Explore the vast range of titles available.

(R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine’s rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine’s effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects). The metabolomic profile of these subjects was characterized at multiple time points, and a comprehensive analysis was investigated between the following: MDD and healthy controls, treatment and placebo in both groups and the corresponding response to ketamine treatment. Ketamine treatment resulted in a general increase in circulating sphingomyelins, levels which were not correlated with response. Ketamine response resulted in more pronounced effects in the kynurenine pathway and the arginine pathway at 4 h post-infusion, where a larger decrease in circulating kynurenine levels and a larger increase in the bioavailability of arginine were observed in responders to ketamine treatment, suggesting possible mechanisms for response to ketamine treatment.

Aims/hypothesisGestational diabetes mellitus (GDM) affects up to 20% of pregnancies, and almost half of the women affected progress to type 2 diabetes later in life, making GDM the most significant risk factor for the development of future type 2 diabetes. An accurate prediction of future type 2 diabetes risk in the early postpartum period after GDM would allow for timely interventions to prevent or delay type 2 diabetes. In addition, new targets for interventions may be revealed by understanding the underlying pathophysiology of the transition from GDM to type 2 diabetes. The aim of this study is to identify both a predictive signature and early-stage pathophysiology of the transition from GDM to type 2 diabetes.MethodsWe used a well-characterised prospective cohort of women with a history of GDM pregnancy, all of whom were enrolled at 6–9 weeks postpartum (baseline), were confirmed not to have diabetes via 2 h 75 g OGTT and tested anually for type 2 diabetes on an ongoing basis (2 years of follow-up). A large-scale targeted lipidomic study was implemented to analyse ~1100 lipid metabolites in baseline plasma samples using a nested pair-matched case–control design, with 55 incident cases matched to 85 non-case control participants. The relationships between the concentrations of baseline plasma lipids and respective follow-up status (either type 2 diabetes or no type 2 diabetes) were employed to discover both a predictive signature and the underlying pathophysiology of the transition from GDM to type 2 diabetes. In addition, the underlying pathophysiology was examined in vivo and in vitro.ResultsMachine learning optimisation in a decision tree format revealed a seven-lipid metabolite type 2 diabetes predictive signature with a discriminating power (AUC) of 0.92 (87% sensitivity, 93% specificity and 91% accuracy). The signature was highly robust as it includes 45-fold cross-validation under a high confidence threshold (1.0) and binary output, which together minimise the chance of data overfitting and bias selection. Concurrent analysis of differentially expressed lipid metabolite pathways uncovered the upregulation of α-linolenic/linoleic acid metabolism (false discovery rate [FDR] 0.002) and fatty acid biosynthesis (FDR 0.005) and the downregulation of sphingolipid metabolism (FDR 0.009) as being strongly associated with the risk of developing future type 2 diabetes. Focusing specifically on sphingolipids, the downregulation of sphingolipid metabolism using the pharmacological inhibitors fumonisin B1 (FB1) and myriocin in mouse islets and Min6 K8 cells (a pancreatic beta-cell like cell line) significantly impaired glucose-stimulated insulin secretion but had no significant impact on whole-body glucose homeostasis or insulin sensitivity.Conclusions/interpretationWe reveal a novel predictive signature and associate reduced sphingolipids with the pathophysiology of transition from GDM to type 2 diabetes. Attenuating sphingolipid metabolism in islets impairs glucose-stimulated insulin secretion.

Background: Myristic acid (MA), a 14-carbon saturated fatty acid, serves as a precursor for the synthesis of non-canonical d16-sphingoid bases via its activated form, C14:0-CoA. However, its broader regulatory role in sphingolipid (SL) metabolism remains poorly defined. Methods: Using HepG2 cells treated with 50 μM MA, we found that sphingolipidomic analysis revealed reprogrammed sphingolipid metabolism. Results: In the canonical d18-SL pathway, MA directs its activated product C14:0-CoA into ceramide N-acyl chains and downstream metabolites—especially d18:1-C14:0 hexosylceramide. Concurrently, in the non-canonical d16-SL pathway, MA promotes d16-SL synthesis, especially d16:1-ceramides (Cer), d16:1-hexosylceramides (HexCer), and d16:1-C14:0 lactosylceramide. MA treatment further induced a coordinated shift in cellular sphingolipid pools, characterized by a significant increase in total ceramide levels (encompassing both d16- and d18-species) alongside concurrent reductions in total sphingomyelin (SM) contents. At the gene transcriptional level, MA significantly suppressed SPTLC2 mRNA expression while markedly upregulating SMPD2 and SMPD3 mRNA levels. Conclusions: Collectively, these findings position MA as a potent regulator of sphingolipid homeostasis, orchestrating dual pathway modulation: disrupting canonical d18-SL equilibrium through the selective enrichment of N-acyl C14:0-containing SLs, and activating non-canonical d16-SL synthesis. This dual pathway regulation reveals that dietary saturated fatty acids exploit sphingolipid subnetworks to regulate lipid metabolism. The interplay between dietary fatty acids and sphingolipid metabolism still requires deeper exploration. Our findings offer preliminary insights into their roles in regulating both normal and disease-associated lipid metabolism, setting the stage for subsequent mechanistic investigations.

Malignant melanoma (MM) is a highly invasive and therapeutically resistant skin malignancy, posing a significant clinical challenge in its treatment. Programmed cell death plays a crucial role in the occurrence and progression of MM. Sphingolipids (SP), as a class of bioactive lipids, may be associated with many kinds of diseases. SPs regulate various forms of programmed cell death in tumors, including apoptosis, necroptosis, ferroptosis, and more. This review will delve into the mechanisms by which different types of SPs modulate various forms of programmed cell death in MM, such as their regulation of cell membrane permeability and signaling pathways, and how they influence the survival and death fate of MM cells. An in-depth exploration of the role of SPs in programmed cell death in MM aids in unraveling the molecular mechanisms of melanoma development and holds significant importance in developing novel therapeutic strategies.

A significant challenge in cancer treatment is the rising problem of drug resistance that reduces the effectiveness of therapeutic strategies. Current knowledge shows that multiple mechanisms play a role in cancer drug resistance. Another mechanism that has gained attention is the alteration in sphingolipid trafficking and the dysregulation of its metabolism, which was reported to cause cancer-associated drug resistance. Sphingolipids are lipids containing sphingosine and have multiple roles, ranging from lipid raft formation, apoptosis, and cell signaling to immune cell trafficking. Recent studies show that in developing cancer cells, altered or dysregulated sphingolipids are associated with drug efflux and promote the survival of cancer cells by bypassing apoptosis. Upregulated levels of the glucosylceramide synthase (GCS), an enzyme that functions in sphingolipid metabolism, lead to the upregulated ABCB1 gene that induces drug efflux from the cancer cells. These bypass mechanisms make drugs that induce apoptosis in tumor cells ineffective. By highlighting the current findings, this review aims to provide a mechanism of drug resistance caused by the dysregulation of glucosylceramide synthase, sphingosine kinase, and acid ceramidase enzymes as possible therapeutic targets to enhance the effectiveness of the currently used chemotherapeutic agents.

Abstract Context Evidence for an association between sphingolipids and metabolic disorders is increasingly reported. Omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) improve apolipoprotein B100 (apoB100)-containing lipoprotein metabolism, but their effects on the sphingolipid content in lipoproteins remain unknown. Objectives In subjects with hypertriglyceridemia, we analyzed the effect of n-3 LC-PUFAs on the turnover apoB100-containing lipoproteins and on their sphingolipid content and looked for the possible association between these lipid levels and apoB100-containing lipoprotein turnover parameters. Methods Six subjects underwent a kinetic study before and after n-3 supplementation for 2 months with 1 g of fish oil 3 times day containing 360 mg of eicosapentaenoic acid (EPA) and 240 mg of docosahexaenoic acid (DHA) in the form of triglycerides. We examined apoB100-containing lipoprotein turnover by primed perfusion labeled [5,5,5-2H3]-leucine and determined kinetic parameters using a multicompartmental model. We quantified sphingolipid species content in lipoproteins using mass spectrometry. Results Supplementation decreased very low-density lipoprotein (VLDL), triglyceride, and apoB100 concentrations. The VLDL neutral and polar lipids showed increased n-3 LC-PUFA and decreased n-6 LC-PUFA content. The conversion rate of VLDL1 to VLDL2 and of VLDL2 to LDL was increased. We measured a decrease in total apoB100 production and VLDL1 production. Supplementation reduced the total ceramide concentration in VLDL while the sphingomyelin content in LDL was increased. We found positive correlations between plasma palmitic acid and VLDL ceramide and between VLDL triglyceride and VLDL ceramide, and inverse correlations between VLDL n-3 LC-PUFA and VLDL production. Conclusion Based on these results, we hypothesize that the improvement in apoB100 metabolism during n-3 LC-PUFA supplementation is contributed to by changes in sphingolipids

Research in recent years has shown that sphingolipids are essential signalling molecules for the proper biological and structural functioning of cells. Long-term studies on the metabolism of sphingolipids have provided evidence for their role in the pathogenesis of a number of diseases. As many inflammatory diseases, such as lysosomal storage disorders and some dermatologic diseases, including psoriasis, atopic dermatitis and ichthyoses, are associated with the altered composition and metabolism of sphingolipids, more studies precisely determining the responsibilities of these compounds for disease states are required to develop novel pharmacological treatment opportunities. It is worth emphasizing that knowledge from the study of inflammatory metabolic diseases and especially the possibility of their treatment may lead to insight into related metabolic pathways, including those involved in the formation of the epidermal barrier and providing new approaches towards workable therapies.

Hypertension-induced myocardial remodelling encompasses both structural and functional changes in cardiac muscle tissue, such as myocardial hypertrophy, fibrosis, and inflammation. These alterations not only impair the systolic and diastolic functions of the heart but also elevate the risk of cardiovascular events and heart failure. One of the primary contributors to hypertensive cardiomyopathy (HTN-CM) is the over-activation of the renin-angiotensin-aldosterone system (RAAS), which subsequently induces myocardial remodeling. Although conventional therapeutic strategies aim to suppress RAAS and slow the progression of heart failure, the primary challenge in treating HTN-CM remains the lack of sensitive and specific biomarkers for early detection of myocardial remodelling. Combined multi-omics analyses, complemented by experimental validation, offer a systematic understanding of the landscape of gene/protein/metabolite expression in HTN-CM, revealing the underlying mechanisms of angiotensin II (Ang II)-induced myocardial remodeling in HTN-CM. Transcriptomic analysis revealed that differentially expressed genes (DEGs) are implicated in sphingolipid metabolic processes and are associated with collagen synthesis and inflammatory responses, collectively contributing to myocardial remodeling in HTN-CM. Proteomic analysis demonstrated that differentially expressed proteins (DEPs) are also involved in inflammatory and fibrotic processes, with associations to sphingolipid signaling pathways, particularly manifested through elevated expression of IL6, COL4A1, FGG, FGB, CREBBP and SPHK2 proteins. Metabolomic profiling further elucidated the increased expression of bioactive sphingolipid metabolites S1P and Sa1P in the myocardium of HTN-CM. Integrative multi-omics analysis revealed that HTN-CM is primarily influenced by the sphingolipid signaling pathway, with additional associations to the HIF-1α and FoxO signaling pathways. Correlation analysis has highlighted strong associations between sphingolipids and genes/proteins related to fibrosis and inflammation, as well as their connection to the HIF-1α and FoxO signalling pathways. Furthermore, certain key indicators were validated through ELISA and Western blot analyses in both plasma and myocardial tissue. In conclusion, the findings of this study suggest that excessive Ang II may induce abnormalities in sphingolipid metabolism, resulting in increased levels of S1P in both circulating and myocardial tissues. This elevation in S1P is implicated in myocardial inflammatory and fibrotic alterations, highlighting its pivotal role in myocardial remodeling. The specific mechanism underlying the sphingolipid signaling pathway in myocardial remodeling may involve downstream biological processes, including oxidative stress and excessive mitochondrial autophagy, mediated by HIF-1α and FoxO.

Numerous studies have demonstrated the positive effects of formulated feeds on gonadal and hepatopancreatic development of Eriocheir sinensis. However, there are limited studies on the effects of formulated feeds on the immune homeostasis and metabolism of muscle tissue in E. sinensis during the fattening period. Therefore, this study used metabolomic and lipidomic to systematically analyze the effects of formulated diets on muscle metabolism in female E. sinensis. The results indicate that the formulated feeds improved immune performance by inhibiting inflammatory responses, apoptosis and autophagy. In addition, the feed promoted amino acid metabolism and protein synthesis while decreasing muscle fatty acid metabolism. Metabolomic analysis reveal that pyrimidine metabolism is involved in the regulation of muscle physiological health in fattening female crabs. Lipidomic analysis revealed that the formulated feeds play a role in muscle immune homeostasis, amino acid and fatty acid metabolism by regulating the level of ceramide (Cer (d18:1/22:0)) in sphingolipid metabolism. Through subnetwork analysis, the functional interactions of sphingolipid metabolism with the pathways of sphingolipid signaling, apoptosis regulation, inflammatory response and lipid dynamic homeostasis were identified, which further defined the important role of sphingolipid metabolism in the regulation of muscle physiological health and metabolic homeostasis was further identified. In summary, the formulated feeds effectively promote immune homeostasis and metabolism in the muscle of female E. sinensis during the fattening period. These findings provide a solid theoretical foundation for feed formulation optimization and application in fattening practices.

Dysregulation of sphingolipid metabolism plays a complex role in hematological malignancies, beginning with the first historical link between sphingolipids and apoptosis discovered in HL-60 leukemic cells. Numerous manuscripts have reviewed the field including the early discoveries that jumpstarted the studies. Many studies discussed here support a role for sphingolipids, such as ceramide, in combinatorial therapeutic regimens to enhance anti-leukemic effects and reduce resistance to standard therapies. Additionally, inhibitors of specific nodes of the sphingolipid pathway, such as sphingosine kinase inhibitors, significantly reduce leukemic cell survival in various types of leukemias. Acid ceramidase inhibitors have also shown promising results in acute myeloid leukemia. As the field moves rapidly, here we aim to expand the body of literature discussed in previously published reviews by focusing on advances reported in the latter part of the last decade.