Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor, necessitating innovative multi-target strategies. Natural compounds like the triterpenoid Alisol B from Alisma orientale hold promise due to their polypharmacological potential, yet their system-level mechanisms are unclear. Using an integrated multi-omics approach (transcriptomics, proteomics, lysine acetyl-proteomics) in resistant GBM cells and validating findings in vitro and in AB strain zebrafish (Danio rerio) xenografts, we found that Alisol B induces endoplasmic reticulum stress and G2/M arrest, initiated by extensive lysine acetylation reprogramming on histones and metabolic enzymes (e.g., FASN, FDFT1). This epigenetic rewiring leads to disrupted cholesterol biosynthesis, characterized by transcriptional activation of the mevalonate pathway alongside post-transcriptional suppression of terminal enzymes (DHCR7, CYP51A1), suggestive of toxic intermediate accumulation. Alisol B also downregulated the oncogenic axis (BIRC5-FOXM1-ITGA4) and SCD5. This study delineates Alisol B's novel multi-mechanistic action through concurrent epigenetic rewiring, metabolic dysfunction induction, and survival network dismantling. Our work elucidates the molecular pharmacology of a natural compound and provides a framework for developing polypharmacological therapies against resistant cancers, exemplifying natural products as tools to reveal new therapeutic paradigms.

Protein Kinase N1 (PKN1) is a PKC-related serine/threonine kinase of the AGC group within the eukaryotic protein kinase superfamily (ePK) that orchestrates oncogenic, metabolic, and cytoskeletal signaling. Despite these critical roles, the phosphorylation-dependent regulatory network of PKN1 remains largely undefined. We performed a large-scale phosphoproteomic data integration of publicly available human datasets (892 profiling datasets and 191 differential datasets) to identify recurrent PKN1 phosphorylation sites. This analysis identified two predominant PKN1 phosphosites, S562 and S916, that were frequently observed and differentially regulated across studies. The S916 maps to a turn motif (TM) in the AGC group of kinases, which is evolutionarily conserved among PKN paralogs, while S562 is non-conserved and appears to be PKN1-specific. Co-regulation and enrichment analyses suggest that S916 is associated with insulin/AMPK signaling and metabolic pathways, whereas S562 co-occurs with phosphosites involved in cell division, cytoskeletal regulation, and microtubule cytoskeleton organization. Integrating predicted and experimentally validated kinases, substrates, and interactors, we reconstructed a phospho-regulatory network that positions PKN1 at the crossroads of cytoskeleton organization and metabolic signaling. To assess the disease relevance of these phosphorylation events, we integrated transcriptomic and phosphoproteomic data from the hepatocellular carcinoma database (HCCDB). PKN1 was markedly up-regulated in HCC, and its phosphorylation at S916 was positively co-regulated with multiple oncogenic and proliferation-associated protein phosphosites. These results predict S562 and S916 as potential sites for targeted biochemical validation and functional experiments. The identification of S562 and S916 as key regulatory sites provides new mechanistic insight into PKN1 activation and highlights potential avenues for therapeutic targeting.

Urothelial carcinoma (UC) of the bladder exhibits low- and high-grade papillary forms with distinct prognoses. High mobility group proteins (HMGA1, HMGA2, HMGB1) and miR-106a-5p are involved in tumor progression, but their interplay in UC remains incompletely understood. The aim of this study was to compare the expression of these parameters in low- and high-grade papillary UC. Tissue samples from 80 patients (40 low-grade and 40 high-grade) undergoing transurethral resection or cystectomy were analyzed, with control samples consisting of tumor-adjacent tissues without histopathological alterations obtained from the same patients. HMGA1, HMGA2, and HMGB1 protein expression was assessed immunohistochemically. Gene expression was quantified by real-time PCR, and miR-106a-5p levels were measured by droplet digital PCR. Statistical analysis was conducted using Statistica 13.3, applying one-way ANOVA with Tukey's post hoc test and correlation analysis, with p < 0.05 considered significant. Expression of HMGA1 and HMGB1 was reduced in low-grade papillary urothelial carcinoma compared to control tissues, whereas both proteins were significantly increased in high-grade lesions. HMGA2 expression was minimal in low-grade tumors but partially restored in high-grade tumors. Analysis revealed the highest levels of miR-106a-5p in normal urothelium, slightly decreased in low-grade tumors, and significantly reduced in high-grade cancers. HMG proteins and miR-106a-5p demonstrate distinct expression patterns in low- versus high-grade papillary UC, which correlates with tumor aggressiveness. These molecules may serve as diagnostic and prognostic biomarkers. Their potential as therapeutic targets requires further mechanistic and translational investigation.

Glycine N-methyltransferase (GNMT), a S-adenosylmethionine (SAM)-dependent methyltransferase, is primarily expressed in the liver and plays a key role in regulating liver metabolism and protecting against liver injury. Several studies have shown that deficiency or downregulation of GNMT is strongly associated with the pathogenesis of hepatocellular carcinoma (HCC), highlighting its critical role as a tumor suppressor. Other studies have shown that GNMT is also strongly correlated with the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). Although many factors regulate GNMT expression, recent studies have identified microRNAs (miRNAs), such as miR-873-5p and miR-224, as key post-transcriptional regulators that directly target GNMT mRNA and suppress its expression in HCC and MAFLD. This review provides an overview of GNMT's role in liver physiology and how its dysregulation contributes to the progression of HCC and MAFLD, with a focus on the regulation of GNMT by miR-873-5p and miR-224. We also highlight the potential of these two miRNAs as biomarkers and therapeutic targets for HCC and MAFLD, discussing emerging strategies such as antisense-based inhibition, gene therapy, and small-molecule inducers aimed at restoring GNMT expression.

Prostate cancer (PCa) is the most general cancer in men and is often linked with distant metastasis in its later stages. The caffeic acid (CA) derivative, N-(4-methoxyphenyl)methylcaffeamide (MPMCA), demonstrates superior liver-protective effects compared to CA. Nevertheless, the functions of MPMCA on prostate cancer metastasis remain unclear. Here, we demonstrate that MPMCA blocks migration and invasion in prostate cancer cells without affecting cell viability. By suppressing the production of mesenchymal markers Vimentin, N-cadherin and β-catenin and upregulating the production of the epithelial marker Zonula Occludens-1 (ZO-1), MPMCA also controls Epithelial-Mesenchymal Transition (EMT). The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility. Transfection with Snail and Slug cDNA reverses MPMCA's suppression of EMT, migration, and invasion in prostate cancer cells. Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer.

The extent of cross-reactive antibodies to SARS-CoV-2 elicited by seasonal human coronaviruses (HCoVs) remains unclear. We analyzed longitudinal preinfection and postinfection IgG responses in 62 older adults with PCR-confirmed HCoV infections from sera collected prior to the emergence of SARS-CoV-2. At baseline, 12.9% and 16.1% had low-titer antibodies against SARS-CoV-2 spike (S) or nucleocapsid (N) proteins, respectively, but postinfection increases were marginal. Our findings suggest seasonal HCoV infections induce limited SARS-CoV-2 cross-reactive antibodies in community-dwelling older adults.

Background: Sudden unexpected death in epilepsy (SUDEP) causes significant mortality, affecting approximately 1 in 1000 people with epilepsy. Clinical and preclinical studies have identified severe seizures, bradycardia, apnea, severe postictal hypoxia, and sleep deficiency that emerge prior to SUDEP and thus may represent temporal biomarkers. The metabolic ketogenic diet (KD) therapy increases longevity in preclinical SUDEP models. Here, the hypothesis that KD therapy would determine whether the emergent sleep deficiency, bradycardia, apnea and/or hypoxemia persist as temporal biomarkers in preclinical SUDEP was tested. Methods: Kv1.1 knockout (KO) mice, a preclinical SUDEP model, and wild-type littermates were weaned onto a standard diet (SD) or treated with KD. In separate cohorts, approximately every 10 days, seizures and sleep architecture were recorded with electroencephalography-electromyography (EEG-EMG), heart rate was measured with noninvasive ECGenie, apnea was assessed with noninvasive airway mechanics, and blood O₂ saturation was measured with pulse oximetry. Data were aligned from the day of sudden death and analyzed retrospectively. Results: KD treatment significantly increased longevity and reduced seizures, reproducing previous studies. Using retrospective analyses from the day of death, KD treatment attenuated the emergence of (i) interictal intermittent bradycardia in the last 20 days of life, (ii) apnea, and (iii) intermittent hypoxemia in the last 10 days of life. In contrast, (iv) KD treatment did not rescue REM and NREM sleep deficiencies during the last 10 days of life. Conclusions: Our findings provide novel preclinical support for KD as a candidate therapy to attenuate seizure frequency and burden, bradycardia, apnea, and hypoxemia in SUDEP. In addition, sleep deficiency persisted as a potential temporal biomarker of preclinical SUDEP; however, causality will need to be tested in future studies.

Building on our previous systematic review that synthesized eight core sustainable appetitive traits central to food behavior research, the present study extends this framework through an empirical investigation of Generation Z university students in Greece. We have established the conceptual foundation by mapping emotional, sensory, and behavioral regulation drivers of eating behavior, underscoring their relevance for nutrition and sustainability. However, empirical applications of this multidimensional framework to Generation Z remained scarce.

This study addresses this gap by examining eating behaviors among approximately 800 students at the University of Ioannina using a validated post-pandemic questionnaire.

Results revealed heterogeneity across six domains, with consensus observed only in sensory-driven eating (M = 3.88) and openness to new foods (M = 4.00). Cluster analysis identified two distinct profiles: Exploratory and Hedonic Responders and Emotionally Regulated and Satiety-Oriented Responders. These clusters delineate a novel profile of Generation Z, portraying them as digitally immersed, sustainability-oriented, and emotionally sensitive, yet divided between impulsive exploration and regulated satiety.

The study contributes new empirical insights into post-pandemic food behavior. It establishes a comprehensive evidence base for designing culturally sensitive wellness programs and targeted nutritional interventions that support sustainable dietary practices. The continuity between the two papers underscores both theoretical importance and the practical necessity of integrating emotional, sensory, and regulatory dimensions in advancing sustainable eating futures among young adults.

Background/Objectives: Cystic fibrosis (CF) is a genetic disorder historically associated with malnutrition. The advent of CF transmembrane conductance regulator (CFTR) modulators and improved pulmonary outcomes have coincided with increased body mass index (BMI). This study aims to evaluate the prevalence of overweight/obesity among children with cystic fibrosis and associated comorbidities. Methods: A retrospective chart review assessed patients with CF (2-23 years of age). Data collected included demographics, CF genotype, anthropometric measurements, pancreatic function, medication history, and any comorbid diagnoses. BMI categories were defined as: underweight (<5th percentile), normal weight (5th-85th percentile), overweight (85th-95th percentile), and obese (>95th percentile). Results: Among 243 patients (mean age 10.4 years, 53% male), 4 (1.6%) were malnourished, 192 (79%) had normal weight, and 47 (19.3%) were overweight (OW)/obese (26 (10.7%) OW, and 21 (8.6%) were obese). OW/obese patients (mean age 11.3 years, 61.7% male) included 20 patients (42.5%) with two severe CF-related mutations, 21 (44%) with pancreatic insufficiency, and 40 (85.1%) receiving CFTR modulator treatment. Obstructive sleep apnea (OSA) was the most common comorbidity in OW/obese patients with CF, followed by impaired glucose intolerance and CF-related diabetes and hyperlipidemia; these associations did not reach statistical significance. Conclusions: Overweight/obesity affects nearly one in five patients with CF, including those with severe genotype and pancreatic insufficiency.

Patients without overt glomerular dysfunction may develop tubular injury, referred to as subclinical acute kidney injury. The burden of COVID-19-related renal damage may therefore be underestimated, as current KDIGO criteria do not include tubular damage biomarkers (TDBs). This study evaluated kidney injury in patients with long COVID by assessing TDBs alongside glomerular biomarkers, proteinuria (UPCr) and albuminuria (UACr). In this cross-sectional study, 75 patients without prior chronic kidney disease were recruited from a long COVID outpatient clinic and stratified according to the time since SARS-CoV-2 infection into 6-, 12-, and 24-month post-COVID-19 groups (referred to as 6-, 12-, and 24-MPC, respectively). Overall, 49.3% of patients had normal estimated glomerular filtration rate (eGFR >90 mL/min/1.73 m²), 34.7% showed mildly reduced eGFR (90-60), and 16% exhibited marked eGFR reduction (<60). Among patients with normal eGFR, the combined mean prevalence (mean ± SD) of abnormal TDBs, UACr, and UPCr was 29.7 ± 4.9%, indicating early tubular injury. Temporal analysis revealed a higher prevalence of TDB abnormalities at 6-MPC, whereas glomerular dysfunction was more pronounced at 24-MPC. These findings suggest that renal injury in long COVID is more prevalent than previously recognized and that TDB assessment may improve early detection of kidney damage.