Micro and nanoplastics are fragments with dimensions less than a millimeter invading all terrestrial and marine environments. They have become a major global environmental issue in recent decades and, indeed, recent scientific studies have highlighted the presence of these fragments all over the world even in environments that were thought to be unspoiled. Analysis of micro/nanoplastics in isolated samples from abiotic and biotic environmental matrices has become increasingly common. Hence, the need to find valid techniques to identify these micro and nano-sized particles. In this review, we discuss the current and potential identification methods used in microplastic analyses along with their advantages and limitations. We discuss the most suitable techniques currently available, from physical to chemical ones, as well as the challenges to enhance the existing methods and develop new ones. Microscopical techniques (i.e., dissect, polarized, fluorescence, scanning electron, and atomic force microscopy) are one of the most used identification methods for micro/nanoplastics, but they have the limitation to produce incomplete results in analyses of small particles. At present, the combination with chemical analysis (i.e., spectroscopy) overcome this limit together with recently introduced alternative approaches. For example, holographic imaging in microscope configuration images microplastics directly in unfiltered water, thus discriminating microplastics from diatoms and differentiates different sizes, shapes, and plastic types. The development of new analytical instruments coupled with each other or with conventional and innovative microscopy could solve the current problems in the identification of micro/nanoplastics.

Signalling lipids are known to control a wide array of cellular processes, including cell proliferation, apoptosis, migration, and energy metabolism. Fatty acids and their derivatives, eicosanoids, phosphoinositides, sphingolipids, some cannabinoid-like molecules bind and activate nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). This subfamily of transcription factors comprises three isotypes - PPARα (NR1C1), PPAR β/δ (NR1C2), PPARγ (NR1C3) - which bind to specific DNA response elements, as heterodimers with retinoid X receptors. PPAR activity is modulated by post-translational modifications and cofactors, towards which they show differential affinity. The three PPARs mutually interact, being integrated in a complex system, leading to the concept of a "PPAR triad". Nevertheless, the isotypes also show distinct actions on cellular physiology and partially different tissue, ligand and target gene specificities. In the brain, while the functions of PPARγ and its ligands are being thoroughly investigated, the actual and potential roles of PPARα and β/δ are far from being clarified. PPARα appears especially intriguing, since it is selectively expressed in certain brain areas and neuronal/glial populations, and modulates antioxidant responses, neurotransmission, neuroinflammation, neurogenesis, and glial cell proliferation/differentiation. This receptor and its endogenous ligands, including oleoylethanoloamide (OEA) and palmitoylethanolamide (PEA), are involved in physiological and pathological responses, such as satiety, memory consolidation, and modulation of pain perception. The protective role of PPARα agonists in neurodegenerative diseases and in neuropsychiatric disorders makes manipulation of this pathway highly attractive as therapeutic strategy for neuropathological conditions. In this review, we focus on the pleiotropic functions of PPARα and its lipid ligands in the nervous tissue, devoting special attention to neuroprotection.

Ewing sarcomas (ES) are biologically aggressive tumors of bone and soft tissues for which no cure is currently available. Most ES patients do not respond to chemotherapeutic treatments or acquire resistance. Since the PI3K/AKT/mTOR axis is often deregulated in ES, its inhibition offers therapeutic perspective for these aggressive tumors. Herein, by using splicing sensitive arrays, we have uncovered an extensive splicing program activated upon inhibition of the PI3K/AKT/mTOR signaling pathway by BEZ235. Bioinformatics analyses identified hnRNPM as a key factor in this response. HnRNPM motifs were significantly enriched in introns flanking the regulated exons and proximity of binding represented a key determinant for hnRNPM-dependent splicing regulation. Knockdown of hnRNPM expression abolished a subset of BEZ235-induced splicing changes that contained hnRNPM binding sites, enhanced BEZ235 cytotoxicity and limited the clonogenicity of ES cells. Importantly, hnRNPM up-regulation correlates with poor outcome in sarcoma patients. These findings uncover an hnRNPM-dependent alternative splicing program set in motion by inhibition of the mTOR/AKT/PI3K pathway in ES cells that limits therapeutic efficacy of pharmacologic inhibitors, suggesting that combined inhibition of the PI3K/AKT/mTOR pathway and hnRNPM activity may represent a novel approach for ES treatment.

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Alternative splicing plays a key role in the DNA damage response and in cancer. Ewing Sarcomas (ES) are aggressive tumors caused by different chromosomal translocations that yield in-frame fusion proteins driving transformation. RNA profiling reveals genes differentially regulated by UV light irradiation in two ES cell lines exhibiting different sensitivity to genotoxic stress. In particular, irradiation induces a new isoform of the RNA helicase DHX9 in the more sensitive SK-N-MC cells, which is targeted to nonsense-mediated decay (NMD), causing its downregulation. DHX9 protein forms a complex with RNA polymerase II (RNAPII) and EWS-FLI1 to enhance transcription. Silencing of DHX9 in ES cells sensitizes them to UV treatment and impairs recruitment of EWS-FLI1 to target genes, whereas DHX9 overexpression protects ES cells from genotoxic stress. Mechanistically, we found that UV light irradiation leads to enhanced phosphorylation and decreased processivity of RNAPII in SK-N-MC cells, which in turn causes inclusion of DHX9 exon 6A. A similar effect on DHX9 splicing was also elicited by treatment with the chemotherapeutic drug etoposide, indicating a more general mechanism of regulation in response to DNA damage. Our data identify a new NMD-linked splicing event in DHX9 with impact on EWS-FLI1 oncogenic activity and ES cell viability.