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Background: Isorhamnetin (ISO), a dietary O-methylated flavonol, was evaluated for hypoglycemic activity and mechanism in a streptozotocin (STZ) model of type 1 diabetes. Methods: We conducted untargeted plasma metabolomics (ESI±), network integration and docking, and measured pancreatic PI3K, phosphorylated AKT, and COX-2; INS-1 β cells challenged with the PI3K inhibitor LY294002 were used to assess viability, intracellular ROS, and PI3K phosphorylation. Results: ISO lowered fasting glycemia, increased circulating insulin, improved dyslipidemia by reducing low-density lipoprotein cholesterol (LDL-C), and preserved islet architecture. Untargeted plasma metabolomics (ESI±) indicated broad remodeling with enrichment of arachidonic-, linoleic-, starch/sucrose- and glycerophospholipid pathways. Network integration and docking prioritized targets converging on PI3K/AKT and COX-2/eicosanoid signaling. Consistently, in pancreatic tissue, ISO increased PI3K, phosphorylated AKT, and reduced COX-2. In INS-1 beta cells challenged with the PI3K inhibitor LY294002, ISO improved viability, decreased intracellular ROS, and partially restored PI3K phosphorylation at 4 µM. Conclusions: Together, these data indicate that ISO exerts hypoglycemic effects while supporting β-cell integrity through activation of PI3K/AKT and tempering of COX-2–linked lipid-mediator pathways. ISO therefore emerges as a food-derived adjunct candidate for autoimmune diabetes, and the work motivates targeted lipidomics and in vivo pathway interrogation in future studies. Full article

Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial to identify novel therapeutic targets. Evidence indicates that the phosphoinositide 3-kinases (PI3Ks)/Akt pathway plays an important role, in particular in advanced cSCC. Questions remain of whether all four PI3K isoforms able to activate Akt are involved and whether selective inhibition of specific isoform(s) might represent a more targeted strategy. Here we determined the sensitivity of four patient-derived cSCC cell lines to isoform-specific PI3K inhibitors to start investigating their potential therapeutic value in cSCC. Parallel experiments were performed in immortalized keratinocyte cell lines. We observed that pan PI3Ks inhibition reduced the growth/viability of all tested cell lines, confirming the crucial role of this pathway. Selective inhibition of the PI3K isoform p110α reduced growth/viability of keratinocytes and of two cSCC cell lines while affecting the other two only slightly. Importantly, p110α inhibition reduced Akt phosphorylation in all cSCC cell lines. These data indicate that growth and viability of the investigated cSCC cells display differential sensitivity to isoform-specific PI3K inhibitors. Full article