Search Results (81)

Chronic stress adversely affects and compromises physiological well-being in humans, inducing hepatic injury, with its pathogenesis mechanistically linked to alterations in macrophage polarization and the regulation of the inflammatory microenvironment. Chlorogenic acid (CGA), a principal active component of Lonicera japonica (honeysuckle), has been shown to have therapeutic effects on various liver diseases. However, the specific mechanism by which CGA confers hepatoprotective effects through the modulation of macrophage polarization and inflammatory responses remains unclear. In this study, rats were subjected to 6 h of daily restraint stress for 21 consecutive days, with the experimental group receiving concurrent administration of CGA (100 mg/kg, via gavage). The results demonstrated that CGA intervention effectively mitigated chronic stress-induced impairments in growth performance and hepatic structural and functional integrity. CGA significantly inhibited M1 macrophage polarization and the expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), while simultaneously promoting M2 polarization and the expression of the anti-inflammatory cytokine IL-10. Furthermore, the administration of CGA was found to inhibit the activation of the JAK2/STAT3 signaling pathway. Additionally, the use of the JAK2/STAT3 signaling pathway inhibitor, S3I-201, demonstrated effects similar to those observed with CGA treatment. In summary, CGA modulates macrophage polarization and the inflammatory response through the regulation of the JAK2/STAT3 signaling pathway, thereby mitigating the liver injury induced by chronic stress. Full article

Canine atopic dermatitis (cAD) is a chronic, pruritic, inflammatory skin disease with complex immunopathogenesis involving dysregulated cytokine networks. In recent years, targeted therapies have transformed the management of cAD by directly or indirectly modulating cytokine activity. Lokivetmab, a monoclonal antibody neutralizing interleukin-31, represents a breakthrough in veterinary dermatology, providing rapid and sustained reduction in pruritus with a favorable safety profile. Janus kinase inhibitors, including oclacitinib and the newer ilunocitinib, act downstream by blocking cytokine signal transduction, offering effective control of both acute and chronic phases of disease. Ciclosporin, a calcineurin inhibitor, remains a valuable immunosuppressant for long-term cAD management, while topical tacrolimus provides localized benefits. Together, these therapies mark a paradigm shift from non-specific immunosuppressants to precision medicine. In this context, precision medicine refers to therapeutic strategies that selectively target key cytokines or intracellular signaling pathways central to the pathogenesis of cAD, such as IL-31 or the JAK/STAT axis. Unlike traditional immunosuppressants such as glucocorticoids, which exert broad and non-selective immune suppression, these agents modulate defined molecular mechanisms, thereby improving efficacy and minimizing adverse effects. Consequently, they enable improved quality of life for affected dogs and their owners. Future strategies will likely focus on patient stratification and personalized approaches based on immunological endotypes. Full article

Despite advances in lipid-lowering and antithrombotic therapy, patients with acute coronary syndromes remain at elevated risk for recurrent events due to persistent atherosclerotic inflammation. This review evaluates inflammation as a therapeutic target in secondary prevention and discusses established, investigational, and emerging strategies. Colchicine, now FDA-approved for cardiovascular risk reduction, lowered major adverse cardiovascular events in COLCOT and LoDoCo2. Canakinumab (IL-1β inhibition) reduced recurrent events in proportion to IL-6 and hsCRP suppression, while ziltivekimab (IL-6 inhibition) achieved profound biomarker reductions but remains investigational. Early-phase studies of anakinra (IL-1 receptor antagonist) and dapansutrile (oral NLRP3 inhibitor) showed anti-inflammatory effects in early trials, whereas varespladib and darapladib illustrated the challenges of targeting lipid-associated pathways. Beyond direct immunomodulators, GLP-1 receptor agonists and SGLT2 inhibitors provide both cardioprotective and anti-inflammatory benefits, reinforcing their expanding role post-ACS. Additional emerging avenues include triptolidiol, dasatinib, and BTK or JAK/STAT inhibitors, while novel approaches, such as nanozyme delivery systems and CRISPR-based editing, extend the therapeutic horizon. This review highlights the potential of inflammation-targeted therapies to advance secondary prevention in ACS by integrating current evidence and perspectives on future therapeutic developments. Full article

In chronic obstructive pulmonary disease (COPD), dysregulated calcium homeostasis, oxidative stress, and mucus hypersecretion converge to suppress ciliary beat frequency (CBF), thereby compromising mucociliary clearance (MCC). These mechanisms are subject to pharmacological modulation. Long-acting muscarinic antagonists (LAMAs) exert direct cilia-stimulatory effects and may counteract pathogen-induced mucin overproduction without impairing clearance. Long-acting β₂-agonists (LABAs) enhance ciliary activity through the cAMP–PKA–dynein (cyclic adenosine monophosphate–protein kinase A–dynein) signalling pathway. Inhaled corticosteroids (ICSs), although largely neutral on CBF, provide indirect protection by suppressing IL-13–driven inflammation. Phosphodiesterase (PDE)-4 inhibitors sustain intracellular cAMP and promote ciliary motility, though their clinical use remains limited by adverse effects. Emerging evidence suggests that dual and triple therapies may provide additive or synergistic benefits for preserving mucociliary function. Clinically, ex vivo CBF interpretation may be influenced by ongoing pharmacotherapy and tissue sampling site. Nasal brush samples may predominantly reflect systemic rather than inhaled therapy. Moreover, differences in PDE isoform expression between nasal and bronchial epithelium further complicate direct extrapolation of results. Rigorous patient stratification by treatment regimen is therefore essential to reconcile inconsistencies reported across studies. Ultimately, preservation of MCC in COPD depends on a delicate balance between oxidative stress and pharmacological modulation of ciliary function. Full article

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

Acute myocardial infarction (AMI) remains the leading cause of death worldwide, with myocardial ischemia/reperfusion injury (MIRI) emerging as a significant factor influencing patient outcomes despite timely reperfusion therapy. MIRI refers to paradoxical myocardial damage that occurs upon restoration of coronary blood flow and is driven by complex inflammatory, oxidative, and metabolic mechanisms, which can exacerbate infarct size (IS), contributing to adverse outcomes. This review explores the molecular and cellular pathophysiology of MIRI, emphasizing both its clinical and forensic relevance. The principal mechanisms discussed include oxidative stress and mitochondrial dysfunction, calcium overload and ion homeostasis imbalance, inflammatory responses, with particular focus on the NLRP3 inflammasome and cytokine pathways, and multiple forms of cell death (apoptosis, necroptosis, pyroptosis, and autophagy). Additionally, the authors present original immunohistochemical findings from autopsy cases of patients who suffered ST-segment elevation myocardial infarction (STEMI) and underwent percutaneous coronary intervention (PCI), but subsequently died. These findings underscore that successful reperfusion does not completely prevent delayed complications, like arrhythmias, ventricular fibrillation (VF), and sudden cardiac death (SCD), often caused by secondary MIRI-related mechanisms. Moreover, the case series highlight the diagnostic value of inflammatory markers for pathologists in identifying MIRI as a contributing factor in such fatalities. Finally, immunotherapeutic strategies—including IL-1 and IL-6 inhibitors such as Canakinumab and Tocilizumab—are reviewed for their potential to reduce cardiovascular events and mitigate the effects of MIRI. The review advocates for continued multidisciplinary research aimed at improving our understanding of MIRI, developing effective treatments, and informing forensic investigations of reperfusion-related deaths. Full article

Background: Inflammatory bowel disease (IBD) represents significant health challenges on a global scale, primarily encompassing Crohn’s disease and ulcerative colitis. These conditions are characterized by cycles of relapse and remission. Current treatment options, including conventional chemical therapies and biologics such as anti-Tumor Necrosis Factor α (anti-TNFα), anti-integrin, anti-interleukins 12 (IL-12) or 23 (IL-23) agents, Janus Kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1p) receptor modulators, provide symptomatic relief but do not offer a cure. These therapies are associated with both localized and systemic adverse effects, necessitating careful patient monitoring. Probiotics and prebiotics have been investigated for their potential to enhance gut microbiota diversity, which may assist in managing IBD. However, their efficacy in preventing disease flares remains limited. Recent advances in drug delivery systems, including pressure-based and pH-sensitive formulations, aim at enhancing localized treatment efficacy while minimizing adverse effects. Additionally, a pharmacogenomic approach could improve treatment personalization, optimize therapeutic outcomes, and enhance patients’ quality of life by addressing mental health needs and ensuring comprehensive follow-up care. Despite increased awareness and education among healthcare providers regarding IBD, there is still a need for clearer guidance on available treatment options. Objective: This review aims at providing deeper understanding of IBD management strategies, ultimately striving to improve the quality of care for individuals affected by this disease. Full article

Background/Objectives: The treatment landscape of psoriasis has changed dramatically with the emergence of novel biological agents such as those targeting interleukin (IL)-23. Despite their high efficacy, evidence regarding their effectiveness and tolerability in elderly patients is currently limited. The number of older adults living with psoriasis is constantly increasing, highlighting the need for evidence-based guidance focused on this population. The aim of this study was to summarize our center’s experience with the IL-23 inhibitors guselkumab and risankizumab for the treatment of moderate-to-severe psoriasis in patients aged ≥65 years. Methods: We retrospectively reviewed all charts of moderate-to-severe psoriasis patients who received at least one dose of guselkumab or risankizumab (tildrakizumab is not available for use in Greece as of this date) and included those aged ≥65 years at the time of drug initiation. Disease severity was assessed using the Psoriasis Area and Severity Index (PASI), which was calculated at baseline and each subsequent visit up to 156 weeks of treatment. Treatment responses were evaluated with the percentages of patients achieving PASI75/90/100 (reductions from baseline PASI by 75, 90, and 100%, respectively) and absolute PASI ≤ 1 and PASI ≤ 3. All adverse events (AEs) were assessed and documented. The drug survival was estimated using the Kaplan–Meier estimate. Results: In total, 93 elderly patients (64 risankizumab and 29 guselkumab) were included. Regarding risankizumab’s effectiveness, PASI75 response rates increased from 77.4% at week 12 to 90.9% at week 52 and remained stable at 90.5% by week 156. Corresponding PASI100 responses were 67.7%, 81.8%, and 80.9%, respectively. Guselkumab-treated patients exhibited PASI75 response rates of 71.4% at week 12, which improved to 91.3% at week 52 and 100% for those evaluated at week 156, with PASI100 responses of 57.1%, 73.9%, and 83.3%. During observation, 6 (9.4%) risankizumab and 2 (6.9%) guselkumab patients discontinued medication. No statistically significant differences were observed regarding drug survival between patients aged ≥65 vs. <65 years. No serious AEs occurred, and no patient discontinued medication due to AEs. Conclusions: Both guselkumab and risankizumab demonstrated sustained efficacy and persistence along with a favorable safety profile in elderly patients with psoriasis over a three-year period. While our study is limited by its retrospective nature, our findings support the use of IL-23 inhibitors in this growing patient population. Full article

Background/Objectives: Psoriasis is a chronic immune-mediated skin disease with an estimated global prevalence of 3%. Real-world studies have demonstrated that biologic therapies have transformed the management of moderate-to-severe psoriasis by providing optimal disease control and a favorable safety profile. However, a new challenge lies in identifying those most likely to achieve an early and sustained response, defined as ‘super-responders’ (SRs). This is particularly relevant given recent evidence suggesting that IL-23 inhibitors may have long-term disease-modifying effects by acting on tissue-resident memory T cells. Identifying positive and negative baseline predictors associated with achieving SR status in patients treated with anti-IL-23 agents. Methods: This retrospective observational study analyzed data from the electronic medical records of IRCCS Humanitas Research Hospital between June 2021 and June 2025. A total of 611 patients with moderate-to-severe psoriasis who were treated with risankizumab, guselkumab or tildrakizumab were included in the study. Clinical assessments were conducted at baseline and weeks 16, 28 and 52. SR status was defined as achieving a PASI score of ≤1 at week 16, with this score being maintained through weeks 28 and 52. Results: Of the 611 enrolled patients, 390 (63.8 %) achieved SR status. In multivariate logistic regression, disease duration ≤ 2 years was the strongest independent predictor (Odds Ratio [OR] 2.47, p = 0.025), followed by bio-naïve status (OR 1.53, p = 0.019). Obesity (OR 0.71, 95 % CI 0.45–1.13) and cardiometabolic comorbidities (OR 0.93, 95 % CI 0.63–1.38) were not significantly associated with response after adjustments. No serious adverse events or treatment discontinuations occurred during 52 weeks of follow-up. Conclusions: Shorter disease duration (≤2 years) and bio-naïve status were identified as independent predictors of SR status. Identifying these patients could inform the development of personalized treatment strategies, including dose optimization and extended dosing intervals. Full article

The use of immune checkpoint inhibitors (ICIs) has increased exponentially in recent years, leading to a significant impact on cancer patient survival. However, their administration can trigger immune-mediated adverse effects, notably pulmonary toxicity, which is a potentially serious complication. ICI-induced pneumonitis has a variable incidence ranging from 5 to 19% and usually appears in the first few months of treatment. The diagnosis requires a high index of suspicion, especially in patients with risk factors (elderly male smokers with squamous cell lung cancer, previous respiratory or autoimmune disease, and receiving combination treatment with other ICIs or chemo-radiotherapy). Chest computed tomography (CT) is a key test, allowing the identification of different radiological patterns. This study can be completed with bronchoscopy with bronchoalveolar lavage (BAL) to rule out infection or tumour progression. In general terms, treatment is based on discontinuing the causative drug, with or without the initiation of systemic corticosteroids, escalating to immunosuppressants depending on the severity and/or refractoriness of the condition. This paper provides an updated narrative review of ICI pulmonary toxicity, addressing its pathophysiology, different types of lung damage, diagnostic and therapeutic algorithms, and the emerging role of biomarkers such as KL-6 or IL-6. This article emphasises the need for a multidisciplinary approach and further prospective studies to optimise the management and prognosis of this immune-mediated complication. Full article

Background/Objectives: Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have achieved clinical success but face drawbacks such as poor oral bioavailability, limited tumor penetration, and immune-related adverse events. Small-molecule inhibitors present a promising alternative that may overcome these challenges. Methods: Here, an integrated computational framework combining ligand-based pharmacophore modeling and structure-based molecular docking was utilized to screen a comprehensive library consisting of traditional Chinese medicine-derived compounds and clinically approved drugs. The binding affinity between identified candidate compounds and PD-L1 was quantitatively assessed using bio-layer interferometry (BLI). In vitro cytotoxicity assays were conducted on A549 human lung carcinoma and LLC mouse lung carcinoma cell lines. In vivo antitumor efficacy was evaluated in LLC tumor-bearing mice through measurement of tumor growth inhibition, serum cytokine levels (IFN-γ and IL-4) by ELISA, and expression levels of IFN-γ and granzyme B (GZMB) within tumor tissues via immunohistochemistry. Results: In vitro, anidulafungin exhibited anti-tumor effects against both human lung cancer A549 cells and mouse Lewis lung carcinoma (LLC) tumor cells, with IC₅₀ values of 170.6 µg/mL and 160.9 µg/mL, respectively. The BLI analysis revealed a dissociation constant (K_D) of 76.9 μM, indicating a high affinity of anidulafungin for PD-L1. In vivo, anidulafungin significantly increased serum levels of IFN-γ and IL-4 in tumor-bearing mice and elevated expression of IFN-γ and granzyme B (GZMB) in tumor tissues, confirming its immune-mediated anti-tumor effects. Conclusions: Anidulafungin represents a promising small-molecule PD-L1 inhibitor, demonstrating significant anti-tumor potential via immune activation and highlighting the feasibility of repurposing approved drugs for cancer immunotherapy. Full article

Gastric ulcer (GU) is a common gastrointestinal disorder that impacts quality of life. Currently, several drugs are available for GU treatment, including proton pump inhibitors like omeprazole (OMP); however, their use is limited by numerous potential adverse effects. Glycyrrhizic acid (GLY), a natural anti-inflammatory agent, exhibits promising gastroprotective properties; however, its use is likewise limited by numerous potential adverse effects. This study aimed to synthesize GLY nanoparticles (GLY-NPs) to enhance their therapeutic potential and to comparatively evaluate their efficacy against OMP in an ethanol-induced GU in male Wistar rats. GLY-NPs were synthesized via a hydrothermal method and characterized using TEM, XRD, FTIR, and zeta potential analyses. In vivo, GLY-NPs significantly attenuated gastric mucosal damage compared to OMP, as evidenced by macroscopic and histopathological analyses. Biochemical assays revealed that GLY-NPs markedly improved antioxidant defenses by elevating SOD, catalase, and glutathione peroxidase activities while reducing MDA levels, surpassing the effects of OMP. Furthermore, GLY-NPs modulated inflammatory responses by downregulating p38 MAPK, NF-κB, and TNF-α expression, concomitant with upregulation of the anti-inflammatory cytokine IL-10. Mechanistic insights indicated that GLY-NPs favorably regulated key signaling pathways implicated in gastric mucosal protection, including suppression of the JAK2/STAT3 and TGF-β1/Smad3 pathways, alongside activation of the SIRT1/FOXO1/PGC-1α axis. In conclusion, these findings indicate that GLY-NPs offer higher gastroprotective effects relative to traditional OMP therapy through comprehensive modulation of oxidative stress, inflammation, and molecular signaling pathways. This study highlights GLY-NPs as a potent nanotherapeutic candidate for the effective management of GU. Full article

Background: Bimekizumab, secukinumab, and ixekizumab are IL-17-targeting biologics approved for the treatment of moderate-to-severe plaque psoriasis. While secukinumab and ixekizumab selectively inhibit IL-17A, bimekizumab targets both IL-17A and IL-17F, potentially providing greater anti-inflammatory efficacy. This study aimed to compare the real-world effectiveness, safety, and tolerability of these agents in a Polish dermatology center between 2019 and 2024. Methods: We conducted a retrospective analysis of 98 patients meeting at least one of the following criteria: PASI ≥ 10, BSA ≥ 10, DLQI ≥ 10, or involvement of special areas with inadequate response or contraindications to ≥2 systemic therapies. Patients with prior exposure only to IL-17 inhibitors were excluded. PASI, BSA, and DLQI scores were recorded at baseline, week 4, and week 12. Due to differences in dosing schedules, outcomes were aligned using standardized timepoints and exponential modeling of continuous response trajectories. Mixed-effects ANOVA was used to assess the influence of baseline factors (age, BMI, PsA status) on treatment outcomes. Adverse events were documented at each monthly follow-up visit. Results: Bimekizumab showed the greatest effect size for PASI reduction (Hedges’ g = 3.662), followed by secukinumab (2.813) and ixekizumab (1.986). Exponential modeling revealed a steeper response trajectory with bimekizumab (intercept = 0.289), suggesting a more rapid PASI improvement. The efficacy of bimekizumab was particularly notable in patients who were previously treated with IL-23 inhibitors. All three agents demonstrated favorable safety profiles, with no serious adverse events or discontinuations. The most frequent adverse events were mild and included upper respiratory tract infections and oral candidiasis. Conclusions: This real-world analysis confirmed that IL-17 inhibitors effectively improved PASI, BSA, and DLQI scores in moderate-to-severe psoriasis. Bimekizumab demonstrated the most rapid early improvements and a higher modeled likelihood of complete clearance, without significant differences at week 12. All agents were well tolerated, underscoring the need for further individualized, large-scale studies. Full article

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet severe immune-related adverse events (irAEs) often necessitate immunotherapy discontinuation and cause life-threatening complications. Circulating plasma proteins, dynamically accessible and functionally linked to immunity, may predict and offer novel targets for irAEs. Methods: Leveraging multi-omics integration, we conducted bidirectional two-sample Mendelian randomization (MR) using protein quantitative trait loci (pQTLs) from 4998 plasma proteins and genome-wide association data of irAE phenotypes. A causal inference framework combining colocalization analysis, multivariable MR (MVMR) adjusting for body mass index (BMI) confounding, and mediation MR elucidated BMI-independent pathways. Systems biology approaches including tissue-specific expression profiling, pathway enrichment, and protein interaction network analysis revealed spatial and functional drivers of irAE pathogenesis. Results: Proteome-wide MR mapping identified eight plasma proteins (CCL20, CSF1, CXCL9, CD40, TGFβ1, CLSTN2, TNFSF12, TGFα) causally associated with all-grade irAEs, and five (CCL20, CCL25, CXCL10, ADA, TGFα) with high-grade irAEs. Colocalization prioritized CD40/TNFSF12 (all-grade) and ADA/CCL25 (high-grade) as therapeutic targets (PPH4 > 0.7). CXCL9/TNFSF12 (all-grade) and CCL25 (high-grade) exerted BMI-independent effects, suggesting intrinsic immune dysregulation mechanisms. Tissue-specific gene expression patterns, CSF1, TGFβ1 in lung, TNFSF12 in the ileum may explain organ-specific irAE vulnerabilities. High-grade irAEs correlated with compartmentalized immune dysregulation and IL-17/immunodeficiency pathway activation. Conclusions: This study establishes the causal atlas of plasma proteins in irAE pathogenesis, bridging biomarker discovery with actionable therapeutic targets. These advances align with next-generation immunotherapy goals: maximizing efficacy while taming the immune storm. Full article

Interleukin-23 (IL-23) is a key cytokine involved in the pathogenesis of various immuno-mediated inflammatory diseases. In recent years, several drugs selectively targeting IL-23 have been developed and three of them (mirikizumab, risankizumab and guselkumab) were successfully investigated in clinical trials for ulcerative colitis (UC). All of them showed a good profile for efficacy, alleviating symptoms, and inducing endoscopic and histologic improvement, with very low incidence of adverse events. Bowel urgency also emerged as a crucial outcome from patients’ perspective in the mirikizumab trials. The correct positioning of IL-23 inhibitors in the therapeutic algorithm for UC represents a new challenge for physicians, especially because it is not guided by biomarkers or predictors of effectiveness. Moreover, no comparative clinical data exist among the available IL-23 inhibitors, although molecular differences might potentially impact their effectiveness. A role for IL-23-inhibitors may also lie in combination with drugs with different mechanisms of action for complex, multi-refractory patients. This review, focusing on UC, summarizes all the clinical data available on IL-23 inhibitors and provides a perspective on the best clinical scenarios to maximize their effectiveness. Full article