Search Results (2,438)

Background: Rotenone is a widely used environmental pesticide, and epidemiological studies suggest that exposure is associated with an increased risk of Parkinson’s disease (PD); however, the molecular toxicological basis of this association remains incompletely defined. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that is relevant to PD and other neurodegenerative disorders. In this study, we provide disease-contextual functional evidence linking ferroptosis to rotenone-induced PD-like neurotoxicity. Methods: We combined network toxicology, human PD substantia nigra transcriptomic analysis using GSE7621, and SH-SY5Y cell-based validation. Rotenone-associated targets were predicted and analyzed for ferroptosis-related enrichment, PD transcriptomic signatures were used for disease-contextual candidate prioritization, and selected findings were validated using qPCR, CCK-8, Western blotting, C11-BODIPY lipid peroxidation staining, and transmission electron microscopy. Results: By further integrating a human PD substantia nigra transcriptomic dataset (GSE7621), we prioritized an 11-gene, PD-contextualized ferroptosis-associated candidate module (LIPF, FAM170A, MCHR1, IL17A, MYB, GFAP, ARMC3, GKN1, GATA3, IL17F, and TEKT1). In SH-SY5Y cells, rotenone exposure consistently upregulated this candidate transcriptional module, and this induction was broadly attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). In parallel, orthogonal functional assays supported an iron- and lipid peroxidation-driven injury state under rotenone exposure that was suppressible by ferroptosis inhibition and iron chelation. Finally, we further performed an exploratory drug–gene association screen to prioritize clinically available candidates, and a limited qPCR check suggested that several selected compounds partially attenuated representative hub-gene induction under rotenone exposure. Conclusions: Collectively, these findings provide disease-contextual and experimentally supported evidence linking rotenone exposure to ferroptosis-associated neurotoxicity, and identify a ferroptosis-responsive transcriptional module for future hypothesis-driven mechanistic investigation. Full article

This translational synthesis highlights the potential role of obesity-induced low-grade chronic inflammation in modulating clinical outcomes among patients with spondyloarthritis (SpA). Obesity transforms adipose tissue into a pro-inflammatory endocrine organ, where hypertrophic adipocytes release adipokines such as leptin alongside cytokines including TNF-α and IL-6, potentially contributing to macrophage polarization toward an M1 phenotype and activating NF-κB signaling pathways. This systemic immunometabolic priming may lower activation thresholds at the enthesis—the primary pathological site in SpA—potentially amplifying IL-23/IL-17 axis activity via Th17 bias, innate-like lymphocyte responses, and stromal–immune crosstalk under mechanical stress. Clinically, patients with SpA and obesity have been reported to demonstrate heightened disease activity (BASDAI, ASDAS), impaired function (BASFI), accelerated radiographic progression (syndesmophytes, enthesophytes), and diminished biologic response rates, potentially attributable to pharmacokinetic alterations (e.g., subtherapeutic TNF inhibitor levels) and pharmacodynamic resistance. Multisystem comorbidities, including non-alcoholic fatty liver disease, cardiovascular events, metabolic syndrome, sleep disturbances, and depression, further exacerbate morbidity and diminish quality of life. Therapeutic implications emphasize obesity as a modifiable disease modifier. Weight loss interventions, including hypocaloric diets, anti-inflammatory regimens (e.g., Mediterranean diet), multicomponent exercise, GLP-1 receptor agonists, and bariatric surgery, have been associated with reductions in inflammatory biomarkers, improved remission rates (MDA, DAPSA), and prolonged drug survival by restoring adipokine balance and disrupting mechano-inflammatory loops. Future randomized controlled trials should prioritize long-term evaluations of integrated multidisciplinary strategies that combine metabolic optimization with immunomodulatory therapies, addressing adherence challenges through psychological support and patient-tailored protocols, while elucidating dose–response relationships for GLP-1RAs and exercise in diverse SpA subtypes to establish precision management paradigms that mitigate cardiometabolic burden and improve holistic outcomes. Full article

Differentiation therapy holds significant potential for the treatment of multiple myeloma (MM). We previously identified that the aminopeptidase N (APN) inhibitor Bestatin promotes MM cell differentiation. Herein, we elucidate the underlying molecular mechanisms of this process. Utilizing MM1.S, U266, and RPMI-8226 cell lines, a combination of CCK-8 assays, flow cytometry, Wright–Giemsa staining, Western blotting, qRT-PCR, ELISA, APN enzymatic activity analysis, SA-β-gal staining, and bioinformatic analyses revealed elevated APN expression across all cell types. Bestatin treatment induced MM cell differentiation in a concentration-dependent manner, which was accompanied by the upregulation of the differentiation marker CD49e, increased immunoglobulin light chain secretion, elevated cellular senescence, and a concomitant suppression of cell proliferation and APN enzymatic activity. Mechanistically, Bestatin exerts its effects by downregulating the CD79B/BTK signaling pathway, thereby activating the downstream transcription factor STAT3. Consistent with this axis, direct inhibition of CD79B/BTK alone was sufficient to induce differentiation, while blockade of STAT3 completely abrogated the differentiation-promoting effect of Bestatin. The APN-neutralizing antibody (WM15) yielded consistent results with Bestatin, further validating this regulatory axis. Furthermore, both the CD79B/BTK inhibitor Ibrutinib and the STAT3 agonist GCDA potentiated the cytotoxicity of the clinical MM drug Ixazomib. Bestatin itself synergized with Ixazomib and enhanced the anti-proliferative effect of IL-6. In summary, our findings establish that the APN inhibitor Bestatin induces MM cell differentiation via the CD79B/BTK-STAT3 signaling axis. Targeting this pathway represents a promising strategy to enhance the efficacy of Ixazomib, providing a compelling rationale for novel combination therapies in MM. Full article

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), which is marked by severe abdominal pain, weight loss, perianal bleeding, and diarrhea. This study successfully isolated and purified four low-molecular-weight fucoidan oligosaccharides through acid hydrolysis and Bio Gel P10 gel filtration. The molecular weights were 2.9 × 10⁴–1.36 × 10⁵ Da, 182–1012 Da, 161–939 Da and 161–939 Da, respectively. A mouse model of colitis was induced using Dextran Sulfate Sodium (DSS). The results indicated that fucoidan and fucoidan oligosaccharides could ameliorate murine ulcerative colitis, with the oligosaccharides (200 mg/kg/d) demonstrating superior therapeutic effects. This superiority was likely attributed to the lower molecular weight and higher content of total sugars and fucose. The primary mechanisms involved the modulation of gene and protein expression levels associated with the Toll-like receptor 4, Myeloid differentiation primary response 88, nuclear factor kappa-light-chain-enhancer of activated B cells, p65, and Inhibitor of kappa light polypeptide gene enhancer in B cells, alpha (TLR4, MYD88, NF-κB p65, and IκB-α) signaling pathways, which reduce the production of inflammatory cytokines such as tumor necrosis factor-alpha, Interleukin-1 beta and Interleukin-6 (TNF-α, IL-1β, and IL-6). Additionally, these oligosaccharides alleviated oxidative stress, enhanced the levels of intestinal barrier proteins (Claudin family member 4 and Zonula occludens protein 1), regulated the abundance and diversity of the gut microbiota, and increased the levels of short-chain fatty acids (SCFAs) in the intestine. It is worth emphasizing that this study can only demonstrate that fucoidan oligosaccharides have a mitigating effect on intestinal inflammation in mice. Further research is needed in the future to investigate the structure–activity relationship of fucoidan oligosaccharides and their impact on human intestinal microbiota, in order to further elucidate their anti-inflammatory mechanisms. Full article

Interleukin-17A (IL-17A) is a proinflammatory cytokine that plays a pivotal role in immune responses and tissue homeostasis. Its expression is strictly regulated by transcription factors including RORγt, and it is mainly produced by Th17 cells, γδ T cells, and innate lymphoid cells. IL-17A signals through a heterodimeric receptor complex consisting of IL-17RA and IL-17RC, activating NF-κB, MAPK, and C/EBP pathways via the adaptor protein Act1. IL-17 signaling is counterbalanced by negative regulators including A20 and Regnase-1. Beyond its classical roles in antimicrobial defense and autoimmune inflammation, recent studies have highlighted its functions in the central nervous system, with associations to multiple sclerosis, autism spectrum disorder, and Alzheimer’s disease. The development of IL-17A inhibitors, including the dual IL-17A/F antagonist bimekizumab, has advanced markedly, with demonstrated efficacy in immune-mediated diseases such as psoriasis and psoriatic arthritis. This review provides a comprehensive overview of current knowledge of IL-17A, from its molecular characteristics to clinical applications. Full article

Folliculitis decalvans (FD) and dissecting cellulitis of the scalp (DCS) are neutrophilic primary cicatricial alopecias characterized by chronic inflammation and irreversible hair loss, with distinct pathogenic mechanisms that make accurate diagnosis essential for appropriate management. This narrative review aims to provide a comprehensive overview of systemic therapeutic options for FD and DCS, to evaluate their efficacy in relation to underlying disease mechanisms, and to explore emerging targeted treatments. A literature search was conducted in PubMed/MEDLINE using relevant keywords related to neutrophilic cicatricial alopecias and therapeutic strategies, including studies reporting clinical outcomes in FD and DCS. Available evidence indicates that conventional therapies remain the cornerstone of management: antibiotics are typically first-line in FD, while isotretinoin represents the mainstay of treatment in DCS and a key option in refractory FD; however, these approaches are often associated with partial responses and frequent relapses. Biologic agents, particularly TNF-α inhibitors, have shown consistent benefit in refractory cases, while IL-17/23 and JAK inhibitors are supported by limited but emerging data. Overall, treatment response appears to reflect underlying pathogenic differences between FD and DCS, underscoring the importance of a tailored, mechanism-based approach. Further studies are needed to establish standardized treatment algorithms and confirm long-term efficacy and safety. Full article

Recurrent pericarditis (RP) remains challenging, especially in tuberculosis (TB)-endemic regions where empirical anti-TB therapy is often unnecessarily prolonged. We report a 35-year-old woman with three RP episodes over six months, presenting with pleuritic chest pain, elevated inflammatory markers, and moderate-to-large pericardial effusion. Extensive infectious (including TB), autoimmune, and malignancy workups were negative. Cardiac magnetic resonance revealed persistent pericardial late gadolinium enhancement despite clinical remission. Whole-exome sequencing identified a heterozygous MEFV c.442G>C (p.Glu148Gln) variant, suggesting an autoinflammatory predisposition. Although the patient finally achieved sustained symptom-free status for six months on a standardized low-dose colchicine regimen, still over 10% of patients have recurrent symptoms receiving colchicine in addition to conventional anti-inflammatory therapy with aspirin or ibuprofen. This case highlights the shifting paradigm from an infection-centered to an autoinflammatory framework for RP in TB-endemic countries, underscores the role of MEFV variants in idiopathic recurrent pericarditis, and illustrates the real-world gap between genetic insights and therapeutic accessibility to IL-1 inhibitors in resource-limited settings. Full article

Macrophage migration inhibitory factor (MIF) has been shown to induce M1 macrophage polarization with oxidative stress and associated metabolic reprogramming. Several tautomerase inhibitors were shown to selectively inhibit either MIF’s ketonase or enolase sub-activities. In this study, we aimed to investigate the role of enolase sub-activity in M1 polarization using the selective enolase inhibitor TE-91. We performed in silico molecular docking analysis and physicochemical characterization of TE-91. LPS + IFN-γ-induced RAW264.7 cells were applied as a model for M1 macrophage activation. We performed ROS and nitrite determinations, ELISA, qPCR, and immunoblot analysis, and measured mitochondrial oxygen consumption rate and extracellular acidification rate. Here, we reveal that TE-91 might directly bind to the MIF tautomerase active site. Furthermore, TE-91 reduces M1 activation by enhancing oxidative phosphorylation and reducing the glycolytic activity in LPS + IFN-γ-induced macrophage cells. In the same model, TE-91 reduces TNF-α, IL-6, CCL2, and iNOS mRNA transcription yet fails to modulate PARP1 and SOD2 mRNA transcription. It also decreases ROS, nitrite, and IL-6 production without influencing TNF-α and CCL2 protein production. TE-91 was unable to reduce either HIF-1α mRNA transcription or its protein expression. Finally, TE-91 reduced IL-1β cleavage, without affecting IL-1β protein expression. These results may highlight the importance of tautomerase sub-activities in M1 polarization. Full article

Background/Objectives: We conducted the first pharmacogenetic investigation of atopic dermatitis in a cohort of 43 Greek patients, focusing on key variants within the IL6/JAK/STAT signaling axis, a pathway central to inflammation and therapeutic targeting. Methods: Patients receiving dupilumab, JAK inhibitors, or topical corticosteroids were prospectively evaluated, with treatment response assessed by changes in the Eczema Area and Severity Index over four months. Targeted genotyping of IL6R rs2228145 A>C, JAK1 rs2780815 T>G, and TRAF3 rs12147254 G>A were performed using PCR-RFLP. Results: Across the full cohort, no robust pharmacogenetic effects were detected, while baseline disease severity was the strongest predictor of absolute clinical improvement. However, stratified analyses revealed a significant association between the IL6R rs2228145 minor allele and reduced upadacitinib response (p-value = 0.026). Consistently, the same variant demonstrated a nominal association with reduced likelihood of achieving ≥75% improvement (p = 0.065). Conclusions: Although limited by sample size, these findings suggest potential treatment-specific pharmacogenetic effects within the IL6 pathway, supporting further investigation in larger cohorts to inform personalized therapeutic strategies in eczema. Full article

Background/Objectives: Rheumatoid arthritis (RA) is an autoimmune disorder manifesting as joint destruction and synovial inflammation, with the aberrant activation of fibroblast-like synoviocytes (FLSs) functioning as a critical pathological mechanism. Liquiritigenin (LIQ), a natural flavonoid extracted from licorice root, possesses anti-inflammatory and antioxidant activities; however, its efficacy and mechanism in RA pathological models remain unclear. This study aimed to investigate the anti-RA effects of LIQ mediated through FLSs and its underlying mechanisms. Methods: Complete Freund’s adjuvant (CFA)-induced rat model and TNF-α-stimulated MH7A cell model were employed to assess the anti-RA effects and underlying mechanisms. In vivo experiments examined the effects of LIQ on RA manifestations, joint damage, and inflammatory responses in CFA-induced rats, while in vitro experiments explored its effects on aberrant activation, oxidative stress, and inflammation in TNF-α-stimulated MH7A cells. The regulatory effects of LIQ on the Nrf2/NF-κB/NLRP3 signaling pathway were validated by immunofluorescence and Western blotting in vivo and in vitro. Results: LIQ alleviated joint swelling and bone damage, reducing synovial cellular infiltration and hyperplastic changes in CFA-induced rats. Furthermore, LIQ inhibited proliferation, migration, and invasion while reducing reactive oxygen species levels in TNF-α-stimulated MH7A cells, and decreased IL-1β and IL-18 levels in rat serum and MH7A cell supernatants. Moreover, LIQ activated Nrf2 and inhibited NF-κB and NLRP3, thereby attenuating inflammatory responses and alleviating oxidative stress. Administration of the Nrf2 inhibitor ML385 partially reversed its suppressive effects on inflammatory responses and oxidative stress in vivo and in vitro. Conclusions: LIQ exerted anti-RA effects in FLSs by suppressing inflammation and aberrant activation. Its mechanism may involve modulation of the Nrf2/NF-κB/NLRP3 signaling pathway. Full article

Background: A substantial proportion of patients with non-small cell lung cancer (NSCLC) derive limited clinical benefit from immunotherapy. Monitoring of peripheral blood immune markers (PBIMs) may emerge as a useful tool to predict treatment outcomes with immune checkpoint inhibitors (ICIs). Patients/Methods: We prospectively measured several PBIMs in a PD-L1 high (TPS ≥ 50%) NSCLC cohort of patients treated with first-line pembrolizumab monotherapy. Kinetics over the first year of treatment were assessed at baseline (T0) and at 21 days (T1), 3 months (T2), 6 months (T3) and at 1 year (T4) post-treatment initiation. Associations with clinical outcomes were explored after a 2-year follow-up period. Results: In total, 31 patients with PD-L1 high locally advanced or metastatic NSCLC were prospectively enrolled. Over the first year of treatment, levels of CRP, IL-17α, IL-6, and IL-8 were significantly decreased. Early kinetics analysis showed significant decrease in total leukocytes, neutrophils, CRP, and MIP-3α/CCL20, as well as significant transient elevation of ITAC/CXCL11, IL-1β, IL-7, and TNFα, during the first 3 months of treatment. Early percent changes (Δ% at T1 and at T2) of ‘low’ vs. ‘high’ pretreatment levels showed significant differences for LDH, ITAC/CXCL11, GM-CSF, MIP-1α/CCL3, IL-2, IL-4, IL-5, and sPD-L1. Longitudinal analysis, stratified per responders and for pre-progression fluctuations, did not reveal significant findings. Among markers with acceptable discriminative performance, higher baseline CRP, complement C4, and IL-6 levels were associated with poorer clinical outcomes. In multivariable analysis, only C4 retained independent prognostic significance; however, integration of these PBIMs into composite indices improved prognostic performance. Conclusions: In this prospective study, longitudinal monitoring of PBIMs provided descriptive insights into immune and inflammatory dynamics during pembrolizumab treatment; however, no significant associations were observed between in-treatment biomarker kinetics and clinical outcomes. In exploratory analyses, baseline CRP, complement C4, and IL-6 levels were associated with clinical outcomes, and their integration into composite indices improved prognostic performance. These findings suggest that specific baseline PBIMs may carry prognostic relevance, while the role of in-treatment monitoring remains to be further clarified in larger prospective studies. Full article

Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening inflammatory dermatosis increasingly recognized as a distinct disease entity rather than a variant of plaque psoriasis. Emerging evidence indicates that GPP is primarily driven by dysregulation of the interleukin-36 (IL-36) signaling axis, leading to amplification of proinflammatory cascades in keratinocytes and a predominantly innate, neutrophil-driven immune response. This promotes rapid neutrophil recruitment, sterile pustule formation, and abrupt cutaneous and systemic inflammation. Consistent with this, GPP demonstrates a greater predominance of innate immune and neutrophil-driven inflammation, whereas plaque psoriasis is more strongly associated with IL-23/Th17-mediated adaptive immune responses. Transcriptomic and genetic studies further support this distinction, demonstrating enrichment of IL-36-associated and neutrophil-related signatures, activation of MyD88-dependent pathways, and mutations in genes regulating the IL-36 axis, including IL36RN, AP1S3, and CARD14. Consequently, conventional systemic therapies and biologics targeting TNF-α, IL-17, and IL-23 pathways show variable efficacy and may act more slowly in GPP. In contrast, IL-36 receptor inhibitors represent a more mechanism-aligned approach and have demonstrated rapid and clinically meaningful responses in acute flares. However, important gaps remain, including the lack of validated biomarkers and limited data on long-term treatment outcomes. This review provides an integrated perspective on IL-36-driven inflammation in GPP, including comparison with plaque psoriasis, and outlines its implications for mechanism-based therapeutic approaches. Full article

TRAF3 (TNF Receptor Associated Factor 3) is a regulator of NF-κB signaling, acting mainly as an inhibitor of the alternative NF-κB pathway. While TRAF3 has a well-established role in immune function, mainly via B- and T-lymphocyte regulation, its roles in cancer remain unclear. Breast cancer is the most common malignancy in women and a neoplasm displaying high levels of intratumoral heterogeneity. Identifying and understanding key molecules at the interface of breast cancer cells and the immune system is crucial for advancing therapeutic strategies for breast cancer patients. Here, by employing publicly available breast cancer datasets, breast cancer cell lines stably expressing TRAF3, mass spectrometry analysis in combination with functional assays, co-culture systems, and signal pathway characterization, we sought to assess the specific role of TRAF3 in breast cancer cells and how TRAF3-expressing breast cancer cells affect their immune microenvironment. Our results indicate that TRAF3 protein overexpression inhibits colony formation through apoptosis regulation. Proteome analysis for TRAF3 interactors and over-representation analysis identified multiple protein complexes related to cell cycle, apoptosis, and immune responses. Furthermore, TRAF3-expressing breast cancer cells displayed reduced levels of PD-L1 and when co-cultured with PBMCs induced a pro-inflammatory profile with increased CD16-NK cells and higher levels of IFN-γ and TNF-α and lower IL-10 and Tregs in the culture. These findings further expand the role of TRAF3 in breast cancer, not only as a regulator of EMT and survival of cancer cells, but also as a modulator of the tumor-immune microenvironment. Full article

Psoriasis is an immune-mediated inflammatory disease with a genetic component, characterized by dysregulation of cytokine signaling and activation of T lymphocytes. This study investigated genetic variants associated with psoriasis, psoriatic arthritis (PsA), and response to tumor necrosis factor alpha (TNF-α) inhibitors (adalimumab, infliximab, and etanercept) in a Russian cohort. A genome-wide association study (GWAS) was conducted in 1026 psoriasis patients and 9212 controls using Infinium Global Screening Array-24 v3.0 microarrays. Exploratory analyses of treatment response (n = 48) and PsA (n = 96) were performed without covariate adjustment or explicit modeling of population structure. Polygenic risk scores (PRS) were derived from internally estimated effect sizes in a split-sample design. The GWAS replicated a robust association in the major histocompatibility complex (MHC) region (rs12189871 near HLA-C, p = 3.2 × 10⁻⁵⁰, OR = 2.99 [2.59–3.45]). Additional loci included variants in ZC3H8 and PLCL2. Nominal signals were observed for IL18R1/IL18RAP in treatment response (including rs17027071) and for RCL1 and FBLIM1 in PsA; these findings remain exploratory. PRS demonstrated moderate predictive performance (AUC = 0.6355) and should be interpreted with caution given the study design. Overall, the results highlight a strong MHC signal in psoriasis, while findings for PsA and treatment response remain hypothesis-generating and require independent validation. Full article

Cervical cancer constitutes a major global health burden with a high incidence rate. Despite its well-established role in genome stability and cell cycle regulation, its specific anti-tumor mechanism involving the induction of a senescence-like state remains unclear. To determine whether Mg²⁺ impedes cervical cancer progression through the induction of a senescence-like phenotype via the ATM/CHK2/p21 pathway, HeLa cells were used in this study. Cell proliferation, migration, and invasion were measured using CCK-8, EdU, wound-healing, and Transwell assays, while SA-β-gal staining and western blotting served to examine both senescence-related markers and pathway protein expression. A BALB/c nude mouse xenograft model was established to evaluate tumor growth and safety following intratumoral Mg²⁺ injection. The results showed that Mg²⁺ inhibited proliferation, migration, and invasion in a concentration-dependent manner. Treatment with 20 mM Mg²⁺ increased SA-β-gal positivity, decreased Lamin B1 expression, and activated the ATM/CHK2/p21 pathway; moreover, this upregulation of p21 was reversed by an ATM inhibitor. ELISA revealed that 10 mM Mg²⁺ enhanced IL-6 and TNF-α secretion, confirming effective induction of the senescence-associated secretory phenotype, while higher concentrations diminished this effect, which may be partly attributed to the reduction in cell viability. In vivo experiments showed that Mg²⁺ inhibited tumor growth without notable alterations in body weight, liver and kidney function, or serum magnesium levels. In summary, the localized high concentration of magnesium ions induces cells to enter a senescence-like state via the ATM/CHK2/p21 pathway, thereby selectively suppressing malignant cellular behaviors. Notably, its in vivo efficacy and safety profile in vivo are favorable. It is also worth noting that these findings should be interpreted within the context of a preclinical, high-dose local Mg²⁺ model. Full article