Metformin and Temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models Metformin and Temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models

Changes in D₂ receptors during antidepressant therapy have been reported in patients with major depressive disorder using PET/SPET. The aim of this study was to evaluate modifications in D₂ receptors that might occur in patients affected by obsessive-compulsive disorder (OCD) during serotonin reuptake sites inhibitors (SSRIs). To this purpose, we measured the in vivo binding of [¹¹C]raclopride ([¹¹C]Rac)in the brain of a group of OCD naïve patients before and after the repeated administration of the inhibitor SSRI fluvoxamine. Eight patients with a Diagnostic and Statistical Manual of Mental Disorders IVth edition diagnosis of OCD completed the study undergoing a PET scan and a complete clinical evaluation before and during treatment with fluvoxamine. Patients have been compared also with a group of nine age-matched normal volunteers. Fluvoxamine treatment significantly improved clinical symptoms and increased [¹¹C]Rac binding potential (BP) in the basal ganglia of OCD patients (7.5±5.2, 6.9±6.9, and 9.9±9.3% in dorsal caudate, dorsal putamen, and ventral basal ganglia, respectively; p<0.01) to values closer to those observed in the group of normal subjects. Chronic treatment with fluvoxamine induces a slight but significant increase in striatal [¹¹C]Rac BP of previously drug-naïve OCD patients. The modifications in D₂ receptor availability might be secondary to fluvoxamine effects on serotoninergic activity.

Aging is associated with an exaggerated response to peripheral inflammatory challenges together with behavioral and cognitive deficits. Studies considering both age and sex remain limited, despite sex dimorphism of astrocytes and microglial cells is largely recognized. To fill this knowledge gap, we investigated the effect of a single intraperitoneal lipopolysaccharide (LPS) administration in adult and aged mice. We assessed the expression of different inflammatory mediators, and the microglial response through binding of [¹⁸F]-VC701 tracer to translocator protein (TSPO) receptors in the male and female brain. Aged female brain showed a higher pro-inflammatory response to LPS compared to adult female and to aged male, as revealed by ex vivo binding to TSPO receptors and pro-inflammatory mediator transcript levels. The highest astroglial reaction was observed in the brain of aged females. Differently to the other groups of animals, in aged males LPS challenge did not affect transcription of triggering receptor expressed on myeloid cells 2 (TREM2). In conclusion, our study shows that in the mouse’s brain the neuro-inflammatory response to an acute peripheral insult is sex- and age-dependent. Moreover, our results might set the basis for further studies aimed at identifying sex-related targets involved in the modulation of the aberrant neuro-inflammatory response that characterizes aging. This knowledge could be relevant for the treatment of conditions such as delirium and dementia.

Systems Biology holds that complex cellular functions are generated as system-level properties endowed with robustness, each involving large networks of molecular determinants, generally identified by “omics” analyses. In this paper we describe four basic cancer cell properties that can easily be investigated in vitro: enhanced proliferation, evasion from apoptosis, genomic instability, and inability to undergo oncogene-induced senescence. Focusing our analysis on a K-ras dependent transformation system, we show that enhanced proliferation and evasion from apoptosis are closely linked, and present findings that indicate how a large metabolic remodeling sustains the enhanced growth ability. Network analysis of transcriptional profiling gives the first indication on this remodeling, further supported by biochemical investigations and metabolic flux analysis (MFA). Enhanced glycolysis, down-regulation of TCA cycle, decoupling of glucose and glutamine utilization, with increased reductive carboxylation of glutamine, so to yield a sustained production of growth building blocks and glutathione, are the hallmarks of enhanced proliferation. Low glucose availability specifically induces cell death in K-ras transformed cells, while PKA activation reverts this effect, possibly through at least two mitochondrial targets. The central role of mitochondria in determining the two investigated cancer cell properties is finally discussed. Taken together the findings reported herein indicate that a system-level property is sustained by a cascade of interconnected biochemical pathways that behave differently in normal and in transformed cells.