Role of 1-Deoxysphingolipids in docetaxel neurotoxicity.

A major dose-limiting side effect of docetaxel chemotherapy is peripheral neuropathy. Patients' symptoms include pain, numbness, tingling and burning sensations, and motor weakness in the extremities. The molecular mechanism is currently not understood, and there are no treatments available. Previously, we have shown an association between neuropathy symptoms of patients treated with paclitaxel and the plasma levels of neurotoxic sphingolipids, the 1-deoxysphingolipids (1-deoxySL) (Kramer et al, FASEB J, 2015). 1-DeoxySL are produced when the first enzyme of the sphingolipid biosynthetic pathway, serine palmitoyltransferase (SPT), uses L-alanine as a substrate instead of its canonical amino acid substrate, L-serine. In the current investigation, we tested whether 1-deoxySL accumulate in the nervous system following systemic docetaxel treatment in mice. In dorsal root ganglia (DRG), we observed that docetaxel (45 mg/kg cumulative dose) significantly elevated the levels of 1-deoxySL and L-serine-derived ceramides, but not sphingosine-1-phosphate (S1P). S1P is a bioactive sphingolipid and a ligand for specific G-protein-coupled receptors. In the sciatic nerve, docetaxel decreased 1-deoxySL and ceramides. Moreover, we show that in primary DRG cultures, 1-deoxysphingosine produced neurite swellings that could be reversed with S1P. Our results demonstrate that docetaxel chemotherapy up-regulates sphingolipid metabolism in sensory neurons, leading to the accumulation of neurotoxic 1-deoxySL. We suggest that the neurotoxic effects of 1-deoxySL on axons can be reversed with S1P.

Sphingoid bases and their involvement in neurodegenerative diseases.

Sphingoid bases (also known as long-chain bases) form the backbone of sphingolipids. Sphingolipids comprise a large group of lipid molecules, which function as the building blocks of biological membranes and play important signaling and regulatory roles within cells. The roles of sphingoid bases in neurotoxicity and neurodegeneration have yet to be fully elucidated, as they are complex and multi-faceted. This comprises a new frontier of research that may provide us with important clues regarding their involvement in neurological health and disease. This paper explores various neurological diseases and conditions which result when the metabolism of sphingoid bases and some of their derivatives, such as sphingosine-1-phosphate and psychosine, becomes compromised due to the inhibition or mutation of key enzymes. Dysregulation of sphingoid base metabolism very often manifests with neurological symptoms, as sphingolipids are highly enriched in the nervous system, where they play important signaling and regulatory roles.

Understanding men's body image in the context of their romantic relationships.

This study examined men's body image in the context of their romantic relationships. One hundred and four heterosexual romantic couples (N = 208 participants) completed measures assessing men's body image, perceptions of men's weight change, relationship length, and sexual intimacy. Men's height and weight were also measured. Results indicate that men were more likely to be satisfied with their bodies when they perceived their partners to be, when their partners actually were satisfied with their bodies, and when they perceived themselves to have gained relatively little weight throughout the duration of their relationships. Analyses also revealed that men expressed greater body satisfaction when there was a relatively high degree of sexual intimacy in the relationship. Findings are discussed in terms of their contributions to researchers' and practitioners' understanding of men's body satisfaction.