Search Results (2,324)

Microglia play a key role in the development of neuroinflammation induced by cerebral ischemia. On the other hand, these cells participate in neurorepair processes. This dual role of microglia stems from the ability to shift their phenotype from pro-inflammatory M1 to protective M2. Histone deacetylase inhibitors (HDACis) are a group of agents that exhibit neuroprotective effects in some models of ischemia, among others, by modulation of signaling pathways that regulate microglial activation. This study aimed to examine the effect of HDACis—sodium butyrate and Givinostat—on polarization of microglia and their potential mechanism of action in a model of ischemia in vitro (oxygen and glucose deprivation, OGD). We examined the expression of pro- and anti-inflammatory markers in the BV2 microglial cell line after OGD and HDACis treatment by qPCR; polarization of microglia by flow cytometry; and the activation/phosphorylation of ERK and AKT in BV2 cells by Western blot and ELISA. Our findings demonstrate a divergent impact of HDACis on the phenotype of microglial cells. Sodium butyrate significantly suppressed the mRNA expression of pro-inflammatory markers (IL-1β, TNF-α, CD86) and increased the level of anti-inflammatory factors in BV2 microglial cells after OGD, whereas Givinostat failed to attenuate these inflammatory responses. Our findings demonstrate that sodium butyrate, but not Givinostat, promotes a shift in microglia toward an anti-inflammatory M2 phenotype under ischemic conditions. This effect is associated with suppression of pro-inflammatory gene expression and activation of the PI3K/AKT signaling pathway. These results identify sodium butyrate as a potential modulator of microglial responses following ischemic injury. Full article

Growing evidence suggests that persistent oral infectious diseases (OIDs) contribute to systemic disease, highlighting the importance of understanding their pathogenic mechanisms. Conventional dental treatments, primarily mechanical debridement, surgical intervention, or antimicrobial therapy, often struggle to fully control inflammation or prevent progressive tissue destruction. The nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome is a key regulator of innate immunity, mediating the maturation of proinflammatory cytokines (IL-1β and IL-18) and the pyroptosis-inducing protein gasdermin D. Dysregulated or excessive activation of NLRP3 contributes to the initiation and progression of major oral diseases, including periodontitis, peri-implantitis, pulpitis, and oral mucosal inflammation. Despite growing interest in NLRP3, comprehensive and up-to-date reviews integrating its pathogenic mechanisms and therapeutic potential remain limited. This review summarizes current and past evidence on the role of the NLRP3 inflammasome in oral disease development, highlights emerging pharmacological strategies, and outlines future research directions. Existing studies demonstrate that microbial components and danger signals from injured tissues activate NLRP3, thereby amplifying inflammation, tissue degradation, and bone resorption. Preclinical studies indicate that inflammasome inhibitors and several natural compounds reduce tissue damage; however, their clinical translation remains limited. These findings emphasize the need for deeper understanding of NLRP3-mediated pathways, with translational and clinical research offering promising therapeutic opportunities for oral diseases. Full article

Psoriasis and psoriatic arthritis (PsA) occasionally coexist with antinuclear antibody (ANA) positivity, cutaneous lupus erythematosus (CLE), or systemic lupus erythematosus (SLE), creating one of the most challenging therapeutic overlap scenarios in immunodermatology. Divergent immune pathways—IL-23/Th17-driven psoriatic inflammation versus type I interferon-mediated autoimmunity—generate unique vulnerabilities when systemic treatments are used. To synthesize treatment outcomes, lupus-related safety signals, and mechanistic insights across systemic therapies in patients with psoriasis or PsA who also exhibit ANA positivity, CLE, or SLE. A systematic review following PRISMA 2020 guidelines was conducted across PubMed/MEDLINE, Embase, the Cochrane Library, Scopus, and ClinicalTrials.gov from database inception through 31 October 2025. Thirty-three eligible reports (29 unique clinical studies; 1429 patients) were included and organized into six prespecified overlap subgroups. Mechanistic and translational studies—including ustekinumab and deucravacitinib SLE trial data and reports of IL-17 inhibitor-associated CLE—were reviewed separately to provide contextual interpretation. IL-23 inhibitors were consistently associated with a favorable cross-disease safety profile, with no clear signal for CLE worsening, SLE flares, or drug-induced autoimmunity. IL-17 inhibitors maintained strong psoriatic efficacy but were associated with an increased frequency of de novo or exacerbated CLE. TNF-α inhibitors showed the strongest association with ANA seroconversion, anti-dsDNA induction, drug-induced lupus, and lupus flares. Ustekinumab demonstrated a stable safety profile across lupus-spectrum disease despite variable efficacy in formal SLE trials. TYK2 inhibition provided dual modulation of IL-23 and type I interferon pathways and showed emerging utility in psoriasis or PsA coexisting with CLE or SLE. Apremilast, methotrexate, and mycophenolate mofetil remained reliable non-biologic systemic options. Phototherapy was associated with potential risk in ANA-positive or lupus-susceptible populations and therefore requires careful consideration. Interpretation is limited by the predominantly observational nature and heterogeneity of the available evidence. IL-23 inhibition and TYK2 inhibition appear to offer a balanced profile of efficacy and lupus-related safety in psoriatic disease complicated by lupus-spectrum autoimmunity. IL-17 inhibitors and TNF-α inhibitors may be associated with higher risk in CLE- or SLE-prone patients and therefore warrant particular caution. Personalized treatment strategies should integrate the relative dominance of psoriatic versus lupus disease, ANA/ENA profile, CLE subtype, and underlying mechanistic considerations. Prospective, biomarker-driven studies are needed to guide therapy in this increasingly recognized overlap population (PROSPERO registration: CRD420251241279). Full article

Background: Pulmonary fibrosis (PF) currently lacks effective therapeutic interventions. Roxadustat, an oral small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase, has been shown in several studies to attenuate the progression of fibrotic diseases. However, its therapeutic efficacy in PF remains to be fully elucidated. The aim of this study was to evaluate roxadustat’s therapeutic benefits on PF as well as the underlying mechanisms of action. Methods: Bleomycin was administered intraperitoneally to establish a PF mouse model. H&E staining, Masson staining, and immunohistochemistry (IHC) were used to assess histopathological and fibrotic changes. Changes in the expression levels of inflammatory mediators, including IL-1β, TGF-β1, and TNF-α, were examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Network pharmacology combined with transcriptomic analysis was employed to identify potential target genes and associated signaling pathways. Subsequently, RT-qPCR and Western blot analyses were carried out to experimentally validate the predicted targets and pathways and to verify the protective effects of roxadustat in PF mice. Results: Roxadustat markedly ameliorated bleomycin-induced pulmonary fibrosis in mice. The therapeutic effect was evidenced by a reduction in alveolar damage, thinner alveolar septa, diminished infiltration of inflammatory cells, and decreased collagen deposition. Concomitantly, the expression levels of inflammatory mediators, including IL-1β, TGF-β1, and TNF-α, were significantly lowered. Integrated network pharmacology and transcriptomic analyses revealed the involvement of critical signaling pathways, specifically nuclear factor-kappa B (NF-κB) and peroxisome proliferator-activated receptor (PPAR). Experimental validation further demonstrated that roxadustat downregulated the expression of key genes (S100A8, S100A9, and Fos) in murine lung tissues. It also suppressed the protein ratios of phosphorylated p65 to total p65 and phosphorylated IκBα to total IκBα. Moreover, roxadustat treatment upregulated PPARγ protein expression. Conclusions: These data indicate that roxadustat ameliorates bleomycin-induced PF in mice, an effect associated with modulation of the NF-κB and PPAR signaling pathways. The findings provide a preclinical rationale for further investigation of roxadustat as a potential treatment for PF. Full article

Joint acidosis is increasingly recognized as an important determinant of cellular behavior in osteoarthritis (OA). Declines in extracellular pH (pHe) occur across cartilage, meniscus, synovium, and subchondral bone, where they influence inflammation, matrix turnover, and pain. Among proton-sensing G protein-coupled receptors, GPR68 responds to the acidic pH range characteristic of human OA joints. The receptor is activated between pH 6.8 and 7.0, couples to Gq/PLC-MAPK, cAMP-CREB, G12/13-RhoA-ROCK signaling pathways, and is expressed most prominently in articular cartilage, with additional expression reported in synovium, bone, vasculature, and some neuronal populations. These pathways regulate transcriptional programs relevant to cartilage stress responses, inflammation, and matrix turnover. GPR68 expression is increased in human OA cartilage and aligns with regions of active matrix turnover. We previously reported that pharmacologic activation of GPR68 suppresses IL1β-induced MMP13 expression in human chondrocytes under acidic conditions, indicating that increased GPR68 expression may represent a microenvironment-responsive, potentially adaptive signaling response rather than a driver of cartilage degeneration. Evidence from intestinal, stromal, and vascular models demonstrates that GPR68 integrates pH changes with inflammatory and mechanical cues, providing mechanistic context, although these effects have not been directly established in most joint tissues. Small-molecule modulators, including the positive allosteric agonist Ogerin and the inhibitor Ogremorphin, illustrate the tractability of GPR68 as a drug target, although no GPR68-directed therapies have yet been evaluated in preclinical models of OA. Collectively, current data support GPR68 as a functionally relevant proton sensor within the acidic OA joint microenvironment. Full article

Regulatory B cells (Bregs) are integral to the tumor microenvironment (TME) and influence immune responses through the secretion of immunosuppressive cytokines such as IL-10, IL-35, and TGF-β. This review highlights recent findings on the phenotype and mechanisms of Bregs, emphasizing their dual role in regulating immune responses within the TME. Importantly, we further explored the latest advances in Breg regulatory mechanisms from the novel perspectives of epigenetics and metabolic remodeling, including the effects of DNA methylation, histone acetylation, glycolysis, and oxidative phosphorylation on Bregs. We also investigate the therapeutic targeting of Bregs, with a focus on STAT3 inhibitors such as lipoxin A4, cucurbitacins, and resveratrol, which show promising potential in mitigating the suppressive function of Bregs. Furthermore, this review provides a detailed analysis of the impact of Bregs on tumorigenesis and metastasis, emphasizing the importance of inhibiting specific immune pathways to prevent tumor escape. Finally, this review offers a prospective outlook on immunotherapy strategies based on Bregs, foreseeing a more nuanced understanding of their TME function and the evolution of targeted treatments with enhanced therapeutic efficacy. Full article

Among the metal-derived complexes, recently, tin derivatives have been investigated as promising anti-cancer drug candidates. Our previous study showed that the tin-based compound Bu₃SnOCOCF₃ (TBT) exerts cytotoxic activity on solid tumor cell lines. In the present study, the effects of TBT were evaluated in vitro on HTLV-1-infected human lymphocytic cell lines at different stages of viral transformation, consisting of IL-2-dependent (PB2/IL-2) and IL-2-independent (PB2/NO-IL-2) cells, generated in our laboratory by HTLV-1 in vitro infection of lymphocytes from the same donor, and the C91/PL cell line established by co-cultivation with T cells from a patient with HTLV-1-positive leukemia. TBT induced a reliable and reproducible dose-dependent inhibition of metabolic activity and viability in the HTLV-1-infected cells. The effect was cell-type-dependent, with C91/PL cells being quite resistant. An investigation into the cytotoxic effects induced by TBT in HTLV-1-infected cells and data on caspase inhibitors/caspase activation indicated that apoptotic cell death was involved, but also that the possible involvement of other forms of cell death could not be excluded. Taken together, the results show for the first time that the tin-based compound, although not devoid of a certain cytotoxicity toward uninfected cells, can induce typical and potent effects on HTLV-1-infected cells. Full article

Background and Objectives: This study aims to analyze the effects of levetiracetam (LEV) and valproic acid (VPA) administration on oxidative stress, inflammation, apoptosis, extracellular matrix dynamics, and bone remodeling parameters in rat alveolar bone exposed to orthodontic force. Materials and Methods: Four experimental groups were designed for this study: Control, Force, Force + LEV, and Force + VPA. LEV (150 mg/kg/day) or VPA (300 mg/kg/day) was administered intraperitoneally to the experimental groups daily for 6 weeks. At the end of the experimental period, the alveolar bone tissues were used for molecular analyses. RT-PCR analysis was performed to assess the expression levels of antioxidant markers [superoxide dismutase, (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH)], inflammatory cytokines [tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β)], apoptosis-related genes (Bax, Bcl-2, and Caspase-3), matrix remodeling genes [matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and metallopeptidase inhibitor 1 (TIMP-1)], and bone metabolism regulators [receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG)]. Oxidative stress and inflammatory measurements were also confirmed via ELISA assays. Results: The results demonstrated that orthodontic force application increased oxidative stress, inflammation, and apoptosis compared to the Control group, disrupted extracellular matrix homeostasis, and increased bone resorption, while LEV administration (LEV + Force) markedly mitigated these abnormalities. In other words, LEV administration increased levels of antioxidant markers, decreased levels of inflammatory cytokines and pro-apoptotic genes, restored extracellular matrix balance (decrease in MMP-2 and MMP-9 with concurrent upregulation of TIMP-1), and limited tissue destruction (decrease in RANKL along with elevation in OPG). In contrast to LEV, VPA did not correct these molecular alterations induced by orthodontic force and, in several parameters, further exacerbated them. Conclusions: In conclusion, molecular data from the animal model indicate that LEV plays a protective role against orthodontic force by reducing excess levels of oxidative stress, apoptosis, and inflammation and homeostatic pathways. Full article

Background/Objectives: Acute generalized exanthematous pustulosis (AGEP) is a severe drug-induced cutaneous reaction characterized by the abrupt onset of sterile pustules, fever, neutrophilia, and a T cell-mediated type IVd hypersensitivity response. This narrative review synthesizes current evidence on pharmacological triggers, immunopathogenic mechanisms, diagnostic criteria, and differential diagnosis to provide a clinically oriented framework. Methods: A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, ScienceDirect, and SpringerLink for studies published between 2000 and 2025, complemented by selected clinical reference sources. Studies addressing clinical features, immunological pathways, pharmacovigilance signals, and diagnostic tools for AGEP were included. Synthesis of Evidence: β-lactam antibiotics remain the most frequent triggers, while increasing associations have been reported with hydroxychloroquine, targeted therapies, immune checkpoint inhibitors, psychotropic agents, and vaccines. Immunopathogenesis is driven by IL-36 activation, CXCL8/IL-8–mediated neutrophil recruitment, and IL36RN mutations, explaining overlap with pustular psoriasis. Diagnostic accuracy improves through integration of drug latency, clinical morphology, histopathology, biomarkers, and standardized tools such as the EuroSCAR score. Conclusions: AGEP is a complex pustular reaction induced by diverse drugs and amplified by IL-36-mediated inflammation. Accurate diagnosis requires a multidimensional approach supported by structured algorithms and robust pharmacovigilance to identify evolving drug-associated patterns. Full article

Background: Psoriasis involving difficult-to-treat anatomical areas, such as the scalp, genitalia, fingernails, and palmoplantar regions, carries a disproportionate disease burden and often requires systemic therapy. In this context, real-life data comparing the long-term effectiveness of tildrakizumab 100 mg versus 200 mg in patients with difficult-to-treat psoriasis remain limited. Methods: This multicenter retrospective observational study included adult patients in three Italian dermatology centers. Global efficacy endpoints included PASI75, PASI90, PASI100, and absolute PASI ≤ 2 at weeks 16, 32, 52, and 104. Site-specific effectiveness was assessed as complete clearance (PGA = 0) in patients with baseline involvement (PGA ≥ 2) of difficult-to-treat areas. Outcomes were described by dose. Results: 183 patients were included (100 mg: n = 89; 200 mg: n = 94). Patients receiving 200 mg had higher baseline BMI and were more frequently biologic-experienced. At week 104, PASI75 was achieved by 94.2% of patients receiving 100 mg and 94.7% receiving 200 mg, while PASI90 and PASI100 were achieved by 82.7% vs. 57.9% and 48.1% vs. 47.4%, respectively. Clearance of difficult-to-treat areas improved progressively across all sites. Scalp and genital psoriasis showed higher and earlier clearance rates, whereas nail and palmoplantar psoriasis showed slower and more heterogeneous responses. No consistent dose-dependent advantage emerged, despite less favorable baseline characteristics in the 200 mg group. Conclusions: Over 104 weeks, tildrakizumab showed sustained long-term effectiveness in both global disease control and difficult-to-treat areas. The 200 mg dose, used in a more difficult-to-treat population, achieved comparable long-term outcomes, supporting dose optimization in clinical practice. Full article

Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a severe form of pulmonary hypertension with poor prognosis. It most commonly arises in systemic sclerosis (SSc), followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Its pathogenesis involves a complex interplay of immune dysregulation, chronic inflammation, endothelial injury, vascular remodeling, and fibrosis. Although vasodilators targeting the endothelin, nitric oxide, and prostacyclin pathways remain the therapeutic backbone, newer agents—including the activin signal inhibitor sotatercept and inhaled treprostinil—have expanded treatment options. Immune-targeted therapies such as glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab, and IL-6 receptor inhibitors may benefit inflammation-dominant PAH phenotypes, while fibrotic phenotypes continue to demonstrate limited responsiveness. In addition to brain natriuretic peptide (BNP), N-terminal (NT)-proBNP and disease-specific autoantibodies, emerging biomarkers show promise for early detection, risk stratification, and personalized treatment, though validation in CTD-PAH is lacking. Advances in animal models replicating immune-mediated vascular injury and fibrosis have further improved mechanistic understanding. Despite these developments, substantial unmet needs remain, including the absence of disease-specific therapeutic strategies, limited biomarker integration into clinical practice, and a scarcity of large, well-designed trials targeting individual CTD subtypes. Addressing these gaps will be essential for improving prognosis in patients with CTD-PAH. Full article

Vasculitides are a heterogeneous group of disorders characterized by inflammation of blood vessel walls, leading to tissue ischemia and organ injury. Traditional inflammatory markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are widely used but lack diagnostic specificity. This has driven the search for more informative biomarkers across vasculitis subtypes. This review summarizes current evidence for validated and emerging biomarkers in large-, medium-, small-, and variable-vessel vasculitis, as well as single-organ vasculitis. Key analytes reflect systemic inflammation, such as serum amyloid A (SAA) and interleukin-6 (IL-6), as well as endothelial activation, complement pathways, neutrophil and macrophage activation, and organ-specific damage. Promising candidates include pentraxin-3 (PTX3) and matrix metalloproteinase-9 (MMP-9) in large-vessel vasculitis; N-terminal pro-B-type natriuretic peptide (NT-proBNP) and S100 proteins in Kawasaki disease; galactose-deficient immunoglobulin A1 (Gd-IgA1) and urinary angiotensinogen (AGT) in IgA vasculitis; and tissue inhibitor of metalloproteinases-1 (TIMP-1), S100 proteins, complement C3, and PTX3 in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Although these biomarkers provide mechanistic insight, most lack disease-specificity, external validation, or standardized assays. Future progress will require multicenter studies, harmonized testing, and integrated biomarker panels combined with imaging modalities to improve diagnosis, activity assessment, and monitoring. Full article

Background: Inflammatory Bowel Disease (IBD) involves a complex interplay between immune dysregulation and intestinal barrier failure. Traditional views focused on individual cell death pathways, but the emerging concept of PANoptosis—a coordinated inflammatory cell death involving apoptosis, necroptosis, and pyroptosis—offers a more holistic understanding of IBD pathogenesis. Objective: This review evaluates the role of PANoptosis in IBD, identifies key molecular triggers (such as the ZBP1-ADAR1 axis), and discusses the therapeutic potential of targeting this process. Methods: We analyzed recent literature and clinical trial data regarding programmed cell death (PCD) inhibitors and natural compounds in IBD models. Results: Preclinical data suggest that targeting PANoptotic regulators like RIPK1 and ZBP1 can restore barrier integrity. However, clinical translation remains challenging; for instance, while targeting pyroptosis via IL-1/IL-18 (Anakinra) showed promise in theory, clinical results in IBD have been disappointing. Furthermore, RIPK1 inhibitors such as GSK2982772 have failed to meet primary endpoints in Phase 2 trials. Conclusions: PANoptosis is a “hot” therapeutic target, but successful treatment likely requires combination therapies or “PANoptosome” specific modulators rather than single-pathway inhibition. Full article

Background: Growing evidence indicates that oral microbiome dysbiosis contributes to systemic inflammation, immune activation, and neural dysfunction. These processes may influence the onset and progression of major neuropsychiatric and neurodegenerative disorders. This review integrates clinical, epidemiological, and mechanistic findings linking periodontal pathogens and oral microbial imbalance to Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, and anxiety. Methods: A narrative review was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify recent studies examining alterations in the oral microbiota, microbial translocation, systemic inflammatory responses, blood–brain barrier disruption, cytokine signaling, and neural pathways implicated in brain disorders. Results: Evidence from human and experimental models demonstrates that oral pathogens, particularly Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, can disseminate systemically, alter immune tone, and affect neural tissues. Their virulence factors promote microglial activation, cytokine release (IL-1β, IL-6, TNF-α), amyloid-β aggregation, and α-synuclein misfolding. Epidemiological studies show associations between oral dysbiosis and cognitive impairment, motor symptoms in PD, and alterations in mood-related taxa linked to stress hormone profiles. Immunometabolic pathways, HPA-axis activation, and the oral–gut–brain axis further integrate these findings into a shared neuroinflammatory framework. Conclusions: Oral dysbiosis emerges as a modifiable contributor to neuroinflammation and brain health. Periodontal therapy, probiotics, prebiotics, synbiotics, and targeted inhibitors of bacterial virulence factors represent promising strategies to reduce systemic and neural inflammation. Longitudinal human studies and standardized microbiome methodologies are still needed to clarify causality and evaluate whether restoring oral microbial balance can modify the course of neuropsychiatric and neurodegenerative disorders. Full article

Atherosclerosis is a chronic, multifactorial vascular disease and the leading global cause of cardiovascular morbidity. Its development reflects interconnected disturbances in lipid metabolism, endothelial function, inflammation, smooth muscle cell (SMC) phenotypic switching, and extracellular matrix remodeling. Genetic predisposition, including monogenic disorders such as familial hypercholesterolemia and polygenic risk variants, modulates disease susceptibility by altering lipid homeostasis as well as inflammatory and thrombotic pathways. Epigenetic regulators and noncoding RNAs, such as histone modifications, microRNAs, and long noncoding RNAs, further shape gene expression and link environmental cues to vascular pathology. Endothelial injury promotes lipoprotein retention and oxidation, triggering monocyte recruitment and macrophage-driven foam cell formation, cytokine secretion, and necrotic core development. Persistent inflammation, macrophage heterogeneity, and SMC plasticity collectively drive plaque growth and destabilization. Emerging insights into immune cell metabolism, intracellular signaling networks, and novel regulatory RNAs are expanding therapeutic possibilities beyond lipid-lowering. Current and evolving treatments include statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, anti-inflammatory agents targeting interleukin-1 beta (IL-1β) or NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and advanced approaches such as gene editing, siRNA, and nanoparticle-based delivery. Integrating multi-omics, biomarker-guided therapy, and precision medicine promises improved risk stratification and next-generation targeted interventions. This review summarizes recent molecular advances and highlights translational opportunities for enhancing atherosclerosis prevention and treatment. Full article