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[Exploring the regulatory mechanism of Sparassis latifolia polysaccharides on hepatic glucose metabolism disorders in mice based on transcriptomics].
Sheng Li Xue Bao
Er-Chen Yang, Feng-Ying Jia, Li-Min Zhang +5 more
This study aimed to investigate the effects and mechanism of Sparassis latifolia polysaccharides (SLPs) on hepatic glucose metabolism disorders induced by a high-fat diet combined with streptozotocin (STZ) in mice. A mouse model of hepatic glucose metabolism disorder was established and treated with different doses of SLPs (100, 200, and 400 mg/kg) via gavage for 8 weeks, alongside control, model, and positive control groups (metformin hydrochloride). The effects of SLPs were systematically evaluated through pyruvate tolerance tests (PTT), hepatic glycogen content measurement, liver histomorphological analysis (HE and oil red O staining), transcriptomics, and validation of key signaling pathways using RT-qPCR and Western blot. The results showed that, compared to the model group, medium and high doses of SLPs significantly reduced area under the curve (AUC) of PTT, increased hepatic glycogen content, and ameliorated liver histopathological damage and lipid accumulation in the liver. Transcriptomic analysis revealed that SLPs intervention significantly modulated differentially expressed genes related to glucose and lipid metabolism, which were enriched in signaling pathways such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/forkhead box O1 (FOXO1) signaling pathway. Further validation demonstrated that SLPs up-regulated mRNA expression levels of insulin-like growth factor 1 receptor (IGF1R), protein kinase B2 (AKT2), and phosphatidylinositol-3-kinase regulatory subunit 1 (PIK3R1) in the liver of mice with glucose metabolism disorders, and down-regulated the mRNA expression levels of FOXO1 and fructose-1,6-bisphosphatase 1 (FBP1). Additionally, SLPs up-regulated p-FOXO1 protein expression level and down-regulated phosphoenolpyruvate carboxykinase (PEPCK) protein expression level. These results suggest that SLPs can effectively improve hepatic glucose metabolism disorders in mice induced by a high-fat diet combined with STZ by activating the PI3K/AKT/FOXO1 signaling pathway, involving the inhibition of key gluconeogenic enzymes and promotion of glucose utilization.
THBS1 as a Key Regulator of Myoblasts: Validation of Its Inhibitory Roles in Skeletal Muscle Development.
Genes (Basel)
Ji Qi, Xinlin Jin, Jing Wang +8 more
Thromboxane B2 Synthase 1 (THBS1), also known as TSP-1, is a multifunctional glycoprotein involved in various cellular processes that plays a crucial role in skeletal muscle development and repair. It acts as a key physiological activator of transforming growth factor-β1 (TGF-β1), both in vivo and in vitro.
Genomic Monitoring and Engineering Stable and Safe Immortalized Cell Platforms for Industrial Cellular Agriculture.
Foods
Karine R D Silveira, Vanessa Haach, Ana Paula Bastos
Cultivated-meat production relies on robust animal cell-line engineering, scalable tissue-engineering strategies, and clearly defined regulatory standards. This review examines the developmental pipeline from primary tissue biopsy to large-scale expansion and regulatory evaluation, focusing on stable and safe immortalized cell platforms. We compare muscle satellite cells, mesenchymal stromal/adipogenic progenitors and induced pluripotent stem cells, highlighting trade-offs among proliferative capacity, lineage commitment, genomic stability, and food-safety considerations. We then analyze immortalization strategies, including spontaneous senescence bypass, telomerase reactivation and CRISPR-based checkpoint modulation, highlighting their impact on genomic stability and food-safety risks. Recent advances in serum-free media, extracellular matrix-mimetic biomaterials and staged co-culture protocols have enabled centimeter-scale tissues with improved texture and marbling; however, cost, reproducibility and scalability remain bottlenecks. Integrating multi-omics surveillance with life-cycle assessment reveals that environmental benefits (land, water and antibiotic reduction) are attainable only when energy inputs and growth-factor sourcing are optimized. Finally, we examine regulatory frameworks that distinguish food-grade immortalized cells from pharmaceutical substrates and genetically modified crops. By integrating cell biology, animal biotechnology, and bioprocess engineering, this review identifies technical priorities for advancing cultivated meat from laboratory development to industrial implementation, positioning genomic monitoring as an essential framework for assessing biological stability, functional predictability, and food-production suitability.
ChREBP Is Dispensable for Myofiber Type Switch but Promotes Skeletal Muscle Regeneration.
Nutrients
Junyu Lu, Jian Chen, Guanyu Zhang +9 more
Background/Objectives: The transcription factor carbohydrate response element-binding protein (ChREBP) is a key glucose-sensing regulator that governs glucose and lipid metabolic homeostasis. However, its specific functions in skeletal muscle remain insufficiently clarified. The present study aimed to investigate the roles of ChREBP in skeletal muscle exercise capacity, energy metabolism, and adaptive remodeling, as well as muscle regeneration. Methods: We generated a skeletal muscle-specific ChREBP knockout mouse model, and assessed their exercise performance, energy metabolism, skeletal muscle fiber composition, and injury repair capacity. Additionally, hypoxia and high-fructose diet models were established to analyze the function of ChREBP in skeletal muscle adaptive remodeling. C2C12 myoblasts and primary muscle satellite cells were used to explore its effects on myogenic differentiation. Results: Genetic deletion of ChREBP induced no detectable alterations in myofiber composition, overall metabolic status, or muscle adaptive remodeling triggered by hypoxia and high-fructose diet. In vitro assays demonstrated that ChREBP overexpression facilitates C2C12 myogenic differentiation. Adeno-associated virus-mediated ChREBP overexpression enhanced histological markers of regeneration, including desmin-positive regenerative area and the cross-sectional area of newly formed myofibers after cardiotoxin-induced injury. Conclusions: Collectively, our experimental data indicate that ChREBP is largely dispensable for maintaining basal skeletal muscle homeostasis and stress-induced adaptive remodeling. Meanwhile, this study identifies a previously unrecognized regulatory role of ChREBP in the processes of skeletal muscle damage repair and post-injury regeneration.
Establishment and Characterization of an Immortalized Porcine Satellite Cell Line from China Junmu No.1 Pigs.
Vet Sci
Jing Li, Yu He, Xiaoran Zhang +7 more
Junmu No.1 is a commercially important Chinese pig breed, yet stable in vitro models for investigating its muscle development mechanisms and genetic regulation remain lacking; this study aimed to establish an immortalized porcine satellite cell line from Junmu No.1 pigs to address this gap. Primary porcine satellite cells (PSCs) were isolated from a 2-day-old Junmu No.1 piglet and immortalized via lentiviral transduction using the pHAGE-EF1α-eGFP-SV40LT-BleoR vector. The resulting cell line (imPSC-JM) was characterized for morphology, satellite cell marker expression, karyotype stability, myogenic differentiation capacity, and long-term proliferative potential, and RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) was performed to assess transcriptomic fidelity relative to primary PSCs. The imPSC-JM line retained characteristic spindle-shaped satellite cell morphology, consistently expressed PAX7, maintained a normal diploid karyotype (2n = 38, XY), and showed stable SV40 large T antigen expression, enabling sustained proliferation exceeding 100 cumulative population doublings while preserving myogenic differentiation and the formation of multinucleated myotubes expressing Desmin, MYHC, and DMD. Transcriptomic profiles were highly concordant with primary PSCs (Pearson r ≥ 0.95; R2 = 0.9188; 83.8% of expressed genes unchanged), with key satellite-cell and myogenic regulator genes (PAX7, MYOD1, MYF5, MYOG, MYF6) unaltered, while GSEA revealed upregulation of autophagy and inflammatory signaling and downregulation of ribosome biogenesis. The imPSC-JM line thus provides a reliable experimental platform with high transcriptomic fidelity for studying muscle development and genetic regulation in Junmu No.1 pigs.
From dual to quintuple agonism for next-generation pharmacology to treat obesity and type 2 diabetes: synergistic incretin and nuclear receptor signaling.
Cardiovasc Diabetol Endocrinol Rep
Gaetano Santulli
Receptor-targeted polypharmacology is emerging as a promising strategy for the treatment of obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis. GLP-1-GIP-lanifibranor, a unimolecular conjugate combining GLP-1R/GIPR co-agonism with pan-PPAR activation, enables receptor-guided intracellular delivery of lanifibranor to incretin receptor-expressing cells while limiting systemic off-target exposure. In obese mouse models, the conjugate produced greater reductions in body weight, adiposity, food intake, and hyperglycemia than semaglutide, GLP-1-GIP co-agonism, or lanifibranor alone, while significantly improving insulin sensitivity. Mechanistic analyses demonstrated receptor-dependent delivery and identified PPARδ signaling as a principal mediator of glycemic improvement independent of weight loss. Unlike unconjugated lanifibranor, the conjugate did not induce anemia, fluid retention, renal dysfunction, or adipocyte differentiation, supporting the concept that tissue-restricted PPAR activation may mitigate classical adverse effects of systemic PPAR agonism. These findings establish peptide-directed nuclear receptor targeting as a potentially important platform for next-generation metabolic therapeutics, although substantial translational uncertainties remain regarding clinical efficacy, safety, and long-term applicability.
Effects of Semaglutide on Cardiometabolic Risk in People with Obesity, With and Without Type 2 Diabetes: A Retrospective Observational Study.
J Clin Med
Loredana Deaconu, Oana Albai, Bogdan Timar +6 more
Background and Objectives: Obesity and insulin resistance are major contributors to cardiometabolic disease and type 2 diabetes mellitus (T2DM). This study evaluated the real-world effects of semaglutide on metabolic parameters, body composition, and cardiometabolic risk factors in people with obesity, with and without T2DM, and explored predictors of treatment response. Materials and Methods: This retrospective longitudinal observational study included 70 adults with obesity (42 with T2DM and 28 without T2DM) treated with semaglutide according to current clinical guidelines. The primary outcomes were changes in body weight, waist circumference, fasting plasma glucose, and glycated hemoglobin (HbA1c). Secondary outcomes included changes in lipid profile, insulin resistance indices, inflammatory markers, hepatic parameters, and body composition assessed by bioelectrical impedance analysis (InBody770). Results: Semaglutide treatment was associated with significant reductions in body weight (-9 kg), waist circumference (-8 cm), HbA1c (-1.1%), systolic blood pressure (-7.5 mmHg), visceral fat area (-30.1 cm2), and insulin resistance markers. Improvements in glycemic parameters were more pronounced in participants with T2DM. Skeletal muscle mass (SMM) was relatively preserved during treatment. Baseline HbA1c and visceral adiposity were independently associated with metabolic response. Conclusions: In this real-world observational cohort, semaglutide was associated with significant improvements in metabolic parameters, body composition, and cardiometabolic risk markers in people with obesity, with and without T2DM. Baseline metabolic characteristics may influence treatment response.
Clinical Effectiveness and Safety of Oral Semaglutide in a Real-World Cohort of Patients with Heart Failure with Reduced Ejection Fraction, Type 2 Diabetes and Obesity: A Propensity Score-Matched Analysis.
Pharmaceuticals (Basel)
Alicia Trenas-Calero, Nuria Prieto-Laín, Miguel A Pérez-Velasco +6 more
Bacground/Objectives: There is limited evidence on the role of glucagon-like peptide-1 receptor agonists in heart failure. We aimed to analyze the clinical efficacy of oral semaglutide in terms of health status and change in body weight in patients with heart failure with reduced ejection fraction, type 2 diabetes, and obesity. Methods: This observational, retrospective, real-world study included patients treated with oral semaglutide (Oral-Sema Group) and without glucagon-like peptide-1 receptor agonists (Control Group). The primary outcome was heart failure status, defined as a ≥5 point difference in the Kansas City Cardiomyopathy Questionnaire total symptom score, and change in body weight at 24 months. Results: After 1:1 propensity score matching, 162 patients were included in each group (mean age 71.0 years, mean body mass index 32.1, 52.9% females). Patients in the Oral-Sema Group were more likely to have improvement in heart failure health status from baseline to 24 months (OR: 2.45; 95%CI: 1.25-3.65; p = 0.012). The mean change in body weight was -8.0 ± 2.1 kg in patients with oral semaglutide and -1.9 ± 1.0 kg in control patients (p < 0.01). After treatment, there were negative correlations between the Kansas City Cardiomyopathy Questionnaire total symptom score and body weight (r = -0.558, p < 0.01) and glycated hemoglobin (r = -0.491, p = 0.017). It had good tolerability and safety. Conclusions: Oral semaglutide was associated with an improvement in heart failure health status and weight loss in patients with heart failure with reduced ejection fraction, type 2 diabetes, and obesity. Further research on glucagon-like peptide-1 receptor agonists in heart failure with reduced ejection fraction is needed.
Sex-Specific and Reproductive Status-Dependent Effects of Liraglutide on Metabolic Disorders Associated with Prediabetes.
Antioxidants (Basel)
Lucie Lebertová, Irena Marková, Martina Hüttl +3 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to have beneficial effects in T2D, reducing hepatic lipid storage and improving metabolic dysfunction-associated steatotic liver disease. However, sex and reproductive age may influence their effect. We investigated the effect of liraglutide administration (0.2 mg/kg/day subcutaneously for 8 weeks) on metabolic disorders in relation to sex and reproductive age, using male, female and ovariectomized female hereditary hypertriglyceridemic (HHTg) rats as a prediabetic model. Liraglutide improved glucose tolerance in all HHTg rats. Female and ovariectomized (OVX) female rats showed a stronger effect of lipid metabolism and visceral adiposity than males. Moreover, no changes in hepatic triacylglycerol (TAG) accumulation were observed in males. Liraglutide partially reversed ovariectomy effects, such as increased body weight, visceral obesity and impaired glucose tolerance. Compared with males, female and OVX female rats showed more significant changes in hepatic gene expression involved in lipogenesis (Scd-1, Srebp1, Pparγ), fatty acid and lipid metabolism (Pparα, Hmgcr, Srebp2) and fibrosis (Tgfβ), which may improve hepatic lipid metabolism. Females of fertile age showed greater improvements in insulin sensitivity, reductions in ectopic lipid accumulation, and improvements in lipid metabolism. Depending on sex and reproductive status, liraglutide can mitigate fatty liver before diabetes onset.
Liraglutide, a GLP-1 Receptor Agonist, Mitigates LPS-Induced Osteoclastogenesis and Bone Loss by Downregulating Macrophage TNF-α Expression.
Int J Mol Sci
Kou Murakami, Hideki Kitaura, Fumitoshi Ohori +8 more
Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explored its potential to suppress osteoclast formation and bone loss triggered by lipopolysaccharide (LPS), an inflammatory agent. In animal models, the co-administration of liraglutide with LPS on the calvaria regions in mice markedly reduced osteoclast numbers and bone resorption areas relative to treatment with LPS alone. Furthermore, the expression levels of receptor activators of the NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA were notably lower in the group receiving liraglutide and LPS compared to treatment with LPS alone. Moreover, in vitro tests revealed that liraglutide has no direct inhibitory effect on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. In addition, liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. Moreover, liraglutide effectively suppressed TNF-α mRNA expression in macrophages stimulated by LPS. These findings suggest that liraglutide prevents inflammatory bone destruction not by targeting osteoclast formation directly but by inhibiting the production of TNF-α within macrophages.
Incretin-Based Drugs for Obesity: Common and Drug-Specific Reporting Patterns of Adverse Drug Reactions-A Comparative Disproportionality Analysis Using EudraVigilance Reports Integrating SmPC Data.
Pharmaceuticals (Basel)
Ioana Rada Popa Ilie, Steliana Ghibu, Anca Butuca +5 more
Background: With the increasing widespread use of GLP-1 RA and dual GIP/GLP-1 RAs in the treatment of obesity, their safety profile remains a concern for healthcare professionals (HPs). Objective: This study aimed to characterize and evaluate safety data from the EudraVigilance (EV) database for semaglutide (SEM), liraglutide (LIR), and tirzepatide (TIR). Methods: A hierarchical pharmacovigilance approach was applied, integrating SOC- and PT-level analyses with SmPC-based evaluation and both frequentist (ROR, 95% CI) and Bayesian (IC025) disproportionality methods. Within each molecule, reporter type-stratified analyses were performed, while across all molecules, disproportionality analyses were conducted separately in HP reports and in the full database to identify reporting patterns and potential safety signals, including those not described in the SmPCs. Results: Some ADRs, listed in the SmPC of only one or two of the three GLP1-RAs were also reported in the EV database for the other agents whose SmPCs do not specify these ADRs including optic ischemic neuropathy (TIR: 0.28% and LIR: 0.17%), alopecia (LIR: 0.81%), headache (TIR: 2.51%), intestinal obstruction (TIR: 1.55%), angioedema (LIR: 0.19%), hypersensitivity (SEM: 0.58% and LIR: 0.73%), etc. Pancreatitis, in particular, showed a significant but low-magnitude signal, being more frequently reported by HPs compared with non-HPs across all three GLP1-RAs. Additionally, statistically significant signals (IC025 > 0) were observed in both the HPs and full datasets. For example, for SEM vs. TIR, signals were identified for optic ischemic neuropathy (0.17; 0.13), gallbladder disorder (0.09; 0.11), and dysesthesia (0.42; 0.43), respectively. For TIR vs. SEM, signals were observed for injection site erythema (0.05; 0.11), injection site pruritus (0.01; 0.11), and injection site reaction (0.02; 0.08). Conclusions: These findings suggest potential safety signals beyond current SmPC information, emphasizing the need for continuous pharmacovigilance and cautious interpretation of reporting biases.
Akkermansia muciniphila and GLP-1-Based Therapies: Bidirectional Interactions and Implications for Type 2 Diabetes and MASLD/MASH.
Biomedicines
Boris Dinkov
The global burden of type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise at an alarming pace, with substantial pathophysiological overlap driven by insulin resistance, visceral obesity, and chronic low-grade inflammation. MASLD may progress to metabolic dysfunction-associated steatohepatitis (MASH), with increased risk of cirrhosis and hepatocellular carcinoma. Glucagon-like peptide 1 (GLP-1)-based therapies have transformed the management of T2DM and obesity. They exert pleiotropic effects whose basis remains incompletely understood. Concurrently, Akkermansia muciniphila has emerged as a keystone gut microbiota species with demonstrated hepatoprotective potential in preclinical models of MASLD/MASH. This narrative review positions A. muciniphila simultaneously as a target of GLP-1-mediated microbiome remodeling and as an independent modulator of hepatoprotection in MASLD/MASH. A structured search of PubMed, Scopus, and Web of Science (last searched: 12 April 2026) was conducted using terms related to Akkermansia muciniphila, GLP-1 receptor agonists, MASLD/MASH and T2DM. A total of 174 records were identified. Of these, 148 were excluded due to duplication or non-relevant study design. 26 studies (23 preclinical, 3 clinical) were included in the synthesis, directly addressing A. muciniphila. Preclinical evidence demonstrates that liraglutide, semaglutide, exenatide, and tirzepatide increase A. muciniphila abundance, while A. muciniphila in turn enhances endogenous GLP-1 secretion via the P9/ICAM-2 axis, forming a hypothetical positive feedback loop. A working mechanistic model integrating these bidirectional interactions is proposed, alongside a discussion of current limitations and future research priorities, including microbiome-guided clinical trials in MASLD/MASH populations.
The Efficacy of Glucagon-like Peptide-1 Based Therapies in Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis.
J Clin Med
Theodoros Christophides, Gisella Figlioli, Sotiris Christoforou +5 more
Background/Objectives: Despite advances in heart failure (HF) pharmacotherapy, novel treatments are needed for its main subtypes: preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. Glucagon-like peptide-1 (GLP-1) based therapies have shown cardioprotective effects. We conducted a systematic review and meta-analysis (Prospero Registration Number CRD42024606997) assessing the efficacy of GLP-1 based therapies (GLP-1 receptor agonists including tirzepatide) across the spectrum of left ventricular ejection fraction on cardiovascular (CV) outcomes. Methods: The PubMed, Embase, Scopus and trial registries were searched until December 2025 for randomised controlled trials (RCTs) involving adults with HF treated with GLP-1 based therapies. Outcomes included heart failure hospitalisations (HFH), CV, and all-cause mortality. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analyses were performed by HF subtype, age, coronary artery disease (CAD) presence, and GLP-1 based therapeutic agent. Results: Fourteen RCTs (15,180 participants), at low risk of bias, were included. These agents significantly reduced HFH (RR: 0.84, 95% CI: 0.71-0.99), especially in HFpEF patients with stable CAD (RR: 0.61, 95% CI: 0.46-0.79). Limited data suggested benefits for exenatide in HFmrEF patients (RR: 0.67, 95% CI: 0.47-0.95). CV mortality was reduced in HFrEF patients <65 years old (RR: 0.71, 95% CI: 0.54-0.95). Benefit was seen in composites of HFH and CV mortality for HFpEF (RR: 0.67, 95% CI: 0.54-0.83). Conclusions: GLP-1 based therapies may reduce HFH in HFpEF and possibly lower CV mortality in younger HFrEF patients, suggesting phenotype-specific effects.
Glucagon-like Peptide-1 Receptor Agonists and Alcohol Use Outcomes: A Systematic Review of Clinical Evidence.
J Clin Med
Ibrahim K Altami, Eyad A Alabdulrahim, Osamah M Alfayez
Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity treatment and may influence reward-related behaviors, including alcohol use. This study aimed to evaluate the effects of GLP-1RAs on alcohol consumption and related outcomes in adults with alcohol use or alcohol use disorder (AUD). Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed and Web of Science were searched from inception to December 2025. Eligible studies included randomized controlled trials (RCTs), secondary analyses of RCTs, and observational studies reporting quantitative alcohol consumption outcomes. Data extraction and risk of bias assessment (RoB 2 and ROBINS-I) were performed independently by two reviewers. Results: Five studies (n = 49,892) were included, comprising three RCT-based analyses and one large cohort study. Semaglutide and dulaglutide were associated with modest reductions in alcohol consumption and craving in several studies, with statistically significant improvements in selected behavioral outcomes. In contrast, exenatide did not demonstrate significant effects in the overall AUD population, with signals limited to subgroups. The cohort study showed small but statistically significant reductions in AUDIT-C scores following GLP-1RA initiation. Objective measures (e.g., PEth, breath alcohol concentration) showed reductions in selected contexts but were reported in a few studies. Conclusions: GLP-1RAs may be associated with modest reductions in alcohol consumption, but evidence remains limited and heterogeneous. Larger, well-designed RCTs are needed to define their role in the management of AUD.
Reducing HPV Viral Burden in Men: A Synergistic Approach Using Pidotimod and Prophylactic Vaccination.
Microorganisms
Claudio Ucciferri, Livia Moffa, Giuseppe Vittorio De Socio +1 more
Human papillomavirus (HPV) infection remains a major global health challenge, particularly when persistent high-risk genotypes lead to oncogenic progression. While prophylactic vaccines are effective, their role in accelerating the clearance of existing infections is still being explored. This study aimed to investigate the potential efficacy of adjunctive Pidotimod therapy combined with the nonavalent HPV vaccine in reducing persistent genotypes and promoting clearance in men. This retrospective pilot study included 23 HIV-negative men with anal and/or genital HPV infections. Participants were divided into two groups: 7 received the standard nonavalent HPV vaccine alone (control), and 16 received oral Pidotimod (800 mg twice daily for 10 days surrounding each vaccine dose) in addition to the vaccine (treatment). HPV genotyping (28 types) was performed at baseline and 12 months using real-time PCR. At 12 months, the HPV-negative conversion rate was 62.5% in the Pidotimod + vaccine group compared to 28.6% in the control group (p = 0.19). While this primary difference in total clearance was not statistically significant due to the limited sample size, the treatment group showed a substantial per-patient reduction in the number of persistent genotypes, decreasing from a mean of 2.75 ± 2.05 to 0.50 ± 0.82, compared to a decrease from 3.43 ± 2.37 to 1.86 ± 1.07 in the control group. The Pidotimod group achieved a significantly lower number of persistent genotypes at 12 months compared to the control group (p = 0.008, Mann-Whitney U test). Additionally, the use of pre-exposure prophylaxis (PrEP) was significantly associated with a lower rate of HPV clearance (12.5% vs. 73.3%, p < 0.01). Adjunctive therapy with Pidotimod suggests a promising trend in facilitating the reduction in HPV strain burden when combined with the HPV vaccine in men. While larger prospective studies are needed to confirm these effects, this exploratory approach could represent a promising immunomodulatory strategy for managing multiple and persistent HPV infections, even in high-risk groups such as PrEP users.
GLO1 cg26053840 Methylation Associates with Kidney Injury and Inflammatory Markers in Hospitalized Older Adults.
Life (Basel)
Carlo Fortunato, Francesco Piacenza, Gretta Veronica Badillo Pazmay +20 more
The glyoxalase pathway detoxifies reactive dicarbonyls generated during hyperglycemia, but the role of its epigenetic regulation in renal dysfunction and inflammatory dysregulation in older adults remains unclear. We investigated CpG-specific DNA methylation within the glyoxal detoxification pathway, focusing on the GLO1 gene, and examined associations with glycemic status, renal function, and systemic inflammation in hospitalized older adults. We identified a single CpG site within the GLO1 gene (cg26053840) significantly associated with fasting glycemia, suggesting that methylation levels at this locus reflects metabolic stress. Higher methylation at cg26053840 was also associated with impaired renal function, including increased serum creatinine and reduced estimated glomerular filtration rate. Additionally, GLO1 methylation correlated with multiple inflammatory indices, including C-reactive protein, erythrocyte sedimentation rate, neutrophil-to-lymphocyte ratio, and the CRP-to-albumin ratio. Associations with circulating cytokines and immune activation markers such as IL-6, IL-17A, GDF-15, CXCL9, CD163, and soluble RAGE further indicated broader immune-metabolic dysregulation. In silico analyses revealed a significant inverse correlation between cg26053840 methylation and GLO1 mRNA expression in the Broad Institute GDAC Firehose dataset. Genomic annotation further identified putative CEBPD and MYF6 transcription factor binding sites in proximity to the CpG site, suggesting a potential regulatory context. These findings support a model in which glycemic dysregulation increases methylglyoxal production, while reduced renal clearance enhances dicarbonyl stress, potentially driving epigenetic modulation of GLO1. These findings suggest the presence of a metabolic-epigenetic-inflammatory axis, although longitudinal and mechanistic studies are required to determine whether it contributes to organ dysfunction and vulnerability in hospitalized older adults.
The Cribriform Plate: A Multifaceted Neuroimmune Hub in CNS Health and Disease.
Medicina (Kaunas)
Kadır Cetınkaya, Oktay Algın
The cribriform plate (CP) functions as a dynamic neuroimmune interface through which olfactory nerve bundles exit the brain within a specialized perineural microenvironment (cpPME). While traditionally viewed as a passive structural barrier, emerging evidence positions the CP as a central hub for cerebrospinal fluid (CSF) drainage, glymphatic-lymphatic clearance, and antigen presentation. This review provides a comprehensive understanding of recent advances in cpPME research, highlighting the adaptive remodeling of the immune landscape in response to neuroinflammation and aging. We critically evaluate the translational gap between rodent models and human physiology, discussing the implications for neurodegenerative diagnostics, neuroinflammatory conditions, infectious diseases and "nose-to-brain" therapeutic delivery. By integrating anatomical, physiological, and immunological perspectives, we offer a comprehensive framework for understanding the CP's role in CNS homeostasis and its potential as a transformative diagnostic and therapeutic target.
Spermidine in Alzheimer's Disease: Evidence from Animal Models and Human Studies.
Degener Neurol Neuromuscul Dis
Francesco Angelucci, Jiří Cerman, Jana Amlerova +3 more
Spermidine is a naturally occurring polyamine involved in multiple cellular processes, including growth regulation, protein translation, and autophagy. Increasing attention has been devoted to its potential neuroprotective effects, particularly in Alzheimer's disease (AD), a neurodegenerative disorder characterized by β-amyloid and phosphorylated tau accumulation, synaptic dysfunction, and progressive neuronal loss. In this narrative review, we examine potential mechanisms through which spermidine may influence AD pathophysiology and summarize available preclinical and clinical evidence. Preclinical studies indicate that spermidine induces autophagy, a key cellular clearance pathway responsible for removing damaged organelles and aggregated proteins. Because impaired neuronal autophagy contributes to the accumulation of β-amyloid and tau in AD, increasing intracellular spermidine levels may enhance the degradation of these toxic species. In addition, spermidine exhibits anti-inflammatory and antioxidant properties, attenuates microglial activation, and supports mitochondrial function. In animal models of AD and brain aging, spermidine administration has been associated with improvements in cognitive performance and synaptic function. However, human clinical evidence remains limited and largely inconclusive. Observational studies suggest associations between higher dietary spermidine intake and better cognitive outcomes, but do not establish causality. Randomized clinical trials to date are few, include small and heterogeneous populations, and have not demonstrated consistent effects on primary cognitive endpoints. Overall, spermidine represents a biologically plausible modulator of pathways relevant to neurodegeneration, but translation of preclinical findings into clinical benefit remains uncertain. Current evidence is insufficient to support its use as a therapeutic or preventive intervention in AD, and further well-designed clinical studies are required to clarify its efficacy and mechanisms of action.
Admission BNP-dominant biomarker phenotypes and in-hospital heart failure or cardiogenic shock in STEMI: a retrospective research note.
BMC Res Notes
Quan Zuo, Li Zhao, Tao Ge
To assess, in a single-center retrospective cohort, whether admission B-type natriuretic peptide (BNP)-dominant biomarker phenotypes incorporating D-dimer are associated with in-hospital heart failure or cardiogenic shock (HF/CS) in patients with ST-segment elevation myocardial infarction (STEMI).
Clinical Impact of Semaglutide in Patients with Heart Failure and Preserved Ejection Fraction.
J Clin Med
Yuki Hida, Teruhiko Imamura, Koichiro Kinugawa
Background: The clinical impact of oral semaglutide on cardiac biomarkers in real-world patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM) remains unclear. We evaluated whether initiation of oral semaglutide was associated with a reduction in B-type natriuretic peptide (BNP) levels and explored factors associated with this response. Methods: We retrospectively enrolled 27 patients with HFpEF who initiated oral semaglutide for T2DM management at a single academic center. Clinical data were collected at three time points: three months before treatment initiation (pre-treatment period), at initiation (baseline), and three months after semaglutide initiation (on-treatment period). The primary outcome was the change in the common logarithm of BNP levels (log BNP) during the on-treatment versus pre-treatment period. Results: Median age was 67 (59, 78) years and 21 (77.8%) were men. Log BNP remained stable during the pre-treatment period (p = 0.34) but decreased significantly during the on-treatment period (p < 0.001). The reduction in log BNP during the on-treatment period was significantly greater than during the pre-treatment period (mean difference -0.35, 95% confidence interval -0.44 to -0.11, p < 0.001). Concomitant reductions were observed in HbA1c, body weight, C-reactive protein, left atrial volume index, and left ventricular mass index. Changes in C-reactive protein levels were significantly correlated with those in log BNP (r = 0.46, p = 0.015). Conclusions: In patients with HFpEF and T2DM, three-month oral semaglutide therapy was associated with reductions in BNP, as well as improvements in glycemic control, systemic inflammation, left atrial volume index, and left ventricular mass index.