 88), a central adaptor for most other TLRs, is traditionally considered dispensable for TLR3 signaling. Here, we demonstrate that MyD88 directly contributes to TLR3-mediated NF-κB activation and cytokine production in macrophages. Bone marrow-derived macrophages (BMDMs) from MyD88 deficient mice exhibited significantly attenuated NF-κB activation in response to the TLR3 agonist polyinosinic–polycytidylic acid (poly(I:C)) compared to wild-type cells, as evidenced by the reduced phosphorylation of NF-κB p65 and IκBα, as well as IκBα degradation. Consistently, pro-inflammatory cytokine production, including IL-6, TNF-α, and IFN-β, was attenuated in MyD88-deficient BMDMs in vitro following stimulation by poly(I:C) or poly(A:U), another TLR3 agonist. Blood concentrations of IL-6, TNF-α, and IFN-β were significantly reduced in both TRIF-deficient mice and MyD88-deficient mice challenged by the i.p. injection of poly(I:C). Mechanistic analyses revealed that MyD88 physically associates with activated TLR3 upon poly(I:C) stimulation, and that TLR3 engagement triggered MyD88 oligomerization, which was absent in TLR3 or TRIF deficient macrophages. Our findings highlight a previously unrecognized dual-adaptor mechanism for TLR3, wherein MyD88 recruitment amplifies NF-κB signaling dynamics by bridging TLR3 to the canonical NF-κB activation cascade and robust cytokine induction. This study expands the paradigm of TLR3 signaling by establishing MyD88 as a direct contributor to TLR3-driven innate immune responses, offering new insight into cross-talk between MyD88-dependent and -independent pathways. Full article

Background: Blast-induced spinal cord injuries (bSCI) account for 75% of all combat-related spinal trauma and are associated with long-term functional impairments. However, limited studies have evaluated the neuropathological outcomes in the spinal cord following blast exposure. Objectives In this study, we aimed to determine the acute and sub-acute neuropathological changes in the spinal cord of ferrets after blast exposure. Methods: An advanced blast simulator was used to expose ferrets to tightly coupled repeated blasts. The Catwalk XT system was used to detect gait performances in ferrets at 24 h and 1 month post-blast exposure. After euthanasia, the cervical spinal cord samples were collected at 24 h or 1 month post-blast. A quantitative real-time polymerase chain reaction was performed to evaluate changes in the gene expression of multiple Toll-like Receptors (TLR), Cyclooxygenase (COX-1 and COX-2) enzymes and cytokines. Western blotting was performed to investigate markers of axonal injury (Phosphorylated-Tau, pTau; Phosphorylated Neurofilament Heavy Chain, pNFH; and Neurofilament Light Chain present in degenerating neurons, NFL-degen) and neuroinflammation (Glial Fibrillary Acidic Protein, GFAP; and Ionized Calcium Binding Adaptor Molecule, Iba-1). Results: Blast exposure significantly affected the gait performances in ferrets, especially at 24 h post-blast. Multiple TLRs, COX-2, Interleukin-1-beta (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) were significantly upregulated in the spinal cord at 24 h after blast exposure. Although only TLR3 was significantly upregulated at 1 month, non-significant increases in TLR1 and TLR2 were observed in the spinal cord at 1 month post-blast. Phosphorylation of Tau at serine (Ser396 and Ser404) and threonine (Thr205) increased in the spinal cord at 24 h and 1 month post-blast exposure. The increased expression of pNFH and NFL-degen proteins was evident at both time points. The expression of GFAP, but not Iba-1, significantly increased at 24 h and 1 month following blast exposure. Conclusions: Our results indicate that blast exposure causes acute and sub-acute neuroinflammation and associated axonal injury in the cervical spinal cord. These data further suggest that inhibition of TLRs and/or COX-2 enzyme might offer protection against blast-induced injuries to the spinal cord. Full article