Search Results (24,298)

Cellular senescence is closely connected with cancer progression, recurrence, and metastasis. Senotherapy aims to soothe the harmful effects of senescent cells either by inducing their apoptosis (senolytic) or by suppressing the senescence-associated secretory phenotype (SASP) (senomorphic). Fisetin, a well-studied senotherapeutic drug, was selected for this study to evaluate its efficiency when delivered in a liposomal formulation. The experiment evaluated the impact of liposome-encapsulated fisetin on senescent cells induced by doxorubicin (DOX) from two cell lines: WI-38 (normal lung fibroblasts) and A549 (lung carcinoma). Senescence was characterized by SA-β-galactosidase (SA-β-gal) activity, proliferation, morphology, and secretion of pro-inflammatory interleukin 6 (IL-6) and interleukin 8 (IL-8). Due to fisetin’s hydrophobic nature, it was encapsulated in liposomes to enhance cellular delivery. Cellular uptake studies confirmed that the liposomes were effectively internalized by both senescent cell types. Treatment with fisetin-loaded liposomes revealed a lack of senolytic effects but showed senomorphic activity, as evidenced by a significant reduction in IL-6 and IL-8 secretion in senescent cells. The liposomal formulation enhanced fisetin’s therapeutic efficacy, showing comparable results even at the lowest tested concentration. Full article

Leptospirosis is a globally significant zoonosis affecting animal health, productivity, and the environment. While typically associated with tropical climates, its persistence in semi-arid regions such as La Laguna, Mexico—characterized by low humidity, high temperatures, and limited water sources—remains poorly understood. Although these adverse environmental conditions theoretically limit the survival of Leptospira, high livestock density and synanthropic reservoirs (e.g., rodents) may compensate, facilitating transmission. In this cross-sectional study, blood sera from 445 dairy cows (28 herds: 12 intensive [MI], 16 semi-intensive [MSI] systems) were analyzed via microscopic agglutination testing (MAT) against 10 pathogenic serovars. Urine samples were cultured for active Leptospira detection. Risk factors were assessed through epidemiological surveys and multivariable analysis. This study revealed an overall apparent seroprevalence of 27.0% (95% CI: 22.8–31.1), with significantly higher rates in MSI (54.1%) versus MI (12.2%) herds (p < 0.001) and an estimated true seroprevalence of 56.3% (95% CI: 50.2–62.1) in MSI and 13.1% (95% CI: 8.5–18.7) in MI herds (p < 0.001). The Sejroe serogroup was isolated from urine in both systems, confirming active circulation. In MI herds, rodent presence (OR: 3.6; 95% CI: 1.6–7.9) was identified as a risk factor for Leptospira seropositivity, while first-trimester abortions (OR:10.1; 95% CI: 4.2–24.2) were significantly associated with infection. In MSI herds, risk factors associated with Leptospira seropositivity included co-occurrence with hens (OR: 2.8; 95% CI: 1.5–5.3) and natural breeding (OR: 2.0; 95% CI: 1.1–3.9), whereas mastitis/agalactiae (OR: 2.8; 95% CI: 1.5–5.2) represented a clinical outcome associated with seropositivity. Despite semi-arid conditions, Leptospira maintains transmission in La Laguna, particularly in semi-intensive systems. The coexistence of adapted (Sejroe) and incidental serogroups underscores the need for targeted interventions, such as rodent control in MI systems and poultry management in MSI systems, to mitigate both zoonotic and economic impacts. Full article

Background/Objectives: Constitutive activation of the PI3K/AKT/mTOR signaling cascade underlies the aggressive phenotype of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA); however, a quantitative synthesis of in vitro data on pathway inhibition remains lacking. This systematic review and meta-analysis aimed to (i) aggregate standardized effects of pathway inhibitors on proliferation, apoptosis, migration/invasion, IL-6/IL-8 secretion, p-AKT, and LC3; (ii) assess heterogeneity and identify key moderators of variability, including stimulus type, cell source, and inhibitor class. Methods: PubMed, Europe PMC, and the Cochrane Library were searched up to 18 May 2025 (PROSPERO CRD420251058185). Twenty of 2684 screened records met eligibility. Two reviewers independently extracted data and assessed study quality with SciRAP. Standardized mean differences (Hedges g) were pooled using a Sidik–Jonkman random-effects model with Hartung–Knapp confidence intervals. Heterogeneity (τ², I²), 95% prediction intervals, and meta-regression by cell type were calculated; robustness was tested with REML-HK, leave-one-out, and Baujat diagnostics. Results: PI3K/AKT/mTOR inhibition markedly reduced proliferation (to –5.1 SD), IL-6 (–11.1 SD), and IL-8 (–6.5 SD) while increasing apoptosis (+2.7 SD). Fourteen of seventeen outcome clusters showed large effects (|g| ≥ 0.8), with low–moderate heterogeneity (I² ≤ 35% in 11 clusters). Prediction intervals crossed zero only in small k-groups; sensitivity analyses shifted pooled estimates by ≤0.05 SD. p-AKT and p-mTOR consistently reflected functional changes and emerged as reliable pharmacodynamic markers. Conclusions: Targeted blockade of PI3K/AKT/mTOR robustly suppresses the proliferative and inflammatory phenotype of RA-FLSs, reaffirming this axis as a therapeutic target. The stability of estimates across multiple analytic scenarios enhances confidence in these findings and highlights p-AKT and p-mTOR as translational response markers. The present synthesis provides a quantitative basis for personalized dual-PI3K/mTOR strategies and supports the adoption of standardized long-term preclinical protocols. Full article

Due to the stroke-protective effects of dietary fiber and anthocyanin together with the synergistic interaction, we hypothesized that the functional drink containing the anthocyanins and dietary fiber-enriched functional ingredient from banana and germinated black Jasmine rice (BR) should protect against ischemic stroke. BR at doses of 300, 600, and 900 mg/kg body weight (BW) was orally given to male Wistar rats weighing 290–350 g once daily for 21 days, and they were subjected to ischemic reperfusion injury induced by temporary occlusion of the middle cerebral artery (MCAO/IR) for 90 min. The treatment was prolonged for 21 days after MCAO/IR. They were assessed for brain infarction volume, neuron density, Nrf2, MDA, and catalase in the cortex together with serum TNF-α and IL-6. Lactobacillus and Bifidobacterium spp. in feces were also assessed. Our results showed that BR improved the increase in brain infarcted volume, MDA, TNF-α, and IL-6 and the decrease in neuron density, Nrf2, catalase, and both bacteria spp. induced by MCAO/IR. These data suggest the stroke-protective effect of the novel functional drink, and the action may involve the improvement of Nrf2, oxidative stress, inflammation, and the amount of Lactobacillus and Bifidobacterium spp. Full article

Background/Objectives: Senecio scandens Buch.-Ham. is a flavonoid-rich traditional medicinal plant with established immunomodulatory properties. However, the mechanisms underlying the immunoregulatory and intestinal protective effects of its flavonoid extract (Senecio scandens flavonoids—SSF) remain unclear. This study characterized SSF’s bioactive components and evaluated its efficacy against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury. Methods: The constituents of SSF were identified using UHPLC/Q-Orbitrap/HRMS. Mice with CTX-induced immunosuppression were treated with SSF (80, 160, 320 mg/kg) for seven days. Immune parameters (organ indices, lymphocyte proliferation, cytokine, and immunoglobulin levels) and gut barrier integrity markers (ZO-1, Occludin, Claudin-1 protein expression; sIgA secretion; microbiota composition) were assessed. Network pharmacology combined with functional assays elucidated the underlying regulatory mechanisms. Results: Twenty flavonoids were identified in SSF, with six prototype compounds detectable in the blood. The SSF treatment significantly ameliorated CTX-induced weight loss and atrophy of the thymus and spleen. It enhanced splenic T- and B-lymphocyte proliferation by 43.6% and 29.7%, respectively; normalized the CD4⁺/CD8⁺ ratio (1.57-fold increase); and elevated levels of IL-2, IL-6, IL-10, TNF-α, IFN-γ, IgM, and IgG. Moreover, SSF reinforced the intestinal barrier by upregulating tight junction protein expression and sIgA levels while modulating the gut microbiota, enriching beneficial taxa (e.g., the Lachnospiraceae_NK4A136_group, Akkermansia) and suppressing pathogenic Alistipes. Mechanistically, SSF activated the TLR/MyD88/NF-κB pathway, with isoquercitrin identified as a pivotal bioactive constituent. Conclusions: SSF effectively mitigates CTX-induced immunosuppression and intestinal damage. These findings highlight SSF’s potential as a dual-functional natural agent for immunomodulation and intestinal protection. Subsequent research should validate isoquercitrin’s molecular targets and assess SSF’s clinical efficacy. Full article

(1) Insulin-like growth factor-1 (IGF-1) is a neurotrophin with anti-inflammatory properties. Neuroinflammation and stress activate peripheral immune mechanisms, which may contribute to the development of depression and anxiety in sporadic Alzheimer’s disease (sAD). This study aims to evaluate whether intracerebroventricular (ICV) premedication with IGF-1 in a rat model of streptozotocin (STZ)-induced neuroinflammation can prevent the emergence of anhedonia and anxiety-like behavior by impacting the peripheral inflammatory responses. (2) Male Wistar rats were subjected to double ICVSTZ (total dose: 3 mg/kg) and ICVIGF-1 injections (total dose: 2 µg). We analyzed the level of anhedonia (sucrose preference), anxiety (elevated plus maze), peripheral inflammation (hematological and cytometric measurement of leukocyte populations, interleukin (IL)-6), and corticosterone concentration at 7 (very early stage, VES), 45 (early stage, ES), and 90 days after STZ injections (late stage, LS). (3) We found that ICVIGF-1 administration reduces behavioral symptoms: anhedonia (ES and LS) and anxiety (VES, ES), and peripheral inflammation: number of leukocytes, lymphocytes, T lymphocytes, monocytes, granulocytes, IL-6, and corticosterone concentration (LS) in the rat model of sAD. (4) The obtained results demonstrate beneficial effects of central IGF-1 administration on neuropsychiatric symptoms and peripheral immune system activation during disease progression in the rat model of sAD. Full article

Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, frequently resulting in septic shock and multi-organ failure. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in the pathophysiology of sepsis. NETs are extracellular structures composed of chromatin DNA, histones, and granular proteins released by neutrophils through a specialized form of cell death known as NETosis. While NETs contribute to the containment of pathogens, their excessive or dysregulated production in sepsis is associated with endothelial damage, immunothrombosis, and organ dysfunction. Several NET-associated biomarkers have been identified, including circulating cell-free DNA (cfDNA), histones, MPO-DNA complexes, and neutrophil elastase–DNA complexes, which correlate with the disease severity and prognosis. Therapeutic strategies targeting NETs are currently under investigation. Inhibition of NET formation using PAD4 inhibitors or ROS scavengers has shown protective effects in preclinical models. Conversely, DNase I therapy facilitates the degradation of extracellular DNA, reducing the NET-related cytotoxicity and thrombotic potential. Additionally, heparin and its derivatives have demonstrated the ability to neutralize NET-associated histones and mitigate coagulopathy. Novel approaches include targeting upstream signaling pathways, such as TLR9 and IL-8/CXCR2, offering further therapeutic promise. Full article

Background: Ulcerative colitis (UC), characterized by chronic intestinal inflammation, epithelial barrier dysfunction, and immune imbalance demands novel ameliorative strategies beyond conventional approaches. Methods: In this study, the probiotic properties of Lactobacillus paracasei L21 (L. paracasei L21) and its ability to ameliorate colitis were evaluated using an in vitro lipopolysaccharide (LPS)-induced intestinal crypt epithelial cell (IEC-6) model and an in vivo dextran sulfate sodium (DSS)-induced UC mouse model. Results: In vitro, L. paracasei L21 decreased levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-8) while increasing anti-inflammatory IL-10 levels (p < 0.05) in LPS-induced IEC-6 cells, significantly enhancing the expression of tight junction proteins (ZO-1, occludin, claudin-1), thereby restoring the intestinal barrier. In vivo, both viable L. paracasei L21 and its heat-inactivated postbiotic (H-L21) mitigated weight loss, colon shortening, and disease activity indices, concurrently reducing serum LPS and proinflammatory mediators. Interventions inhibited NF-κB signaling while activating HIF1α/AhR pathways, increasing IL-22 and mucin MUC2 to restore goblet cell populations. Gut microbiota analysis showed that both interventions increased the abundance of beneficial gut bacteria (Lactobacillus, Dubococcus, and Akkermansia) and improved faecal propanoic acid and butyric acid levels. H-L21 uniquely exerted an anti-inflammatory effect, marked by the regulation of Dubosiella, while L. paracasei L21 marked by the Akkermansia. Conclusions: These results highlight the potential of L. paracasei L21 as a candidate for the development of both probiotic and postbiotic formulations. It is expected to provide a theoretical basis for the management of UC and to drive the development of the next generation of UC therapies. Full article

Lotus corniculatus L. is a valuable fodder legume, recognized for its ecological adaptability and high potential for production and fodder quality. In this study, 18 genotypes collected from wild flora were analyzed to highlight genetic variability and facilitate the selection of genotypes with superior potential. The collection area was in the western part of Romania and featured a diverse topography, including parts of the Banat Plain, the Banat Hills, and the Southern and Western Carpathians. The genotypes selected from the wild flora were cultivated and evaluated for morpho-productive and forage quality traits, including pod weight, average number of seeds/pods, green mass production, and protein percentage. PCA highlighted the main components explaining the variability, and K-means clustering allowed for the identification of groups of genotypes with similar performances. ANOVA showed statistically significant differences (p < 0.001) for all traits analyzed. According to the results, genotypes LV-LC-3, LV-LC-4, LV-LC-6, and LV-LC-16 showed high productive potential and were highlighted as the most valuable for advancing in the breeding program. The moderate relationships between traits confirm the importance of integrated selection. The identified genetic variability and selected genotypes support the implementation of effective breeding strategies to obtain high-performance Lotus corniculatus L., adapted to local soil and climate conditions and with a superior forage yield. Full article

This research examined the impact of dietary supplementation with Phlogacanthus pulcherrimus extract (PPE) on the growth, disease resistance, and expression of immune-, growth-, and antioxidant-related genes in Labeo chrysophekadion. Over 150 days, 90 fish from each group were fed diets with 0 (control), 0.25, 0.50, or 0.75 g/kg of PPE. Phytochemical analysis revealed phenolics (96.00 mg GAE/g), flavonoids (17.55 mg QE/g), anthraquinones, and triterpenoids, along with moderate antioxidant activity (IC₅₀ = 1314.08 μg/mL). One-way ANOVA of growth indices, including weight gain, specific growth rate, feed conversion ratio, and survival rate, revealed no significant differences (p > 0.05); however, PPE supplementation significantly enhanced immune and antioxidant gene expression. IL-1β was significantly (p < 0.05) upregulated at all doses, with the highest expression observed at 0.50 g/kg, showing a fivefold increase compared to the control. In addition, the highest relative expressions of IGF-1 and CAT were found at 0.75 g/kg, with 4.5-fold and 3.5-fold increases compared to the control, respectively. PPE at 0.75 g/kg decreased the cumulative mortality rate (CMR) by 20% compared to the control group, which had a CMR of 50% following exposure to Aeromonas hydrophila. PPE acted as an effective immunostimulant and antioxidant, supporting reduced antibiotic reliance in aquaculture. 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: Septic arthritis is an orthopedic emergency. However, optimal biomarkers and diagnostic criteria remain unclear. The study aimed to evaluate the diagnostic performance of routinely used and novel biomarkers, including serum C-reactive protein (CRP), synovial white blood cells (WBC), pentraxin-3 (PTX3), interleukin-6 (IL-6), and presepsin, in distinguishing septic from non-septic arthritis. Methods: Thirty-one patients undergoing arthrocentesis were included. Patients were categorized into septic and non-septic arthritis groups. Synovial fluid and serum samples were analyzed for five biomarkers. Diagnostic performance was assessed by calculating the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Synovial WBC demonstrated the highest diagnostic performance among single biomarkers (AUC = 0.837, p = 0.012). Among novel biomarkers, PTX3 showed the highest accuracy and sensitivity. The serum CRP and synovial WBC combination yielded an AUC of 0.853, with 100% sensitivity, 68.0% specificity, 42.9% PPV, and 100% NPV. Adding all three novel biomarkers to this combination increased the AUC to 0.887 (p = 0.004), maintaining 100% sensitivity and NPV. When individually added, PTX3 achieved 100% sensitivity and NPV, while presepsin showed the highest specificity (96.0%), PPV (75.0%), and accuracy (87.1%). Conclusions: Serum CRP and synovial WBC remain essential biomarkers for diagnosing septic arthritis; however, combining them with PTX3, IL-6, and presepsin improved diagnostic accuracy. PTX3 is best suited for ruling out septic arthritis due to its high sensitivity and NPV, whereas presepsin is more useful for confirmation, given its specificity and PPV. These results support a tailored biomarker approach aligned with diagnostic intent. Full article

Activation of macrophages plays a key role in both inflammation and oxidative stress, key features of many chronic diseases. Pro-inflammatory M1-like macrophages, in particular, contribute to pro-oxidative environments and are a frequent focus of immunological research. This research examined the effects of kiwifruit allergen Act d 1, in comparison to LPS, on THP-1 macrophages in vitro differentiated under optimized conditions, both in the presence and in the absence of selected vanilloids. THP-1 monocyte differentiation was optimized by varying PMA exposure and resting time. Act d 1 induced M1-like phenotypic changes comparable to LPS, including upregulation of CD80, IL-1β and IL-6 secretion, gene expression of iNOS and NF-κB activation, in addition to increased reactive oxygen species (ROS) and catalase activity. Treatment with specific vanilloids mitigated these responses, primarily through reduced oxidative stress and NF-κB activation. Notably, vanillin (VN) was the most effective, also reducing CD80 expression and IL-1β levels. These results suggest that vanilloids can affect pro-inflammatory signaling and oxidative stress in THP-1 macrophages and highlight their potential to alter inflammatory conditions characterized by similar immune responses. Full article

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly targets host cytoskeletal proteins for metabolic–immune regulation. Using an innovative GST pull-down/mass spectrometry approach, we made the seminal discovery of β-actin (ACTB) as the primary host target of ENO1—the first reported bacterial effector–cytoskeleton interaction mediating metabolic reprogramming. ENO1–ACTB binding depends on a hydrogen bond network involving ACTB’s 117Glu and 372Arg residues. This interaction triggers (1) glycolytic activation via Glut1 upregulation, establishing Warburg effect characteristics (lactic acid accumulation/ATP inhibition), and (2) ROS-mediated activation of dual inflammatory axes (HIF-1α/IL-1β and IL-6/TNF-α). This work establishes three groundbreaking concepts: (1) the first evidence of a pathogen effector hijacking host ACTB for metabolic manipulation, (2) a novel ‘glycolysis–ACTB–ROS-inflammation’ axis, and (3) the first demonstration of bacterial proteins coordinating a Warburg effect with cytokine storms. These findings provide new targets for anti-infection therapies against Mycoplasma bovis. Full article

Introduction: Chronic kidney disease (CKD) increases cardiovascular risk through mechanisms such as oxidative stress and the accumulation of advanced glycation end products (AGEs). Glycated albumin (GA) is associated with cardiovascular risk in CKD patients, but its relationship with AGEs and systemic inflammation remains unclear. This study investigated these associations in old patients with severe CKD, with and without diabetes. Methods: We conducted a cross-sectional analysis in 122 patients aged ≥ 65 years with CKD stages G3a–G5, including 67 diabetics and 55 non-diabetics. Patients with confounding comorbidities were excluded. We measured GA, AGEs, various AGEs receptors (RAGE) isoforms, and inflammatory cytokines (CRP, IL-6, TNFα, and MCP-1) using standardized assays. Statistical analyses included group comparisons, correlation coefficients, and multivariate regression. Results: Of 122 patients (mean age 77.7 ± 11.3 years), diabetics had higher GA percentages than non-diabetics (22.0 ± 7.1% vs. 17.5 ± 5.4%, p = 0.0001), while AGEs (2931 ± 763 vs. 3156 ± 809 AU; p = 0.118) and inflammatory markers (CRP 0.240[0.380] vs. 0.200[0.280] mg/dL; p = 0.142; IL-6 3.4[4.0] vs. 3.0[3.8] pg/mL; p = 0.238) were similar between groups. Overall, GA was inversely correlated with estimated glomerular filtration rate (eGFR) (ρ = −0.189, p = 0.037) and positively with glycated hemoglobin (HbA1c) (ρ = 0.525, p < 0.0001), but showed no significant correlation with AGEs, RAGE isoforms, or inflammatory cytokines. In multivariate analysis, only HbA1c remained independently associated with GA (β = 0.222, p = 0.005). Conclusions: In old patients with severe CKD, GA appears to be a more useful marker of glycemic control than glycation stress, the latter of which is the result of multiple factors, including impaired kidney function and systemic inflammation. Full article