Gliomas are primary brain tumors characterized by genetic heterogeneity, metabolic reprogramming, and resistance to therapy, which collectively contribute to tumor progression and aggressive clinical behavior. Heightened aerobic glycolysis in these tumors is associated with altered glycolytic flux and dysregulated metabolic landscape. The ubiquitous dicarbonyl metabolite methylglyoxal (MGO) is a highly reactive glycating agent produced from glycolytic intermediates. MGO is a major precursor of advanced glycation end products (AGEs), and excessive AGE accumulation is associated with disruption of cellular homeostasis. Inhibitors of key bioenergetic pathways have shown potential in glioma, indicating that altered glycolysis may create metabolic vulnerabilities that influence tumor cell survival. In this context, increased glycolytic flux in glioma may provide a mechanistic link between glycation stress and tumor progression. This review discusses the influence of glycation stress in glioma biology and emphasize the importance of considering genetic heterogeneity, redox landscape, and metabolic comorbidities to better understand glycation burden and inform therapeutic strategies. Not applicable.
Cystic fibrosis (CF) is a life-limiting genetic disease caused by pathogenic variants in the CFTR gene. CFTR modulators (CFTRms) have substantially improved clinical outcomes, but real-world data on symptoms reported during therapy in pediatric populations remain limited. This study evaluated the frequency and distribution of adverse events (AEs) reported during 12 months of CFTR modulator (CFTRm) therapy in pediatric and adolescent patients with CF. This prospective, dual-center observational study conducted in Poland included 74 patients aged 2–18 years receiving lumacaftor/ivacaftor (LI), tezacaftor/ivacaftor (TI), or elexacaftor/tezacaftor/ivacaftor (ETI). Reported symptoms were monitored prospectively and categorized as respiratory, nervous system, gastrointestinal, or other AEs. AE profiles according to patient characteristics and CFTRm regimen were explored. At least one adverse event (AE) was reported by 90.5
The role of MKP family dual-specificity phosphatases (DUSPs) in oncogenesis, together with their potential as therapeutic targets in precision oncology, is now well established. These enzymes dephosphorylate both phosphotyrosine and phosphothreonine residues on extracellular signal-regulated kinase ERK1/2, thereby attenuating mitogen-activated protein kinase (MAPK) signalling. DUSP6/MKP3 acts as a context-dependent regulator with tumour-suppressive or tumour-promoting roles across cancers. Glioblastoma (GBM), an aggressive primary brain tumour with dismal clinical outcomes, has shown limited response to both oncogene-targeted and immunotherapeutic approaches. DUSP6/MKP3 is frequently overexpressed in GBM and contributes to tumour growth, invasive behaviour, and treatment resistance. Computational analyses identify DUSP family genes, including DUSP6/MKP3, as recurrently dysregulated within GBM driver networks, supporting a central role in gliomagenesis. Here, we discuss DUSP6/MKP3 in glioblastoma, integrating transcriptional and cell-based evidence to define its molecular mechanisms and clinical relevance.
Snake envenoming triggers a complex inflammatory response that substantially contributes to local tissue destruction and systemic complications. Among the innate immune pathways implicated in venom-induced injury, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-), and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key sensor-effector platform linking tissue damage, ionic imbalance, reactive oxygen species (ROS), lipid mediators, and cytokine maturation. Experimental studies indicate that crude venoms and isolated snake toxins, including Lys49 and Asp49 phospholipase A2 (PLA2), metalloproteinases, and C-type lectin/C-type lectin-like proteins, can activate NLRP3 inflammasome-dependent signaling, leading to caspase-1 activation, interleukin (IL)-1β release, and, in some settings, pyroptotic cell death. These findings position the NLRP3 inflammasome as a promising adjunctive therapeutic target in snakebite envenoming, although causal evidence remains restricted to selected toxin models and broader validation across venom classes is still required. This review summarizes the current understanding of NLRP3 inflammasome biology in the context of snake venoms and toxins, discusses the molecular mechanisms proposed for inflammasome priming and activation, and highlights unresolved questions relevant to toxinology, immunology, and adjunctive therapy development. Recent literature also places venom-derived molecules within the broader framework of NLRP3 inflammasome modulation, reinforcing the idea that venoms may serve both as drivers of pathology and as sources of pharmacological leads.
Glioblastoma (GBM) exhibits extensive metabolic reprogramming, including glucose and glutamine (Gln) addiction, with Gln being converted into glutamate by glutaminase, encoded by the GLS and GLS2 genes. GLS2 acts as a context-dependent tumor suppressor, although the underlying mechanisms remain poorly understood. GLS2 is silenced in GBM, and we previously showed that its re-expression modulates pyruvate dehydrogenase (PDH) activity and tricarboxylic acid cycle (TCAC) metabolism, suggesting a distinct metabolic rewiring associated with its tumor-suppressive function. LN229 and T98G GBM cell lines were used as experimental models. Metabolomic profiling by liquid chromatography-mass spectrometry was performed to compare changes in central metabolic pathways following GLS2 or GLS overexpression. Glutaminase and PDH enzymatic activities were measured, and Western blotting was performed to assess GLS, GLS2, and PDHA1 protein levels and PDHA1 phosphorylation. A Seahorse analyzer was employed to quantify real-time ATP production derived from glycolysis and oxidative phosphorylation. Overexpression of GLS2, but not GLS, in LN229 cells caused the accumulation of TCAC-related metabolites, except for citrate, whose depletion is attributed to GLS2’s effect on PDH phosphorylation, causing reduced PDH activity. This was accompanied by decreased levels of several acyl-carnitines. Furthermore, GLS2 induced the accumulation of glucose/fructose, while reducing levels of glucose-6-phosphate and pentose-phosphates, consistent with altered glycolysis. GLS2 also diminished the ATP/AMP ratio, confirmed by a reduced ATP synthesis rate, particularly glycolytic ATP, whereas mitochondrial ATP production remained unaltered. GLS2 exerts an isoenzyme-specific effect on Gln and glucose metabolism in GBM, likely modulating the glycolysis/pentose-phosphate pathway (PPP)-TCAC-axis.
