Search Results (1,091)

Polyporusterone B, a triterpene carboxylic acid isolated from Polyporus umbellatus Fries, exhibits anti-cancer and anti-hemolytic activities; however, its anti-inflammatory properties and underlying mechanisms remain unelucidated. We studied the anti-inflammatory effects of Polyporusterone B using lipopolysaccharide (LPS)-stimulated Raw264.7 murine macrophages (in vitro) and LPS-induced endotoxin shock in C57BL/6 mice (in vivo). Results showed that Polyporusterone B (1, 5, and 10 μM) had no cytotoxicity toward Raw264.7 cells, but significantly inhibited LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines (tumor necrosis factor (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6)) in a concentration- and time-dependent manner, as demonstrated by Griess assay, qPCR, and ELISA. Western blot analysis revealed that Polyporusterone B suppressed LPS-induced phosphorylation of mitogen-activated protein kinases (ERK, P38, and NK) and reduced phosphorylation-mediated degradation of inhibitor of κBα (IκBα). Immunofluorescence and immunohistochemical staining further confirmed that Polyporusterone B blocked nuclear translocation of nuclear factor kappa-B (NF-κB)/Rel A in both Raw264.7 cells and mouse tissues. In the in vivo model, Polyporusterone B pretreatment significantly mitigated LPS-induced multi-organ pathological damage (e.g., lung edema, hepatic inflammation, renal hemorrhage) and downregulated tissue levels of TNF-α, IL-1β, and IL-6. These findings suggest that Polyporusterone B exerts anti-inflammatory effects by inhibiting the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, suggesting its potential as a therapeutic candidate for inflammatory diseases. Full article

Background: The growing number of ulcerative colitis (UC) treatments has complicated the selection process. We hypothesized that the degree of epithelial neutrophilic infiltration, which is a hallmark of interleukin-23 (IL-23) pathway activation, could guide personalized therapy. Methods: This single-center, prospective study included 42 patients with active UC who were treated between July 2024 and September 2025. The study was registered (NCT 06626165) on 20 July 2024. Prior to treatment, all patients underwent colonoscopy with biopsy. Using a refined subclassification of the Geboes histopathology score, patients were stratified into two groups based on the percentage of crypts with neutrophilic infiltration: Grade ≥ 3.2 and Grade < 3.2. The primary outcome was clinical remission at four weeks. The secondary outcome was endoscopic remission at six months. Results: Of the 42 patients, 22 were classified as Grade ≥ 3.2, and 20 were classified as Grade < 3.2. Baseline clinical and endoscopic characteristics were similar between the two groups. All 22 patients in the Grade ≥ 3.2 group treated with mirikizumab achieved clinical remission within four weeks. Nineteen (86%) of the twenty-two patients achieved endoscopic remission within six months. All 20 patients in the Grade < 3.2 group who received vedolizumab (16) or upadacitinib (4) achieved clinical remission within the same timeframe. Both treatment strategies led to a statistically significant reduction in the inflammatory biomarker leucine-rich alpha-2-glycoprotein (LRG) (p < 0.001). Conclusions: Our findings suggest that UC patients with advanced epithelial neutrophil infiltration (Geboes Grade ≥ 3.2) may have a disease that is predominantly driven by the IL-23 pathway, making them potential candidates for selective IL-23p19 inhibitors. This histopathology-driven approach appears to be a useful strategy for tailoring treatment to patients with active UC, though further validation is required. Full article

Background/Objectives: The advent of biologics targeting key inflammatory pathways has significantly advanced psoriasis treatment. Among them, the Interleukin-23 inhibitors Guselkumab and Risankizumab have demonstrated high efficacy and rapid clinical response in both clinical trials and real-world studies. However, up to 30% of patients fail to respond. This study aimed to identify pharmacogenetic markers associated with treatment response using a genome-wide association study (GWAS) and protein network-based approach. Methods: Fifty-three patients of Greek origin with moderate-to-severe plaque psoriasis were treated with Guselkumab or Risankizumab. Based on Psoriasis Area and Severity Index (PASI) improvement at 3 and 6 months, patients were categorized as responders or non-responders. Approximately 730,000 single-nucleotide polymorphisms (SNPs) were genotyped. After filtering, a GWAS was performed to identify variants associated with treatment response. Additionally, protein–protein interaction (PPI) network analysis was applied to the two Interleukin-23 subunits and SNPs within or near genes encoding Interleukin-23-interacting proteins to test for their association. Results: The GWAS identified two novel variants, rs73641950 and rs6627462, significantly associated with treatment response, with both surpassing the genome-wide significance threshold after Bonferroni correction. The PPI-based approach revealed rs13086445, located downstream of the Interleukin-12 subunit alpha (IL12A) gene, as another associated variant. All three SNPs lie in genomic regions with potential regulatory roles. Conclusions: This study identifies three novel genetic variants associated with response to Interleukin-23 inhibitors in psoriasis. These findings provide promising pharmacogenetic markers which, upon validation in larger, independent cohorts, will enable the translation of a patient’s genotype into a response phenotype, thereby guiding clinical decisions and improving drug effectiveness. Full article

Background/Objectives: Psoriasis is currently treated with biologics targeting the IL-17A signaling, which plays a major role in immune response and keratinocyte hyperproliferation. These include inhibitors of IL-17A and/or its heterodimer with IL-17F (Secukinumab, Ixekinumab and Bimekizumab) and the receptor IL17-RA (Brodalumab). Although these drugs are safe and highly effective, there is significant variability in response among patients. This can be partly attributed to the patients’ genetic background, thus pointing to the need to identify pharmacogenetic markers for treatment response. Methods: The study involved 88 Greek patients who were treated with inhibitors of the IL-17A signaling for at least 6 months. Patients were classified as responders and non-responders according to the change in Psoriasis Area Severity Index. A total of 730,000 variants were genotyped and analyzed for association with the 3-month and 6-month responses to treatment. Results: The analysis identified 21 variants which were associated with the response, showing statistical significance after Bonferroni correction. These include variants located in protein coding genes (TP63, NRG1, SCN8A, TAF9, TMEM9, SMIM36, SYT14, BPIFC, SEZ6L2, PCARE), as well as intergenic and long non-coding RNA intronic variants. The functional significance of the variants was assessed using in silico analysis and for several variants, a link with immune processes was proposed. Notably, rs11649499 status, which was associated with complete clinical remission at 3 months, may influence key lipid mediators involved in psoriasis. Conclusions: This GWAS identified novel variants that could be utilized upon validation in larger populations as predictive markers regarding patient response to drugs targeting the IL-17A pathway. Full article

The human endometrium is unique in that it has a high potential for regeneration after menstruation without scarring. Although growth factors are thought to be responsible for scar formation, it has recently been shown for foetal skin that CD26-negative fibroblasts are essential. Thus, we investigated whether CD26 might be involved in scar formation. Primary human endometrial stromal cells (HPESCs) were stimulated with interleukin-1 alpha (IL1α) to induce CD26 protein expression, and secretion of the scar-associated proteins collagen 1 alpha 1 (COL1A1) and TGF-β3 was measured using ELISAs. The contribution of CD26 to wound closure was analysed using a wound healing assay. The CD26 inhibitor diprotin A (DPA) was used to attenuate CD26 activity. Immunohistochemistry of human uterine samples showed negligible stromal staining of CD26, but CD26 was abundant in the endometrial glands. Treatment of CD26-negative HPESCs with IL1α induced CD26 protein expression, strongly stimulated wound healing in vitro, and increased secretion of COL1A1, but decreased TGF-β3 secretion. DPA effectively attenuated all IL1α-induced effects. We suggest that the stromal non-expression of the scar-associated protein CD26 might contribute to non-scarring during endometrial wound healing. Full article

Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, plays a vital role in regulating immune responses across various infectious and inflammatory conditions. While IL-10 is essential for preventing excessive tissue damage and maintaining immune homeostasis (e.g., respiratory syncytial virus), its elevated levels could result in immunosuppression during viral infections, enabling viruses to evade host defenses (e.g., foot-and-mouth disease virus). This review aims to elucidate the mechanisms through which IL-10 mediates immunosuppression in viral infections and to explore the implications of these mechanisms for therapeutic intervention. The key scientific concepts outlined in this review include the mechanisms of IL-10 production and its varied impacts on the immune response during viral infections. Specifically, we discuss the multifaceted inhibitory effects of IL-10 on innate and adaptive immunity, including its implications for antigen presentation, T cells activation, pro-inflammatory cytokine production, immune cell differentiation, trafficking, apoptosis, and co-inhibitory expression related to T cells exhaustion. Finally, we discuss the therapeutic potential of targeting IL-10, such as monoclonal antibodies and small molecule inhibitors, and their potential to restore effective immune responses. By summarizing current knowledge on IL-10’s role in viral infections, this review offers a thorough insight into its immunosuppressive mechanisms and their therapeutic potential, paving the way for innovative treatment strategies in viral diseases. Full article

Background: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood. Methods: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine. Results: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells. Conclusions: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance. Full article

Tyrosine kinase 2 (TYK2) mediates the signaling pathways of proinflammatory cytokines such as interleukin (IL)-12, IL-23, and type I interferons (IFNs) and plays a pivotal role in the pathogenesis of psoriasis and various other immune-mediated diseases. Deucravacitinib, a selective oral TYK2 inhibitor, has been approved for the treatment of psoriasis and demonstrated high efficacy and a favorable safety profile. This review summarizes the potential for expanding deucravacitinib indications based on case reports, clinical trials, and preclinical studies. Diseases in which TYK2 pathway has been demonstrated to be involved and for which clinical benefit of deucravacitinib has been reported include discoid lupus erythematosus, systemic lupus erythematosus, alopecia areata, lichen planus, palmoplantar pustulosis, psoriatic arthritis, systemic sclerosis, interstitial pneumonia, inflammatory bowel disease, and chronic recurrent multifocal osteomyelitis. Furthermore, emerging research suggests potential therapeutic applications in neurodegenerative diseases such as Alzheimer’s disease, and malignancies such as type 1 diabetes, vascular calcification in chronic kidney disease, T-cell acute lymphoblastic leukemia, and multiple sclerosis. Deucravacitinib may exert therapeutic effects by broadly suppressing cytokine signaling in a diverse range of inflammatory disorders. Ongoing clinical trials and mechanistic studies are required to clarify the efficacy and support its future indications. Full article

Acute kidney injury (AKI) is a frequent and severe complication in trauma patients, affecting up to 28% of intensive care unit (ICU) admissions and contributing significantly to morbidity, mortality, and long-term renal impairment. Trauma-related AKI (TRAKI) arises from diverse mechanisms, including hemorrhagic shock, ischemia–reperfusion injury, systemic inflammation, rhabdomyolysis, nephrotoxicity, and complex organ crosstalk involving the brain, lungs, and abdomen. Pathophysiologically, TRAKI involves early disruption of the glomerular filtration barrier, tubular epithelial injury, and renal microvascular dysfunction. Inflammatory cascades, oxidative stress, immune thrombosis, and maladaptive repair mechanisms mediate these injuries. Trauma-related rhabdomyolysis and exposure to contrast agents or nephrotoxic drugs further exacerbate renal stress, particularly in patients with pre-existing comorbidities. Traditional markers such as serum creatinine (sCr) are late indicators of kidney damage and lack specificity. Emerging structural and stress response biomarkers—such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), C-C motif chemokine ligand 14 (CCL14), Dickkopf-3 (DKK3), and the U.S. Food and Drug Administration (FDA)-approved tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein 7 (TIMP-2 × IGFBP-7)—allow earlier detection of subclinical AKI and better predict progression and the need for renal replacement therapy. Together, functional indices like urinary sodium and fractional potassium excretion reflect early microcirculatory stress and add clinical value. In parallel, risk stratification tools, including the Renal Angina Index (RAI), the McMahon score, and the Haines model, enable the early identification of high-risk patients and help tailor nephroprotective strategies. Together, these biomarkers and risk models shift from passive AKI recognition to proactive, personalized management. A new paradigm that integrates biomarker-guided diagnostics and dynamic clinical scoring into trauma care promises to reduce AKI burden and improve renal outcomes in this critically ill population. Full article

Cellular senescence plays a critical role in tumorigenesis and is recognized as a hallmark of colorectal cancer (CRC). Emerging evidence suggests that 5-fluorouracil (5-FU)-induced senescence may contribute to chemoresistance and tumor recurrence. Here, we investigated the effect of 5-FU on colon cancer cell senescence and whether MM-129 (pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine sulfonamide) can antagonize this activity. Senescence was identified by the expression of senescence-associated β-galactosidase (SA-β-gal) and cyclin-dependent kinase inhibitor 1A (p21) using qPCR, microscopy, flow cytometry, and immunohistochemistry. We also measured interleukin 6 (IL-6) and tumor necrosis factor (TNF-α) as key SASP cytokines, along with E-cadherin (CDH1), a marker of epithelial integrity. The SIRT1/STAT3 pathway was evaluated to elucidate the mechanism of MM-129′s action. MM-129 counteracted 5-FU-induced senescence in colon cancer models, reducing p21 levels in zebrafish xenografts and the number of SA-β-gal-positive cells in vitro and in tumor tissues from DLD-1 and HT-29 mouse xenografts. MM-129 also inhibited senescence-associated responses by suppressing SASP cytokines (IL-6, TNF-α) and restoring E-cadherin (CDH1), and it modulated the SIRT1/STAT3 axis, which may underlie the observed senotherapeutic effects. In conclusion, MM-129 represents a novel senotherapeutic candidate. By modulating the SIRT1/STAT3 axis, it may suppress the SASP and weaken pro-survival signaling, thereby facilitating selective clearance of senescent cells. Integrating senotherapeutics with conventional cancer therapies may enhance efficacy and open new avenues for translational research. Full article

Background/Objectives: Large-scale bibliometric assessments of psoriasis pharmacotherapy research remain limited despite significant research output in this rapidly evolving field. This study aimed to map the evolution of systemic psoriasis therapy research over five decades and demonstrate how systematic analysis of research trajectories can illuminate the transformation of specialized medical fields into central components of precision medicine. Methods: A comprehensive bibliometric analysis was conducted using Web of Science Core Collection as the single data source, examining 19,284 publications spanning 1975–2025. The methodology employed AI-enhanced terminology normalization for standardizing pharmaceutical nomenclature, VOSviewer version 1.6.20 for network visualization, and Bibliometrix package for temporal trend analysis and thematic evolution mapping. International collaboration networks, thematic evolution across three distinct periods (1975–2000, 2001–2010, 2011–2025), and citation impact patterns were systematically analyzed. Results: Four distinct developmental phases were identified, with publications growing from 9 articles in 1975 to 1638 in 2024. The United States dominated research output with 5959 documents, while Canada achieved the highest citation efficiency at 62.65 citations per document. Global collaboration encompassed 70 countries organized into four regional clusters, with a 28-nation Asia–Pacific–Africa–Middle East alliance representing the largest collaborative group. Citation impact peaked during 2001–2008, coinciding with revolutionary biological therapy introduction. Thematic evolution demonstrated systematic transformation from two foundational themes to nine specialized domains, ultimately consolidating into four core areas focused on targeted therapeutics and evidence-based methodologies. Keyword analysis demonstrated progression from basic immunological studies to sophisticated targeted interventions, evolving from tumor necrosis factor alpha inhibitors to contemporary interleukin-17/interleukin-23 pathway targeting and Janus kinase inhibitors. Conclusions: Over five decades, psoriasis therapeutics research has shifted from a niche dermatological discipline to a central model for innovation in immune-mediated diseases. This evolution illustrates how bibliometric approaches can capture the dynamics of scientific transformation, offering strategic insights for guiding pharmaceutical innovation, shaping research priorities, and informing precision medicine strategies across inflammatory conditions. Full article

Cellular senescence is a major barrier to the therapeutic application of human mesenchymal stem cells (hMSCs), as it compromises their proliferative capacity, differentiation potential, and regenerative efficacy. In this study, we investigated whether FN9-10ELP, a recombinant extracellular matrix (ECM)-mimetic fusion protein composed of fibronectin type III domains 9 and 10 conjugated to elastin-like polypeptides (ELPs), could attenuate etoposide-induced senescence in human turbinate-derived MSCs (hTMSCs). Premature senescence was induced by treatment with 20 µM etoposide, and the protective effects of FN9-10ELP were evaluated in terms of cell viability (using the MTT assay), senescence-associated gene expression (by RT-qPCR analysis), nuclear morphology (after staining with 4’,6-diamidino-2-phenylindole (DAPI)), and SA-β-galactosidase activity. FN9-10ELP treatment significantly improved cell viability and reduced the expression of senescence-associated secretory phenotype (SASP) genes, including interleukin-6 (IL-6), interleukin-8 (IL-8), and plasminogen activator inhibitor-1 (PAI-1). Furthermore, FN9-10ELP alleviated nuclear enlargement and decreased the proportion of SA-β-gal-positive cells, indicating suppression of the senescence phenotype. These findings demonstrate that FN9-10ELP effectively counteracts chemotherapy-induced senescence in hMSCs and highlight its potential as a promising biomaterial for regenerative medicine and anti-aging therapies. Full article

Background: Diabetes mellitus (DM), periodontal disease (PD), and cardiovascular disease (CVD) are highly prevalent global health conditions with overlapping pathophysiological mechanisms. Emerging evidence suggests a bidirectional and synergistic relationship among them, driven by chronic inflammation, immune dysregulation, oxidative stress, and microbial dysbiosis. Objective: This review synthesizes current literature on the interconnectedness of DM, PD, and CVD, emphasizing shared molecular pathways, clinical implications, and opportunities for integrated management. Methods: A systematic review and narrative synthesis of recent clinical trials, observational studies, and multi-omics investigations was conducted to explore the mechanisms linking these three conditions. A structured literature search was performed across PubMed, Scopus, and Web of Science from database inception until 30 June 2025. Key findings were contextualized within systems biology, precision medicine, and real-world clinical strategies. Results: DM exacerbates periodontal inflammation and accelerates tissue destruction via hyperglycemia-induced inflammatory mediators, while periodontitis worsens glycemic control and insulin resistance. Both conditions independently elevate cardiovascular risk, and their co-occurrence significantly amplifies the incidence of adverse cardiovascular events. Shared biomarkers such as Interleukin (IL)-6, Tumor Necrosis Factor (TNF)-α, and CRP, as well as overlapping genetic and epigenetic signatures, underscore a common inflammatory axis. Periodontal therapy has demonstrated modest but meaningful benefits on glycemic control and endothelial function, while cardiometabolic therapies (e.g., statins, Glucagon-Like Peptide (GLP-1) receptor agonists, SGLT2 inhibitors) show potential to improve periodontal outcomes. Probiotics, microbiome-targeted therapies, and AI-based risk models are emerging as future tools. Conclusions: DM, PD, and CVD form a mutually reinforcing triad mediated by systemic inflammation and metabolic dysregulation. Integrated, multidisciplinary care models and precision health strategies are essential to address this inflammatory burden and improve long-term outcomes. Further large-scale interventional trials and mechanistic human studies are needed to establish causal links and optimize combined therapeutic approaches. Full article

Background/Objectives: The consumption of ultra-processed foods (UPF) has increased worldwide and has been hypothesized to contribute to chronic diseases, including conditions characterized by inflammatory dysregulation. We conducted a scoping review to map the human evidence on the relationship between UPF consumption and systemic inflammatory biomarkers. Methods: We developed a search strategy combining terms for UPF with terms for circulating inflammatory biomarkers, including C-reactive protein (CRP/hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and leptin. Findings were synthesized separately for children/adolescents and adults. Results: A total of 24 studies were included. CRP/hs-CRP was assessed in 21; IL-6 in 9; TNF-α in 8; IL-1β in 5; leptin in 5; MCP-1 in 5; PAI-1 in 5; and IL-8 in 2. In children/adolescents, CRP/hs-CRP tended to be higher with greater UPF intake in large cohorts and in preterm infants, whereas smaller or clinically selected samples did not show an association. For other biomarkers, IL-6 generally did not vary with UPF, TNF-α and IL-1β showed no association across studies, and the two IL-8 analyses yielded mixed results. In adults, 11/17 analyses reported higher CRP/hs-CRP levels with greater UPF intake, 5/17 reported no association, and 1/17 reported an association limited to women. IL-6 was predominantly higher with greater UPF intake; TNF-α likewise tended to be higher with UPF across several settings; IL-1β showed no association; MCP-1 and PAI-1 provided limited, inconsistent signals; leptin results were mixed. Conclusions: Higher UPF consumption is frequently associated with elevated systemic inflammatory biomarkers—most consistently CRP/hs-CRP—across adults and selected pediatric contexts. Signals for IL-6 and TNF-α appear in specific populations, whereas IL-1β, MCP-1, PAI-1, and leptin show inconsistent patterns. Full article

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by immune-mediated β-cell destruction, where interleukin-6 (IL-6) signaling plays a complex and context-dependent role. Tocilizumab, an IL-6 receptor (IL-6R) inhibitor, is effective in several autoimmune conditions, but its influence on the onset and progression of T1DM remains uncertain. This scoping review aimed to map current clinical, genetic, and mechanistic evidence linking IL-6/IL-6R signaling to T1DM risk and to identify key research gaps. Following PRISMA-ScR guidelines, PubMed, Embase, and Web of Science were searched for studies from 2005 to 2025 reporting associations between tocilizumab or IL-6R modulation and T1DM onset. Six studies were included: one case report describing T1DM onset during tocilizumab therapy in a genetically predisposed patient, one randomized controlled trial showing no significant β-cell preservation with tocilizumab, three Mendelian randomization analyses with conflicting findings on IL-6R signaling, and one mechanistic study showing enhanced IL-6 responsiveness in early-stage T1DM. Collectively, evidence remains fragmented and inconclusive, highlighting research gaps in the differential roles of IL-6 classic versus trans-signaling and the impact of genetic predisposition. Future prospective studies should clarify whether selective IL-6 trans-signaling blockade may offer safer, targeted strategies for modulating autoimmune β-cell destruction. Full article