Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that is present in all eukaryotic cells and plays key roles in various extracellular, cytosolic, and nuclear signaling pathways. Two sphingosine kinase isoforms, sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2), synthesize S1P by phosphorylating sphingosine. While SPHK1 is a cytoplasmic kinase, SPHK2 is localized to the nucleus, endoplasmic reticulum, and mitochondria. The SPHK2/S1P pathway regulates transcription, telomere maintenance, mitochondrial respiration, among many other processes. SPHK2 is under investigation as a target for treating many age-associated conditions, such as cancer, stroke, and neurodegeneration. In this review, we will focus on the role of SPHK2 in health and disease.

Coronavirus disease (COVID-19), caused by SARS-CoV-2, leads to symptoms ranging from asymptomatic disease to death. Although males are more susceptible to severe symptoms and higher mortality due to COVID-19, patient sex has rarely been examined. Sex-associated metabolic changes may implicate novel biomarkers and therapeutic targets to treat COVID-19. Here, using serum samples, we performed global metabolomic analyses of uninfected and SARS-CoV-2-positive male and female patients with severe COVID-19. Key metabolic pathways that demonstrated robust sex differences in COVID-19 groups, but not in controls, involved lipid metabolism, pentose pathway, bile acid metabolism, and microbiome-related metabolism of aromatic amino acids, including tryptophan and tyrosine. Unsupervised statistical analysis showed a profound sexual dimorphism in correlations between patient-specific clinical parameters and their global metabolic profiles. Identification of sex-specific metabolic changes in severe COVID-19 patients is an important knowledge source for researchers striving for development of potential sex-associated biomarkers and druggable targets for COVID-19 patients.

No abstract

No abstract

BackgroundCognitive impairments may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity (chemobrain) can be subtle or disabling and frequently include disturbances in memory, attention, executive function, and processing speed. Cognitive impairments may go away soon after chemotherapy is over or may persist for years and yet, there is a paucity of effective treatments. Research has shown that chemotherapy drugs such as doxorubicin promote neurotoxicity and cognitive disturbances. Critically, some studies demonstrated that dementia occurs more commonly in cancer patients who had chemotherapy treatment compared to individuals never exposed to chemotherapy. Understanding whether and how chemotherapy may promote dementia later in life is needed.MethodTo establish new insights into chemotherapy‐induced cognitive impairments, we use wild‐type and Tg2576 mice (a model of Alzheimer’s disease (AD)) treated with Doxil, a liposomal form of doxorubicin. Mice are injected intraperitoneally with saline or Doxil for six weeks. These conditions recapitulate a dosing schedule used in human patients and are the same as those used in similar studies in mice. Mice are then tested with cognitive and behavior assays, and their brains are analyzed for aging and AD phenotypes.ResultIn our studies, we discovered that Doxil promotes cognitive impairment in wild‐type mice. We also found that the brains of young mice exposed to Doxil contain lipofuscin—a mixture of oxidized proteins and lipids that is usually found only in the aged or diseased brains. DNA damage occurred with Doxil treatment in mice, confirming Doxil accelerated features of brain aging. Critically, Doxil enhances the deposition of amyloid in Tg2576 mice.ConclusionOur study demonstrates evidence of accelerated brain aging in wild‐type mice and amyloid deposition in AD mice due to Doxil treatment. Our data provide a foundation for investigating chemotherapy as a potential risk factor for AD that warrants further study. This research is being pursued in our laboratory.