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Background: There is a need to develop biomarkers for diagnosis and prediction of treatment responses in depression and post‐traumatic stress disorder (PTSD). Methods: Cross‐sectional study examining correlations between tear inflammatory proteins, meibum and tear sphingolipids, and symptoms of depression and PTSD‐associated anxiety. Ninety individuals filled depression (Patient Health Questionnaire 9, PHQ‐9) and PTSD‐associated anxiety (PTSD Checklist‐Military Version, PCL‐M) questionnaires. In 40 patients, a multiplex assay system was used to quantify 23 inflammatory proteins in tears. In a separate group of 50 individuals, liquid chromatography‐mass spectrometry was performed on meibum and tears to quantify 34 species of sphingolipids, encompassing ceramides, monohexosyl ceramides and sphingomyelins. Results: The mean age of the population was 59.4 ± 11.0 years; 89.0% self‐identified as male, 34.4% as White, 64.4% as Black, and 16.7% as Hispanic. The mean PHQ‐9 score was 11.1 ± 7.6, and the mean PCL‐M score was 44.3 ± 19.1. Symptoms of depression and PTSD‐associated anxiety were highly correlated (ρ =0.75, p < 0.001). Both PHQ9 and PCL‐M scores negatively correlated with multiple sphingolipid species in meibum and tears. In multivariable models, meibum Monohexosyl Ceramide 26:0 (pmol), tear Ceramide 16:0 (mol%), meibum Monohexosyl Ceramide 16:0 (mol%), and tear Ceramide 26:1 (mol%) remained associated with depression and meibum Monohexosyl Ceramide 16:0 (mol%), meibum Monohexosyl Ceramide 26:0 (pmol), tear Sphingomyelin 20:0 (mol%), and tear Sphingosine‐1‐Phosphate (mol%) remained associated with PTSD‐associated anxiety. Conclusions: Certain meibum and tear sphingolipid species were related to mental health indices. These interactions present opportunities for innovative diagnostic and therapeutic approaches for mental health disorders. [ABSTRACT FROM AUTHOR]

Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-β) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-β and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-β1 (β1), 1 μM sphingosine-1-phosphate (S1P), and 5 μM Sphingosine kinase inhibitor 2 (I2). Five groups were tested: (1) control (no treatment); rescue groups; (2) β1/S1P; (3) β1/I2; prevention groups; (4) S1P/β1; and (5) I2/β1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-β signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-β binding proteins (LTBPs), TGF-β receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I2 prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I2 prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I2 treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-β receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I2 as a novel therapy for corneal fibrosis. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids (PUFAs) generate pro- and anti-inflammatory eicosanoids via three different metabolic pathways. This study profiled tear PUFAs and their metabolites and examined the relationships with dry eye (DE) and meibomian gland dysfunction (MGD) symptoms and signs. A total of 40 individuals with normal eyelids and corneal anatomies were prospectively recruited. The symptoms and signs of DE and MGD were assessed, and tear samples (from the right eye) were analyzed by mass spectrometry. Mann–Whitney U tests assessed differences between medians; Spearman tests assessed correlations between continuous variables; and linear regression models assessed the impact of potential confounders. The median age was 63 years; 95% were male; 30% were White; and 85% were non-Hispanic. The symptoms of DE/MGD were not correlated with tear PUFAs and eicosanoids. DE signs (i.e., tear break-up time (TBUT) and Schirmer's) negatively correlated with anti-inflammatory eicosanoids (11,12-dihydroxyeicosatrienoic acid (11,12 DHET) and 14,15-dihydroxyicosatrienoic acid (14,15, DHET)). Corneal staining positively correlated with the anti-inflammatory PUFA, docosahexaenoic acid (DHA). MGD signs significantly associated with the pro-inflammatory eicosanoid 15-hydroxyeicosatetranoic acid (15-HETE) and DHA. Several relationships remained significant when potential confounders were considered. DE/MGD signs relate more to tear PUFAs and eicosanoids than symptoms. Understanding the impact of PUFA-related metabolic pathways in DE/MGD may provide targets for new therapeutic interventions. [ABSTRACT FROM AUTHOR]

Context: Ceramides and sphingolipids have been linked to type 2 diabetes (T2D). The Ceramides and Sphingolipids as Predictors of Incident Dysglycemia (CASPID) study is designed to determine the association of plasma sphingolipids with the pathophysiology of human T2D. Objective: A comparison of plasma sphingolipids profiles in Black and White adults with (FH+) and without (FH−) family history of T2D. Design: We recruited 100 Black and White FH− (54 Black, 46 White) and 140 FH+ (75 Black, 65 White) adults. Fasting plasma levels of 58 sphingolipid species, including 18 each from 3 major classes (ceramides, monohexosylceramides, and sphingomyelins, all with 18:1 sphingoid base) and 4 long-chain sphingoid base–containing species, were measured by liquid chromatography/mass spectrometry. Results: Sphingomyelin was the most abundant sphingolipid in plasma (89% in FH−), and was significantly elevated in FH+ subjects (93%). Ceramides and monohexosylceramides comprised 5% and 6% of total sphingolipids in the plasma of FH− subjects, and were reduced significantly in FH+ subjects (3% and 4%, respectively). In FH+ subjects, most ceramide and monohexosylceramide species were decreased but sphingomyelin species were increased. The level of C18:1 species of all 3 classes was elevated in FH+ subjects. Conclusion: Elevated levels of sphingomyelin, the major sphingolipids of plasma, and oleic acid–containing sphingolipids in healthy FH+ subjects compared with healthy FH− subjects may reflect heritable elements linking sphingolipids and the development of T2D [ABSTRACT FROM AUTHOR]

Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. With a wide range of mutations and conditions leading to degeneration, targeting downstream processes is necessary for developing effective treatments. Ceramide and sphingosine-1-phosphate, a pair of bioactive sphingolipids, are involved in apoptosis and its prevention, respectively. Apoptotic cell death is a potential driver of RD, and in order to understand the mechanism of degeneration and potential treatments, we studied rhodopsin mutant RD model, P23H-1 rats. Investigating this genetic model of human RD allows us to investigate the association of sphingolipid metabolites with the degeneration of the retina in P23H-1 rats and the effects of a specific modulator of sphingolipid metabolism, FTY720. We found that P23H-1 rat retinas had altered sphingolipid profiles that, when treated with FTY720, were rebalanced closer to normal levels. FTY720-treated rats also showed protection from RD compared with their vehicle-treated littermates. Based on these data, we conclude that sphingolipid dysregulation plays a secondary role in retinal cell death, which may be common to many forms of RDs, and that the U.S. Food and Drug Administration-approved drug FTY720 or related compounds that modulate sphingolipid metabolism could potentially delay the cell death.