Search Results (612)

Background: Brugada Syndrome (BrS) is a cardiac arrhythmia associated with an increased risk of ventricular arrhythmias and sudden cardiac arrest. Although the arrhythmic substrate is traditionally localized to the ventricles, atrial fibrillation (AF) is frequently observed, suggesting a shared molecular substrate between atrial and ventricular arrhythmias. C-type natriuretic peptide (CNP) and related microRNAs (miRNAs) modulate atrial and ventricular physiology, but their roles in exosomes in BrS have not been investigated. Objectives: To investigate alterations in CNP mRNA expression and changes in the expression of selected CNP-associated miRNAs implicated in AF, both analyzed in exosomes isolated from individuals with BrS and from healthy controls. Methods: Exosomes were isolated from the plasma of BrS patients without a history of overt AF and from healthy controls. In silico analyses identified CNP-targeting miRNAs implicated in AF. Exosomal CNP and CNP-related miRNAs were analyzed using Droplet Digital PCR. Results: BrS patients exhibited a significant increase in exosomal CNP mRNA expression levels compared with controls. MiR-138-5p was selectively downregulated, whereas other AF-related CNP-targeting miRNAs (miR-4443, miR-206, miR-142-5p, miR-223-5p) showed comparable levels between groups. A positive correlation between exosomal CNP and miR-223-5p and miR-4443 suggests shared regulatory pathways. Conclusions: these findings indicate that exosomal profiling may provide a more sensitive approach than conventional circulating measurements to detect molecular remodeling in BrS. The observed alterations highlight a potential shared molecular substrate between atrial and ventricular arrhythmias and may inform future studies aimed at refining diagnostics and developing targeted therapeutic strategies. Full article

This study aimed to identify umami peptides in non-alcoholic beer and clarify their potential contribution to taste reconstruction and aftertaste improvement. Peptides were profiled by RPLC-Q-TOF-MS and screened using machine learning prediction, molecular docking, MM-GBSA analysis, and sensory validation. Under the criteria of −10logP ≥ 15 and ALC ≥ 90.00%, 2081 peptides were identified. Among them, 122 potential umami peptides were predicted, and 117 peptides were successfully docked with the T1R1/T1R3 umami receptor. The docked peptides were mainly short to medium oligopeptides, especially tetrapeptides and pentapeptides, which accounted for 40.17% and 35.90%, respectively. Based on docking score, structural diversity, and peptide length distribution, CTGAA, IDQILG, KDTHP, QRQ, and EITGR were selected as representative candidates. These peptides showed favorable receptor binding, mainly supported by hydrogen bonding, electrostatic interactions, and local hydrophobic contacts. Sensory validation further showed that the 5 peptides improved umami and aftertaste cleanliness to different degrees. Umami intensity increased by 7.58% to 22.73%, while aftertaste cleanliness increased by 5.80% to 17.39%. Among them, CTGAA showed the strongest umami enhancement, and QRQ produced the greatest improvement in aftertaste cleanliness. These results suggest that selected umami peptides may contribute to flavor reconstruction in non-alcoholic beer by enhancing umami perception and improving aftertaste quality. Full article

Background/Objectives: Obesity is a complex metabolic disorder associated with chronic low-grade inflammation, insulin resistance, and increased risk of metabolic complications. Traditional measures, such as body mass index (BMI), may not detect early metabolic disturbances. Myokines and cytokines, including irisin, C-C Motif Chemokine (CCL2), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-15 (IL-15), have been proposed as potential biomarkers. This study aimed to investigate the relationships between these biomarkers and metabolic parameters in adults with varying BMI. Methods: Fifty-one adults (mean age 38 ± 11 years) were stratified by BMI into normal weight, overweight, and obese groups. Serum irisin, CCL2, IL-1β, IL-6, and IL-15 concentrations were measured along with metabolic parameters, including insulin, HOMA-IR, C-peptide, and visceral fat. Statistical analyses included Pearson’s correlation, Kruskal–Wallis ANOVA with Bonferroni correction, and subgroup analyses for insulin resistance (HOMA-IR ≥ 2.5). Results: Irisin concentrations were significantly higher in overweight and obese participants compared with normal-weight individuals (p < 0.001) and positively correlated with insulin (r = 0.77), HOMA-IR (r = 0.63), C-peptide (r = 0.71), and BMI (r = 0.54). In contrast, IL-6 and IL-15 levels did not differ significantly across BMI groups, although IL-15 showed a borderline increase in insulin-resistant individuals (p = 0.048). Both IL-1β and CCL2 were significantly elevated across increasing body-weight categories and showed strong positive correlations with measures of adiposity, visceral fat, and insulin resistance; however, neither marker differed significantly when participants were stratified by insulin-resistance status. Additionally, multivariable linear regression identified irisin as the only independent predictor of insulin resistance, while CCL2 was the strongest predictor of BMI. Principal component analysis (PCA) revealed two dominant components separating metabolic (irisin, HOMA-IR, insulin, BMI) and inflammatory (IL-1β, CCL2) profiles, supporting the distinction between metabolic and inflammatory pathways in obesity. Conclusions: Irisin appears to be a sensitive associative marker of metabolic dysregulation associated with increased body mass and insulin resistance. In contrast, IL-1β and CCL2 reflect obesity-related inflammatory burden rather than early metabolic changes, while IL-6 and IL-15 did not reflect early metabolic alterations in this study. Together, these findings suggest that irisin may serve as an associative biomarker for identifying individuals at risk of obesity-related metabolic disturbances, whereas CCL2 and IL-1β may be more indicative of chronic adipose tissue inflammation. Full article

Background and hypothesis: Sodium–glucose cotransporter 2 inhibitors (SGLT2i) provide consistent cardiorenal benefits; however, tissue-level mechanisms remain insufficiently characterized. We investigated whether SGLT2i were associated with longitudinal remodeling of organ-specific adipose depots in patients with chronic kidney disease (CKD). Methods: In this observational study cohort (ADIPO-CKD; NCT07309094), adults with CKD stages 1–4 underwent clinical, biochemical and ultrasound imaging assessment at baseline (T0) and 8-month follow-up (T8). Thus, epicardial (EAT) and perirenal adipose tissue (PRAT) thickness were measured. Changes over time between patients under SGLT2i treatment and those without (Non-SGLT2i) were assessed using repeated-measures ANOVA and multivariable linear regression models adjusted for age, sex, baseline estimated glomerular filtration rate (eGFR), diabetes status, concomitant glucagon-like peptide 1 (GLP-1) receptor agonist therapy, body mass index (BMI) and visceral fat area (VFA) changes. Results: Among 189 CKD patients (50 SGLT2i and 139 non-SGLT2i), SGLT2i therapy was associated with significant reductions in PRAT (1.28 ± 0.70 to 0.91 ± 0.61 cm; ΔPRAT −0.37 cm; p < 0.002) and EAT (0.57 ± 0.27 to 0.36 ± 0.14 cm; ΔEAT −0.21 cm; p < 0.012), whereas no significant changes were observed in the Non-SGLT2i group. In multivariable models, SGLT2i exposure remained independently associated with ΔPRAT (β = 0.447; 95% CI 0.211–0.682; p < 0.001; R² = 0.371) and ΔEAT (β = 0.061; 95% CI 0.009–0.113; p < 0.021; R² = 0.053), including adjustment for changes in BMI and VFA. These findings were accompanied by trends toward improvement in renal function and systemic inflammation biomarkers in the SGLT2i group, although these changes did not reach statistical significance. In a secondary analysis, dapagliflozin was significantly associated with PRAT reduction, whereas a significant association was found between empagliflozin and EAT decrease. Conclusions: In CKD stages 1–4, SGLT2i use was independently associated with reductions in EAT and PRAT. These findings support a potential link between organ-specific adipose tissue and cardiorenal disease; however, given the observational design, these results should be interpreted as associative and hypothesis-generating. Dedicated mechanistic and adequately powered studies are warranted to determine their clinical relevance. Full article

Background: Untargeted proteomics enables quantitative host cell protein (HCP) determination in biotherapeutics, yet no workflow has been validated under ICH Q2(R2) for regulated quality control. Methods: A prospective total-error (TE) validation of label-free ddaPASEF proteomics was performed. A stable isotope-labeled whole-proteome standard was spiked into NISTmAb at seven levels (20–80 ng) and analyzed in four independent assays (198 injections), supporting one-way random-effects ANOVA with Welch–Satterthwaite adjustment. Peptide-level identification error was evaluated by dual entrapment. Results: Empirical false-discovery proportions were below 1% at q = 0.01. Weighted least-squares regression (R² = 0.993) confirmed stable proportional compression with 81–85% recovery. Repeatability dominated the variance structure (median CV 2.7%); intermediate precision SD ranged from 0.69% to 3.81%. Both 95% β-expectation and 95/95 content tolerance intervals were contained within ±30% at all levels, defining a validated range of 20–80 ng. Abundance-stratified TE profiling revealed concentration-dependent calibration heterogeneity, with stratum-specific intervals within ±35% defining an abundance-aware LLOQ of 3.6 ppm (P95 = 3.87 ppm). Robustness under independent search software (FragPipe v24.0, CCC = 0.998) and cross-platform acquisition (Astral, CCC = 0.980) remained within ±30% limits. Conclusions: This constitutes the first prospective ICH Q2(R2)-aligned validation of untargeted proteomics for HCP quantification, with a transferable statistical framework for high-dimensional analytical methods. Full article

Background: Pacemakers enable continuous long-term surveillance of atrial fibrillation detected by implanted devices. Circulating biomarkers reflecting endothelial dysfunction, inflammation, and myocardial stress may help identify patients at risk for atrial fibrillation (AF) progression and higher arrhythmic burden. Methods: This analysis included patients from the prospective ACaSA study (NCT05127720) with a dual chamber pacemaker (Microport^® BOREA DR or TEO DR) and monitored weekly via remote monitoring technology (SMARTVIEW^®). Individuals with permanent AF or single-chamber systems were excluded. Baseline plasma concentrations of angiopoietin-2 (ANGPT2), growth differentiation factor-15 (GDF-15), fibroblast growth factor-23 (FGF-23), bone morphogenetic protein-10 (BMP10), and tumor necrosis factor–related apoptosis-inducing ligand receptor-2 (TRAIL-R2) were quantified using enzyme-linked immunosorbent assays. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was measured using electrochemiluminescence immunoassay. Biomarkers were log₂-transformed, with values below assay detection limits imputed at half the lower limit of detection. Two endpoints were assessed following a 30-day blanking period: (1) progression to persistent AF, defined as ≥7 consecutive days with >99% daily AF burden, analyzed using Cox regression; and (2) AF burden, calculated as total AF time normalized to monitored days and categorized as <25%, 25–75%, or >75%, analyzed using multinomial logistic regression. Multivariable models were adjusted for age, sex, heart failure, diabetes, and prior myocardial infarction; Cox models were limited to age, sex, and heart failure due to fewer events. Results: A total of 223 patients were included (median age 75 years; 37.2% women). During follow-up, 28 patients (13.3%) progressed to persistent AF. Higher baseline ANGPT2 was the strongest predictor of progression (HR per doubling 1.83, 95% CI 1.27–2.66, p = 0.001), followed by GDF-15 (HR 1.52, 95% CI 1.03–2.24, p = 0.036). In the burden analysis, ANGPT2 demonstrated a pronounced graded relationship with arrhythmic load, with markedly increased odds of high (>75%) AF burden (OR 8.31, 95% CI 2.63–26.26, p < 0.001). GDF-15 independently predicted both medium (OR 2.05, p = 0.025) and high burden (OR 2.32, p = 0.037). NT-proBNP displayed a borderline association with high burden (OR 2.02, p = 0.061). No significant associations were observed for FGF-23, BMP10, or TRAIL-R2. Conclusions: In continuously monitored pacemaker patients, ANGPT2 and GDF-15 emerged as key biomarkers associated with AF disease severity. ANGPT2 was strongly linked to both progression to persistent AF and high AF burden, whereas GDF-15 consistently predicted higher AF burden and also contributed to risk of progression. These findings highlight endothelial and inflammatory pathways as potential markers of atrial disease progression. Full article

Background: Ectopic fat deposition has been demonstrated to play a critical role in the onset and progression of renal dysfunction. However, research on renal parenchymal fat deposition and its association with renal dysfunction in type 2 diabetes mellitus (T2DM) remains limited, particularly regarding its association with early kidney injury. The present study aimed to further investigate the relationship between renal fat fraction (FF) and biomarkers of kidney injury, thereby providing new evidence for the potential link between intrarenal fat accumulation and early renal impairment in T2DM. Methods: This cross-sectional study enrolled 60 patients with T2DM. Renal FF was quantitatively assessed using magnetic resonance imaging (MRI). Clinical characteristics, body composition parameters, and biochemical indices were collected. Levels of kidney injury biomarkers, including tumor necrosis factor receptors 1 (TNF-R1), tumor necrosis factor receptors 2 (TNF-R2), chitinase-3-like protein 1 (YKL-40), and kidney injury molecule-1 (KIM-1), were measured using enzyme-linked immunosorbent assay (ELISA). To evaluate the correlations between fat distribution and inflammatory biomarkers, Pearson correlation analysis was performed. Furthermore, linear regression analysis was conducted to explore the associations between renal FF and kidney injury biomarkers with adjustments for potential confounders such as smoking status, diabetes duration, and visceral fat. Lasso regression was used to screen variables. Results: The results demonstrated that renal FF was significantly positively correlated with serum YKL-40 (r = 0.3, p = 0.021), TNF-R1 (r = 0.246, p = 0.042), and urinary KIM-1 (r = 0.396, p = 0.004), indicating a close association between renal fat accumulation and early kidney injury biomarkers. In regression analyses adjusted for age, sex, and duration of diabetes, the associations between renal FF and these biomarkers remained significant. After further adjustment for potential confounders, including smoking history, alcohol consumption, hypertension, renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, glucagon-Like Peptide-1 (GLP-1) receptor agonists, and lipid-lowering drugs, renal FF remained significantly associated with TNF-R1 (β = 0.327, p = 0.015), KIM-1 (β = 0.352, p = 0.021), and YKL-40 (β = 0.275, p = 0.025). Moreover, even after additional adjustment for visceral fat, the associations of renal FF with TNF-R1 and KIM-1 persisted. After using the Benjamini–Hochberg procedure for false discovery rate, the relationship between renal FF and KIM-1 had a significant difference. Variables of age and gender were excluded to build the parsimonious modeling using Lasso regression. It suggested that renal fat accumulation may contribute to kidney injury independently of visceral adiposity. Conclusions: The study systematically demonstrates a significant association between renal FF and early biomarkers of kidney injury in T2DM, which may suggest the potential role of renal fat accumulation in the pathogenesis of diabetic nephropathy. These findings provide clinical data support for the development of a fat-targeted intervention study. Future research should further elucidate the long-term mechanistic role of renal FF in diabetic nephropathy, as well as its potential value in early diagnosis and therapeutic applications. Full article

Background/Objective: The identification of novel non-invasive diagnostic and prognostic biomarkers is urgently needed in pleural mesothelioma (PM). While soluble mesothelin-related peptides (SMRP) are the most established circulating biomarker, their prognostic value is limited. A wide range of microRNAs (miRs) play diverse roles in regulating gene expression in PM. MiR-21 has been shown to be upregulated in mesothelioma tissue; nevertheless, the diagnostic and prognostic utility of miR-21 in the circulation and its association with survival in PM have not been extensively investigated to date. The objective of the current study was to evaluate miR-21 as a potential blood-based diagnostic and prognostic biomarker in PM. Methods: Plasma samples from PM patients (n = 94) were collected at the time of diagnosis, prior to treatment. Sex- and age-matched healthy individuals (n = 30) served as controls. MiR-21 levels were measured using quantitative RT-PCR and normalized to miR-16, and potential correlations with clinicopathological data were analyzed. Serum SMRP levels were measured in matched patients (n = 84), and a direct comparative analysis of miR-21 and SMRP was conducted. In situ hybridization (ISH) was used to confirm the presence of miR-21 in tumor cells. Results: Plasma miR-21 levels were significantly elevated in PM patients compared to healthy controls (p < 0.001), demonstrating good diagnostic performance (AUC 0.81). The localization of miR-21 in PM cells was confirmed by ISH. High miR-21 levels were associated with significantly shorter median overall survival (12.4 vs. 24.3 months, p < 0.001). Elevated SMRP levels were also associated with reduced survival (12.4 vs. 19.5 months, p = 0.032); however, SMRP did not retain independent prognostic significance in multivariable analysis. In contrast, high-circulating miR-21 was confirmed as an independent predictor for poor survival (HR 3.12, p < 0.001). Conclusions: Our findings highlight that circulating miR-21 is a potential non-invasive biomarker with both diagnostic and independent prognostic value in pleural mesothelioma and outperforms SMRP in multivariable survival analysis. Further research is warranted to validate its role in the biology of this disease and to assess its correlation with outcome and treatment responses. Full article

Background/Objectives: Obesity is a global health emergency with a complex etiology, in which monogenic forms, although rare, are significantly underdiagnosed. In our clinical setting, first-tier genetic screening panels targeting LEP, LEPR, BDNF, FTO, and MC4R often fail to identify a causative variant, leaving a significant diagnostic gap. This study aimed to assess the prevalence of variants in other critical genes of the melanocortin pathway to improve diagnostic yield. Methods: We analyzed 88 patients with non-syndromic obesity (Body Mass Index, BMI > 30 kg/m²), who were first screened for our standard obesity-related genes. In those testing negative, we expanded the analysis to include the MC3R and POMC genes. In silico bioinformatic tools were used to predict the functional consequences of identified variants on protein structure and splicing. Results: We found several variants in POMC, specifically within the regions coding for alpha-, beta-, and gamma-MSH peptides. A bioinformatic analysis suggests that these variants disrupt the melanocortin signaling pathway, likely contributing to an intermediate susceptibility phenotype in our adult cohort. Additionally, a clinical follow-up of a patient carrying the rare BDNF p.Thr2Ile variant revealed a suboptimal response to high-dose tirzepatide treatment (9% weight loss over 72 weeks), notably inferior to the average response observed in clinical trials. Conclusions: Our findings demonstrate that expanding first-level routine testing to include POMC and MC3R is essential to maximize diagnostic yield and improve clinical management. Full article

Cosmetic dermatology has largely focused on topical applications targeting the stratum corneum. However, emerging evidence suggests that visible aging is a systemic readout of internal “organ clocks” and molecular dysregulation across the epidermis and dermis. This review proposes an “inside–out strategy” that seeks to re-conceptualize aesthetic vitality as a measurable indicator of systemic physiological resilience. The author describes theoretically proposed organ–skin axes, including the role of molecular signaling of kidney-derived klotho (KL1 fragment) via FGFR1-α–klotho complexes and muscle-derived irisin through the AMPK/PGC-1-α pathway in modulating skin homeostasis. Drawing on recent breakthroughs in non-human primate models (2023–2025), this synthesis explores the potential of systemic interventions—including nicotinamide adenine dinucleotide (NAD+) precursors (sirtuin 1 SIRT1 activators), senolytics (targeting BCL-2/p16), and glucagon-like peptide-1 (GLP-1) receptor agonists—as candidates to potentially synchronize these internal clocks. Furthermore, the review identifies direct regenerative interventions, such as retinoids (RAR/RXR signaling), chemical peels (HIF-1-α induction), exosomes (miR-21/29 delivery), and poly-L-lactic acid PLLA (mechanotransduction via YAP/TAZ), positioning them as potential physical and chemical epigenetic modulators that may support the restoration of cellular transcriptional fidelity. This article proposes a new paradigm for regenerative aesthetics that focuses on restoring the youthful phenotype by optimizing systemic molecular crosstalk and epigenetic transcriptional fidelity. Full article

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the “first-in-class” small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC₅₀ = 7.72, pCC₅₀ < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure–activity relationship insights. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies and characterized by pronounced heterogeneity and widespread dysregulation of microRNAs (miRNAs) that influence epithelial-to-mesenchymal transition (EMT) and metastasis. Tumor-derived extracellular vesicles (tEVs) further contribute to TNBC progression by transporting oncogenic cargo that can enhance pro-inflammatory signaling. The synthetic SMRwt peptide has been suggested to modulate oncogenic pathways; however, its effects on EV miRNA composition and inflammatory transcript profiles in TNBC remain unclear. Here, we investigated whether SMRwt alters tEV-associated miRNAs and cytokine transcript signatures relevant to EMT and inflammasome-linked pathways. Extracellular vesicles were isolated from SMR-treated and untreated MDA-MB-231 cells, followed by nanoparticle tracking analysis and small RNA sequencing. SMRwt treatment enriched 11 tumor-suppressive miRNAs (including Let-7a-5p, Let-7b-5p, miR-24-3p, miR-26b-5p, miR-92a-3p, miR-93-5p, and miR-496) previously associated with the regulation of proliferation, EMT, migration, and metastasis. We also observed modest, non-significant decreases (1.01–1.27-fold) in oncogenic miR-1200, miR-374a-5p, and miR-937-3p, which have been implicated in the progression of breast, lung, and bone malignancies. Complementary transcriptomic profiling using the NanoString nCounter Breast Cancer 360 Gene Expression Panel (NanoString Technologies, Inc., Seattle, CA, USA) demonstrated reduced expression of inflammasome-associated cytokines in TNBC cells relative to non-tumorigenic controls, including a log₂ fold change of −1.15 for IL 1β (MDA-MB-231 vs. MCF10A). These transcript-level changes suggest potential modulation. Additionally, SMRwt suppresses ASC-mediated caspase-1 activation and reduces IL-1β secretion, thereby inhibiting NLRP3 inflammasome signaling. Therefore, we infer that SMRwt simultaneously restores tumor-suppressive miRNA networks and suppresses inflammasome-driven inflammation, supporting its potential as a dual-target therapeutic strategy for TNBC. Full article

Celiac disease (CD) is an autoimmune disorder triggered by immunogenic gluten peptides that resist gastrointestinal digestion. The only current treatment is a strict gluten-free diet, which is challenging to maintain. Lactic acid bacteria (LAB) with specific proteolytic systems offer a promising strategy for gluten hydrolysis and potential reduction of immunogenicity. This study aims to isolate and characterize gluten-degrading LAB from traditional Spanish and Algerian dairy products. A total of 27 artisanal dairy samples were collected. LAB were isolated on MRS and Elliker agar. Gluten-degrading activity was screened using a well diffusion assay with cell-free supernatants and a spot assay with live cultures. Active isolates were identified by 16S rRNA gene sequencing. Out of 123 isolates, 40 (32.5%) were positive in the well assay, while 67 (54.5%) were positive in the spot assay, indicating the latter’s higher sensitivity for detecting cell-associated proteases. Halo diameters ranged from 6 to 16 mm. Algerian isolates exhibited significantly stronger activity (mean halo: 12.6 ± 2.1 mm) compared to Spanish isolates (10.2 ± 2.0 mm; p < 0.001). Molecular identification of the 32 most active isolates revealed the following dominant species: Lactiplantibacillus plantarum, L. pentosus, Levilactobacillus brevis, and Enterococcus faecium. This study confirms that artisanal dairy fermentations are rich sources of LAB with robust gluten-degrading potential. The superior activity of Lactiplantibacillus spp. aligns with their complex peptidase systems. The geographical variation highlights the influence of local fermentation practices. Selected strains represent excellent candidates for developing adjunct cultures to produce gluten-reduced foods and warrant further investigation as potential probiotics, pending safety and efficacy validation in vivo and in clinical studies. Full article

Background/Objectives: Real-world persistence of traditional oral migraine preventive medications is low in routine care. Prior large claims-based analyses demonstrated early discontinuation of oral prophylaxis, but such datasets neither included modern preventive options such as monoclonal antibodies (mAB) against calcitonin-gene-related peptide (CGRP), nor were able to capture clinically validated reasons for discontinuation. The primary aim was to compare real-world treatment persistence and discontinuation reasons due to adverse drug reactions (ADRs) or insufficient efficacy among three preventive therapy classes: subcutaneous CGRP mAB and oral high- (HEVP) and low-evidence preventive medications (LEVP). A secondary aim was to examine persistence patterns of individual substances within the HEVP cohort. Methods: This exploratory observational study used depersonalized real-world data from the German Pain e-Registry (GPeR), a national multicenter clinical registry. Persistence trajectories were evaluated over six months, together with cumulative proportions of ADR-related and inefficacy-related discontinuations. Pairwise comparisons across the three cohorts based on chi-square analyses, odds ratios, relative risks, effect sizes, and numbers needed to harm. Results: At six months, persistence was highest for CGRP monoclonal antibodies at 89.4%, compared with 43.0% for LEVP and 34.0% for HEVP (all p < 0.001). ADR-related discontinuation occurred in 7.0% with CGRP vs. 35.7/44.5% with LEVP/HEVP, and discontinuations due to insufficient efficacy occurred in 3.6% with CGRP vs. 21.3/21.5% with LEVP/HEVP, without influence of sex or migraine frequency. Substance-level analysis within HEVP showed the steepest early attrition for tricyclic antidepressants, followed by beta-blockers, with comparatively more favorable though still suboptimal persistence for topiramate and flunarizine. Conclusions: Real-world treatment persistence is markedly higher with CGRP mAB than with HEVP/LEVP. Oral preventives show high discontinuation rates due to both ADR and insufficient efficacy, indicating substantial limitations in real-world applicability. These findings highlight the clinical relevance of a modern mechanism-based migraine prevention with CGRP mAB. Full article

Staphylococcus aureus (S. aureus) is the most prevalent pathogen associated with subclinical mastitis, which significantly impacts dairy farming worldwide. Fluctuations in reproductive hormones, such as bovine prolactin (bPRL) and 17β-estradiol (E2), are known to compromise the innate immune response (IIR) of the mammary gland (MG). In this study, we evaluated the effects of bPRL and E2 on the effector response of primary bovine macrophages, isolated from lactating Holstein cows, challenged with S. aureus. We demonstrated that physiological concentrations of bPRL (5 ng/mL) and E2 (50 pg/mL) induced differential changes in the expression of pro-inflammatory (TNF-α, IL-6, and IL-1β) and anti-inflammatory (IL-10) cytokines, chemokines (IL-8), antimicrobial peptides (BNBD10 and S100A7), and miRNAs (miR-451, miR-155, miR-7863, miR-146a, miR-21a, Let-7a-5p, miR-30b, and miR-23a) in S. aureus-challenged macrophages. Moreover, these hormones promoted global histone H3 acetylation and the epigenetic H3K9ac mark without affecting H3K9me2 levels. Hormonal treatment also modulated histone deacetylase (HDAC) activity. Furthermore, hormonal treatment altered macrophage chemotaxis and phagocytosis. In conclusion, bPRL and E2 modulate the effector functions of bovine macrophages during S. aureus infection. This process could be associated with the regulation of histone H3 modifications, such as H3K9ac, in IIR-related genes. Full article