Search Results (474)

The innate immune system protects against infection and cellular damage by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications—such as altered DNA methylation and histone marks—can serve as immunogenic signals that activate pattern recognition receptor (PRR)-mediated immune surveillance. This review explores the concept that epigenetic marks may function as DAMPs or even mimic PAMPs. I highlight how unmethylated CpG motifs, which are typically suppressed using host methylation, are recognized as foreign via Toll-like receptor 9 (TLR9). I also examine how cytosolic DNA sensors, including cGAS, detect mislocalized or hypomethylated self-DNA resulting from genomic instability. In addition, I discuss how extracellular histones and nucleosomes released during cell death or stress can act as DAMPs that engage TLRs and activate inflammasomes. In the context of cancer, I review how epigenetic dysregulation can induce a “viral mimicry” state, where reactivation of endogenous retroelements produces double-stranded RNA sensed by RIG-I and MDA5, triggering type I interferon responses. Finally, I address open questions and future directions, including how immune recognition of epigenetic alterations might be leveraged for cancer immunotherapy or regulated to prevent autoimmunity. By integrating recent findings, this review underscores the emerging concept of the epigenome as a target of innate immune recognition, bridging the fields of immunology, epigenetics, and cancer biology. Full article

Idiopathic inflammatory myopathies (IIMs) are rare autoimmune disorders characterized by muscle weakness. As currently used immunosuppressive treatment presents several limitations, recent investigations focus on elucidating immune and nonimmune molecular mechanisms underlying its pathogenesis. Mitochondrial dysfunctions, endoplasmic reticulum stress, neutrophil dysregulation, and alterations in myokines and cell death pathways have been implicated in IIM pathophysiology. In this paper, the newest therapeutic strategies targeting reactive oxygen species overproduction, neutrophil extracellular traps formation, and pyroptotic and necroptotic pathways together with mitochondrial transplantations will be presented, and their safety and efficacy will be discussed. As physical therapy constitutes an essential part of IIM management, an additional focus will be directed towards molecular mechanisms underlying the effects of exercises in myositis treatment. Furthermore, the interplay between immune and nonimmune mechanisms will be analyzed and the translational challenges and limitations of current studies will be investigated. Full article

Background: Clear cell renal cell carcinoma with rhabdoid features (ccRCC-R) is a highly aggressive variant of renal cell carcinoma that carries a poor prognosis and limited treatment options. Methods: To better define the clinicopathologic and molecular landscape of ccRCC-R, we conducted an integrated clinicopathologic and molecular study of 17 tumors of ccRCC-R, utilizing comprehensive histomorphologic evaluation, immunohistochemistry, and targeted next-generation sequencing (NGS). Results: Histologically, all tumors demonstrated classic clear cell renal cell carcinoma morphology with focal to extensive rhabdoid differentiation, characterized by eccentrically located nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and paranuclear intracytoplasmic inclusion. Architectural alterations, including solid/sheet-like, alveolar/trabecular, and pseudopapillary growth patterns, were frequently observed. Immunohistochemically, tumors commonly exhibited loss of PAX8 and Claudin4 expression, preserved cytokeratin AE1/AE3 staining, and diffuse membranous CAIX expression. Frequent loss of SMARCA2 with retained SMARCA4 supported aberrations in chromatin remodeling. Unsupervised hierarchical clustering based on pathway-specific somatic mutations identified four distinct molecular subgroups defined by recurrent alterations in (1) DNA damage repair (DDR) genes, (2) chromatin remodeling genes, (3) PI3K/AKT/mTOR signaling components, and (4) MAPK pathway genes. Clinicopathologic correlation revealed that each subgroup was associated with unique biological characteristics and suggested distinct therapeutic vulnerabilities. Conclusions: Our findings underscore the molecular heterogeneity of ccRCC-R and support the utility of pathway-based stratification for guiding precision oncology approaches and biomarker-informed clinical trial design. Full article

Sulforaphane (SFN) is a bioactive compound belonging to the isothiocyanate family, known for its neuroprotective properties. While transcriptomic studies have highlighted SFN’s role in regulating gene expression, its impact on alternative splicing (AS), a key regulatory mechanism in neuronal metabolism, remains underexplored. In this study, we investigated whether SFN pre-treatment influences mRNA splicing patterns in an in vitro neuronal model using retinoic acid (RA)-differentiated SH-SY5Y cells. Using a dedicated RNA-seq-based splicing analysis pipeline, we identified 194 differential alternative splicing events (DASEs) associated with SFN treatment. Gene Ontology enrichment revealed significant over-representation of DNA repair processes. To better understand the functional implications, we integrated in silico predictions of premature stop codons, DASE/miRNA hybridizations, and DASE/RNA-binding protein (RBP) motif occurrences. Our findings suggest that SFN may modulate splicing of key DNA repair genes, contributing to protecting neurons against DNA damage. These preliminary results underscore a novel layer of SFN’s molecular effects and propose it as a valuable adjuvant in physiological conditions to enhance cellular health. Further studies are warranted to dissect the mechanistic underpinnings of SFN-mediated AS and its relevance in DNA-damage-related disorders. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic hepatopathy and a leading precursor of hepatocellular carcinoma (HCC) worldwide. Initially attributed to insulin resistance (IR)-driven metabolic imbalance, recent insights highlight a multifactorial pathogenesis involving oxidative stress (OS), chronic inflammation, and immune dysregulation. The hepatic accumulation of free fatty acids (FFAs) initiates mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, culminating in lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns (DAMPs), together with gut-derived pathogen-associated molecular patterns (PAMPs), activate innate immune cells and amplify cytokine-mediated inflammation. Kupffer cell activation further exacerbates OS, while ROS-induced transcriptional pathways perpetuate inflammatory gene expression. Traditional immunity refers to the well-established dichotomy of innate and adaptive immune responses, where innate immunity provides immediate but non-specific defense, and adaptive immunity offers long-lasting, antigen-specific protection. However, a paradigm shift has occurred with the recognition of trained immunity (TI)—an adaptive-like memory response within innate immune cells that enables enhanced responses upon re-exposure to stimuli. Following non-specific antigenic stimulation, TI induces durable epigenetic and metabolic reprogramming, leading to heightened inflammatory responses and altered functional phenotypes. These rewired cells acquire the capacity to produce lipid mediators, cytokines, and matrix-modifying enzymes, reinforcing hepatic inflammation and fibrogenesis. In this context, the concept of immunometabolism has gained prominence, linking metabolic rewiring with immune dysfunction. This literature review provides an up-to-date synthesis of emerging evidence on immunometabolism and trained immunity as pathogenic drivers in MASLD. We discuss their roles in the transition from hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis, and explore their contribution to the initiation and progression of MASLD-related HCC. Understanding these processes may reveal novel immunometabolic targets for therapeutic intervention. Full article

Cholangiopathies, a diverse group of diseases affecting the biliary tract, are characterized by the activation of cholangiocytes, fibrosis, and inflammation. Recent research has identified extracellular vesicles (EVs) as crucial mediators of communication within the hepatobiliary system. This review aims to explore the impact of EVs on cholangiocyte behavior and their role in disease development. EVs originating from cholangiocytes, hepatocytes, and immune cells carry a variety of molecules, including non-coding RNAs, proteins, and lipids, which influence immune responses, fibrosis, and epithelial repair. Specifically, EVs released by activated or senescent cholangiocytes can worsen inflammation and fibrosis by delivering molecules such as lncRNA H19, miR-21, and damage-associated molecular patterns (DAMPs) to hepatic stellate and immune cells. Additionally, the polarity and content of EVs are influenced by specific subcellular domains of cholangiocytes, indicating distinct signaling functions. In conditions such as primary sclerosing cholangitis (PSC), cholangiocarcinoma (CCA), and biliary atresia, EVs play a role in disease progression and offer potential as non-invasive biomarkers and therapeutic targets. This review underscores the importance of in-depth profiling and validation of EVs to fully utilize their diagnostic and therapeutic capabilities. Overall, EV-mediated signaling is a critical mechanism in cholangiopathies, providing a new avenue for understanding disease progression and developing precision medicine approaches. Full article

Background: Accumulating evidence indicates that SARS-CoV-2 infection results in long-term multiorgan complications, with the kidney being a primary target. This study aimed to characterize the long-term transcriptomic changes in the kidney following coronavirus infection using a murine model of MHV-1-induced SARS-like illness and to evaluate the therapeutic efficacy of SPIKENET (SPK). Methods: A/J mice were infected with MHV-1. Renal tissues were collected and subjected to immunofluorescence analysis and Next Generation RNA Sequencing to identify differentially expressed genes associated with acute and chronic infection. Bioinformatic analyses, including PCA, volcano plots, and GO/KEGG pathway enrichment, were performed. A separate cohort received SPK treatment, and comparative transcriptomic profiling was conducted. Gene expression profile was further confirmed using real-time PCR. Results: Acute infection showed the upregulation of genes involved in inflammation and fibrosis. Long-term MHV-1 infection led to the sustained upregulation of genes involved in muscle regeneration, cytoskeletal remodeling, and fibrotic responses. Notably, both expression and variability of SLC22 and SLC22A8, key proximal tubule transporters, were reduced, suggesting a loss of segment-specific identity. Further, SLC12A1, a critical regulator of sodium reabsorption and blood pressure, was downregulated and is associated with the onset of polyuria and hydronephrosis. SLC transporters exhibited expression patterns consistent with tubular dysfunction and inflammation. These findings suggest aberrant activation of myogenic pathways and structural proteins in renal tissues, consistent with a pro-fibrotic phenotype. In contrast, SPK treatment reversed the expression of most genes, thereby restoring the gene profiles to those observed in control mice. Conclusions: MHV-1-induced long COVID is associated with persistent transcriptional reprogramming in the kidney, indicative of chronic inflammation, cytoskeletal dysregulation, and fibrogenesis. SPK demonstrates robust therapeutic potential by normalizing these molecular signatures and preventing long-term renal damage. These findings underscore the relevance of the MHV-1 model and support further investigation of SPK as a candidate therapy for COVID-19-associated renal sequelae. Full article

S100 proteins, a family of Ca²⁺-binding proteins, play numerous roles in cellular processes such as proliferation, differentiation, and apoptosis. Recent evidence has highlighted their critical involvement in neuroinflammation, a pathological hallmark of various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Among these proteins, S100B and S100A8/A9 are particularly implicated in modulating inflammatory responses in the CNS. Acting as DAMPs, they interact with pattern recognition receptors like RAGE and TLRs, triggering pro-inflammatory signaling cascades and glial activation. While low concentrations of S100 proteins may support neuroprotective functions, increased levels are often associated with exacerbated inflammation and neuronal damage. This review explores the dualistic nature of S100 proteins in neuroinflammatory processes, their molecular interactions, and their potential as biomarkers and therapeutic targets in neurodegenerative disease management. Full article

Status epilepticus occurs when a seizure lasts more than five minutes or when multiple seizures occur with incomplete return to baseline. SE induces a myriad of pathological changes involving synaptic and extra-synaptic factors. The transition from a self-limiting seizure to a self-sustaining one is established by maladaptive receptor trafficking, whereby GABA_A receptors are progressively endocytosed while glutamatergic receptors (NMDA and AMPA) are transported to the synaptic membrane, causing excitotoxicity and alteration in glutamate-dependent downstream signaling. The subsequent influx of Ca²⁺ exposes neurons to increased levels of [Ca²⁺]i, which overwhelms mitochondrial buffering, resulting in irreversible mitochondrial membrane depolarization and mitochondrial injury. Oxidative stress resulting from mitochondrial leakage and increased production of reactive oxygen species activates the inflammasome and induces a damage-associated molecular pattern. Neuroinflammation perpetuates oxidative stress and exacerbates mitochondrial injury, thereby jeopardizing mitochondrial energy supply in a state of accelerated ATP consumption. Additionally, Ca²⁺ overload can directly damage neurons by activating enzymes involved in the breakdown of proteins, phospholipids, and nucleic acids. The cumulative effect of these effector pathways is neuronal injury and neuronal death. Surviving neurons undergo long-term alterations that serve as a substrate for epileptogenesis. This review highlights the multifaceted mechanisms underlying SE self-sustainability, pharmacoresistance, and subsequent epileptogenesis. Full article

Background: High Mobility Group Box 1 is a mediator in inflammation, acting as a damage-associated molecular pattern molecule in various diseases. This review examines its role in nasal inflammatory disorders, such as chronic rhinosinusitis and allergic rhinitis. Methods: A comprehensive review of recent literature was conducted using a refined PubMed search strategy, focusing on studies published from 2015 onward and targeting HMGB1’s role in nasal inflammatory diseases. Results: HMGB1 emerges as a central factor in amplifying and modulating inflammatory responses through interactions with multiple receptors. It regulates cytokine production, epithelial–mesenchymal transition, and tissue remodeling, particularly in eosinophilic CRS. While discrepancies in the literature highlight its context-dependent activity, therapeutic strategies like glycyrrhetinic acid and PPAR-γ agonists demonstrate potential in modulating its effects. Conclusions: HMGB1 represents a promising diagnostic biomarker and therapeutic target in nasal inflammatory diseases. However, due to its intrinsic nature and multiple localizations, much remains to be understood. It is precisely by reflecting on its role as an “inflammatory crossroads” that we aim to underscore the need for targeted translational research to elucidate the molecular mechanisms and therapeutic applications of HMGB1. Full article

In acute lymphoblastic leukemia (ALL), neutropenia and fever of unknown origin may occur, indicating the use of antimicrobials to control a probable infection. However, in 60–70% of cases there is no obvious infectious focus so treatment is empirical, increasing the risk of developing systemic inflammatory response syndrome (SIRS). The construction of a prognostic model of fever and development of SIRS based on the identification of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs) and inflammatory cytokines, can help identify children with ALL and fever or SIRS and who do not have an infection. A cohort of 30 children with recently diagnosed ALL and absence of infectious microorganisms before starting the remission induction phase was studied. Two groups were identified: (1) a group with SIRS (fever, tachycardia, tachypnea, and leukopenia, without focus of infection) and (2) a group without SIRS. The DAMPs, namely HMGB1 and S100A8 proteins, were quantified by ELISA and inflammatory mediators were determined by multiple protein analysis. The medians of DAMPs and inflammatory mediators in children with SIRS were higher than in children who did not have SIRS, and the delta values of the biomarkers studied in patients with and without SIRS showed important differences, with statistically higher medians in patients with SIRS compared to those without SIRS. HMGB1 together with IL-1β, IL-8, IL-10, and MCP-1 can serve as biomarkers to identify children with ALL and fever or SIRS who should not receive antimicrobial treatment because the origin of their fever is not due to an infectious agent. Full article

The Gliomas account for 81% of all malignant central nervous system tumors and are classified by WHO into four grades of malignancy. Glioblastoma multiforme (GBM), the most common grade IV glioma, exhibits an extremely aggressive phenotype and a dismal five-year survival rate of only 6%, underscoring the urgent need for novel therapeutic approaches. Immunotherapy has emerged as a promising strategy, and photodynamic therapy (PDT) in particular has attracted attention for its dual cytotoxic and immunostimulatory effects. In GBM models, PDT induces immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs), which promote antigen presentation and activate T cell responses. Additionally, PDT transiently increases blood–brain barrier permeability, facilitating immune cell infiltration into the tumor microenvironment, and enhances clearance of waste products via stimulation of meningeal lymphatic vessels. Importantly, PDT can reprogram or inactivate immunosuppressive tumor-associated macrophages, thereby counteracting the pro-tumoral microenvironment. Despite these encouraging findings, further preclinical and clinical studies are required to elucidate PDT’s underlying immunological mechanisms fully and to optimize treatment regimens that maximize its efficacy as part of integrated immunotherapeutic strategies against GBM. Full article

As a plant-specific peroxidase family, class III peroxidase (PRX) plays an important role in plant growth, development, and stress response. In this study, a preliminary functional analysis of CqPRX9L1 was conducted. Bioinformatics analysis revealed that CqPRX9L1 encodes a 349-amino acid protein belonging to the plant-peroxidase-like superfamily, featuring a transmembrane domain and cytoplasmic localization. The promoter region of CqPRX9L1 harbors various cis-acting elements associated with stress responses, hormone signaling, light regulation, and meristem-specific expression. The tissue-specific expression pattern of the CqPRX9L1 gene and its characteristics in response to different stresses were explored using subcellular localization, quantitative real-time PCR (qRT-PCR), and heterologous transformation into Arabidopsis thaliana. The results showed that CqPRX9L1, with a transmembrane structure, was localized in the cytoplasm, which encodes 349 amino acids and belongs to the plant-peroxisome-like superfamily. The promoter region contains stress-response elements, hormone-response elements, light-response elements, and meristem expression-related elements. The expression of CqPRX9L1 was relatively higher in ears and roots at the panicle stage than in stems and leaves. CqPRX9L1 showed a dynamic expression pattern of first decreasing and then increasing under abiotic stresses such as 15% PEG 6000, low temperature, and salt damage, with differences in response time and degree. CqPRX9L1 plays an important role in response to abiotic stress by affecting the activity of antioxidant enzymes such as superoxide dismutase (SOD) and peroxidase (POD), as well as the synthesis and decomposition of proline (Pro). CqPRX9L1 also affects plant bolting and flowering by regulating key flowering genes (such as FT and AP1) and gibberellin (GA)-related pathways. The results establish a foundation for revealing the functions and molecular mechanisms of the CqPRX9L1 gene. Full article

Post-traumatic stress disorder (PTSD) has traditionally been viewed as a psychiatric disorder of fear, memory, and emotional regulation. However, growing evidence implicates systemic and neuroinflammation as key contributors. Individuals with PTSD often exhibit elevated blood levels of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and C-reactive protein, indicating immune dysregulation. Dysfunctions in the hypothalamic–pituitary–adrenal (HPA) axis marked by reduced cortisol levels impair the body’s ability to regulate inflammation, allowing persistent immune activation. Circulating cytokines cross a weakened blood–brain barrier and activate microglia, which release additional inflammatory mediators. This neuroinflammatory loop can damage brain circuits critical to emotion processing including the hippocampus, amygdala, and prefrontal cortex, and disrupt neurotransmitter systems like serotonin and glutamate, potentially explaining PTSD symptoms such as hyperarousal and persistent fear memories. Rodent models of PTSD show similar inflammatory profiles, reinforcing the role of neuroinflammation in disease pathology. Bromo-epi-androsterone (BEA), a synthetic analog of dehydroepiandrosterone (DHEA), has shown potent anti-inflammatory effects in clinical trials, significantly reducing IL-1β, IL-6, and TNF-α. By modulating immune activity, BEA represents a promising candidate for mitigating neuroinflammation and its downstream effects in PTSD. These findings support the rationale for initiating clinical trials of BEA as a novel therapeutic intervention for PTSD. Full article

This study investigated the therapeutic potential of Bacillus thuringiensis extracellular polysaccharide BPS-2 in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) murine models. BPS-2 demonstrated significant efficacy in ameliorating UC-associated pathologies through three principal mechanisms: (1) attenuating histopathological damage while preserving colon epithelial integrity, (2) modulating immune marker expression patterns in colon tissues, and (3) restoring gut microbiota homeostasis. BPS-2 exhibited multi-faceted protective effects on the gut by mitigating oxidative stress responses and enhancing short-chain fatty acid biosynthesis, leading to an improved gut microbial community structure. Molecular docking analysis displayed strong binding affinity (ΔG = −7.8 kcal/mol) between the BPS-2U fragment and the Nuclear Factor κB (NF-κB) p50/p65 heterodimer, suggesting the potential disruption of NF-κB signaling pathways. Complementary molecular dynamics simulations revealed exceptional conformational stability in the p65-BPS-2U complex. These findings establish BPS-2 as a natural food additive that modulates the microbiota-barrier–inflammation axis through dietary intervention, offering a novel strategy to alleviate UC. Full article