Findings that in ZDF rats proteinuria preceded FGF23 upregulation in the kidney and that the antiproteinuric effect of ACE inhibitor was associated with reduced FGF23 expression, could be taken to suggest proteinuria as a potential trigger of renal FGF23. Future studies are needed to address this possibility. In this context, a recent study demonstrated that in patients with CKD FGF23 was positively associated with proteinuria. Consistenly, we have documented here a positive correlation between renal FGF23 expression and proteinuria in diabetic rats. In conclusion, our data indicate that in experimental type 2 diabetes 1. the kidney is a site of FGF23 production; 2. during the progression of the disease, renal FGF23 increased in the face of Klotho and NaPi-2a co-transporter reduction; 3. ACE inhibitor therapy besides exhibiting antiproteinuric and renoprotective actions, attenuated FGF23 renal production and preserved the expression of Klotho resulting in sustained improvement of phosphate homeostasis. These data may offer new clues to understand how to interfere with the delicate balance of FGF23 and phosphorus in diabetes with potential implications in clinics. Glioblastoma multiforme is the most common and aggressive brain tumor in humans, and despite technical advances in neurosurgery and clinical neuro-oncology, the prognosis for GBM patients remains very poor. Most patients die within one year of diagnosis and are generally insensitive to current therapeutic genotoxic interventions. In the majority of GBM cases, resistance to such genotoxic modalities has been attributed to the attenuation of p53 function by alterations within the p53 signalling axis, including the overexpression of Murine Double Minute-2. The MDM2 oncoprotein, a major physiological negative regulator of p53, can bind to the p53 transactivation domain and interfere with the transcriptional regulatory mechanisms of p53. MDM2 is also an E3 ubiquitin ligase that promotes p53 proteasomal degradation. For this reason, inhibition of the interaction between MDM2 and p53 to reactivate endogenous p53 activity offers the opportunity for therapeutic intervention, particularly in GBMs. In GBMs, the p53 gene is relatively infrequently mutated; however, wild-type p53 remains dysfunctional due to overexpressed MDM2. Intensive work on different classes of MDM2 inhibitors has proven their therapeutic utility as activators of p53 in multiple tumor models. Indeed, it has been demonstrated that a number of small-molecule MDM2 inhibitors can disrupt the MDM2-p53 interaction, release p53 from negative control and activate the p53 pathway, leading to cell cycle arrest and apoptosis in a number of solid cancers and haematological malignancies. Moreover, many laboratories have shown that MDM2 inhibitors can synergise with conventional chemotherapeutic agents, resulting in enhanced efficacy. Interestingly, MDM2 inhibitors have been reported to induce cancer cell apoptosis even without the concomitant application of genotoxic stimuli. Little is known about the effects of MDM2 inhibitors on the in vitro growth of GBM cells. Recently, Nutlin-3, the first potent MDM2 small-molecule inhibitor identified, and new D-peptide derivatives were reported to be effective at inhibiting GBM cell growth in vitro, suggesting the validity of this experimental approach for the treatment of GBM. In the present study, we investigated the responsiveness of human GBM cell lines to a novel small-molecule MDM2 inhibitor with a spirooxoindolepyrrolidine core structure, named ISA27, which has been recently shown by nuclear magnetic resonance Everolimus mTOR inhibitor analysis to efficiently dissociate the reconstituted human MDM2-p53 complex. Consistently, ISA27 activated the p53 pathway in GBM cells and elicited the dose- and time-dependent inhibition of cell growth. ISA27 induced apoptosis and evoked cellular senescence, indicating that ISA27 promotes a pleiotropic anticancer effect in the GBM cells. The administration of ISA27 in vivo efficiently inhibited tumor growth in nude mice bearing a human GBM Bortezomib abmole bioscience xenograft. Significantly, ISA27 was non-toxic both in vitro in a normal human cell model and in vivo in a mouse model. A graphical assessment of synergy with regard to growth inhibition was performed using isobolographic analysis. In an isobologram, the equi-effective pairs of doses of two drugs are represented using rectangular coordinates. In the present study, the dose of ISA27 required to give a 50% effect was plotted on the abscissa, and the iso-effective dose of Temozolomide was plotted on the ordinate.