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Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 adults with PTSD and 40 trauma-exposed non-PTSD individuals (n = 20/sex/condition; 19-39 years old). Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ~ 90 measures were collected, on sleep, and mental and physical health indices. Poorer sleep quality was associated with greater PTSD severity in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 lipid subclasses. After adjusting for BMI and sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The correlations between triglycerides and ceramide metabolites with cholesterol metabolites and systolic blood pressure were dependent upon sex and PTSD status. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher body mass may have contributed to changes in the lipidome found in PTSD.

Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration. This study explores the effects of AdipoR1 gene deficiency in mice, revealing a striking decline in ω3 polyunsaturated fatty acids (PUFA), an increase in ω6 fatty acids, and elevated ceramides in the retina. The AdipoR1 deficiency impairs peroxisome proliferator-activated receptor α signaling, which is crucial for FA metabolism, particularly affecting proteins associated with FA transport and oxidation in the retina and retinal pigmented epithelium. Our lipidomic and proteomic analyses indicate changes that could affect membrane composition and viscosity through altered ω3 PUFA transport and synthesis, suggesting a potential influence of AdipoR1 on these properties. Furthermore, we noted a reduction in the Bardet-Biedl syndrome proteins, which are crucial for forming and maintaining photoreceptor outer segments that are PUFA-enriched ciliary structures. Diminution in Bardet-Biedl syndrome-proteins content combined with our electron microscopic observations raises the possibility that AdipoR1 deficiency might impair ciliary function. Treatment with inhibitors of ceramide synthesis led to substantial elevation of ω3 LC-PUFAs, alleviating photoreceptor degeneration and improving retinal function. These results serve as the proof of concept for a ceramide-targeted strategy to treat retinopathies linked to PUFA deficiency, including age-related macular degeneration.

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that metabolic correction of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR)

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

The lipidomic secretions of embryos provide a unique opportunity to examine the cellular processes of the early conceptus. In this study we profiled lipids released by the early equine conceptus, using high-resolution mass spectrometry to detect individual lipid species. This study examined the lipidomic profile in embryo-conditioned media from in vivo-produced, 8-9 day-old equine embryos (n = 3) cultured in vitro for 36 h, analyzed over 3 timepoints. A total of 1,077 lipid IDs were recorded across all samples, containing predominantly glycerolipids. Seventy-nine of these were significantly altered in embryo conditioned-media versus media only control (p < 0.05, fold-change >2 or < 0.5). Fifty-five lipids were found to be released into the embryo-conditioned media, of which 54.5% were triacylglycerols and 23.6% were ceramides. The sterol lipid, cholesterol, was also identified and secreted in significant amounts as embryos developed. Further, 24 lipids were found to be depleted from the media during culture, of which 70.8% were diacylglycerols, 16.7% were triacylglycerols and 12.5% were ceramides. As lipid-free media contained consistently detectable lipid peaks, a further profile analysis of the various components of non-embryo-conditioned media consistently showed the presence of 137 lipids. Lipid peaks in non-embryo-conditioned media increased in response to incubation under mineral oil, and contained ceramides, diacylglycerols and triacylglycerols. These results emphasize the importance of a defined embryo culture medium and a need to identify the lipid requirements of the embryo precisely. This study sheds light on early embryo lipid metabolism and the transfer of lipids during in vitro culture. [ABSTRACT FROM AUTHOR]

Background/Objectives: The diverse effects of fructose and glucose on the progression of metabolic dysfunction-associated steatotic liver disease remain uncertain. This study investigated the effects, in animal models, of high-fat diets (HFDs) supplemented with either glucose or fructose. Methods: Six-week-old, male C57BL/6J mice were randomly allocated to four groups: normal diet (ND), HFD, HFD supplemented with fructose (30% w/v, HFD + Fru), and HFD supplemented with glucose (initially 30%, HFD + Glu). After 24 weeks, liver and plasma samples were gathered for analysis. In addition, 39 patients with obesity undergoing bariatric surgery with wedge liver biopsy were enrolled in the clinical study. Results: The HFD + Glu group consumed more water than did the HFD and HFD + Fru groups. Thus, we reduced the glucose concentration from 30% at baseline to 15% at week 2 and 10% starting from week 6. The HFD + Fru and HFD + Glu groups had a similar average caloric intake (p = 0.463). The HFD increased hepatic steatosis, plasma lipid levels, lipogenic enzymes, steatosis-related oxidative stress, hepatic inflammation, and early-stage liver fibrosis. Supplementation with fructose or glucose exacerbated liver damage, but no significant differences were identified between the two. The expression patterns of hepatic ceramides in HFD-fed mice (with or without supplemental fructose or glucose) were similar to those observed in patients with obesity and severe hepatic steatosis or metabolic dysfunction–associated steatohepatitis. Conclusions: Fructose and glucose similarly exacerbated liver damage when added to an HFD. Ceramides may be involved in the progression of hepatic lipotoxicity. [ABSTRACT FROM AUTHOR]

Psoriasis is an inflammatory skin disease associated with an impaired skin barrier. The skin barrier function is dependent on the extracellular lipid matrix which surrounds the corneocytes in the stratum corneum. Ceramides comprise essential components of this matrix. Alterations in the stratum corneum ceramide profile have been directly linked to barrier dysfunction and might be an underlying factor of the barrier impairment in psoriasis. In this study, we investigated the ceramide profile and barrier function in psoriasis. Lesional and non‐lesional skin of 26 patients and 10 healthy controls were analysed using in‐depth ceramide lipidomics by liquid chromatography‐mass spectrometry. Barrier function was assessed by measuring transepidermal water loss. Lesional skin showed a significant decrease in the abundance of total ceramides with significant alterations in the ceramide subclass composition compared to control and non‐lesional skin. Additionally, the percentage of monounsaturated ceramides was significantly increased, and the average ceramide chain length significantly decreased in lesional skin. Altogether, this resulted in a markedly different profile compared to controls for lesional skin, but not for non‐lesional skin. Importantly, the reduced barrier function in lesional psoriasis correlated to alterations in the ceramide profile, highlighting their interdependence. By assessing the parameters 2 weeks apart, we are able to highlight the reproducibility of these findings, which further affirms this connection. To conclude, we show that changes in the ceramide profile and barrier impairment are observed in, and limited to, lesional psoriatic skin. Their direct correlation provides a further mechanistic basis for the concomitantly observed impairment of barrier dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Ceramides are essential epidermal constituents that play a critical role in skin moisturization treatment as a raw material in cosmetics formulation. Recently, ceramides have been known to be frequently applied in various cosmetic formulations. Despite ceramide's beneficial characteristics, academic research regarding ceramides and their skin absorption remains insufficient. Therefore, our study conducted clinical research employing Raman spectroscopy to investigate the effects of ceramides on skin absorption to enhance the understanding of ceramides' dermatological functionality and their topical application in cosmetics science. Materials and Methods: Twenty healthy individuals with dry skin have participated in this clinical trial. In this double‐arm designed trial, the test group received an investigational product with ceramides (5000 ppm) and a control group received an investigational product without the ceramides while all other components remained identical. The subjects visited the clinical research center and acclimatized for 30 min in constant humidity and temperature for equilibrium, subsequently conducting a measurement. Before the trial, the research subject's target site (lower arm area) was kept clean, devoid of any cosmetic administering 24 h before the trial when investigational product was topically applied. Results: Our findings with Raman spectroscopy statistically demonstrate that skin absorption amount, speed and depth for both groups improved overall (p < 0.05) after administration of the investigational product. Notably, the test group received an investigational product with ceramides (5000 ppm) indicating superior effectiveness across all parameters compared to a control group from comparison analysis of each parameter (p < 0.05). Conclusion: This study concludes that ceramide‐containing cosmetics provide a beneficial effect on skin absorption via visual and statistical results of Raman spectroscopy analysis. [ABSTRACT FROM AUTHOR]

Ceramides are a highly heterogeneous group of stratum corneum sphingolipids with hundreds of structures. They are essential for skin health by strengthening the skin barrier, retaining moisture, and protecting against environmental damage. With their broad spectrum of benefits for the skin and their scientifically validated efficacy, ceramides have emerged as hero ingredients in modern skincare. This article explores two innovative ceramide products with smart concepts that offer superior properties compared to pure ceramide powders on the market. DS-CERAmix-V™ is an easy-to-formulate sphingolipid complex that delivers key ceramides for the skin in optimal bio-designed ratios. It soothes the skin, boosts hydration, and reinforces the skin barrier. DS-HydroCeramide50™ is a water-dispersible, preservative-free ceramide NP powder with improved formulation stability, solubility, and higher bioavailability than standard ceramide NP. It is of 100% natural origin content and can be incorporated in water-based products at temperatures of around 50°C. [ABSTRACT FROM AUTHOR]

Coral restoration efforts have rapidly increased worldwide, including the development of several programmes on the Great Barrier Reef (GBR) in recent years. While many restoration programmes utilise in-water nurseries to accelerate coral biomass yields, the impact of nursery environments on propagule quality has not been examined despite the importance of coral fitness for ensuring resistant populations. Here, we investigated two fitness indicators (lipid diversity and tissue protein abundance) of Acropora millepora adults and eggs grown on coral nurseries versus native reef on the GBR, with adults assessed at two sites (Blue Lagoon and Rayban) and eggs assessed at one site (Blue Lagoon). Lipid profiles of adult colonies varied by site and origin (nursery versus wild reef), with adult nursery corals exhibiting an elevated relative abundance of storage lipids (diacylglycerols and triacylglycerols) and lipid classes responsible for regulating membrane structure (phosphatidylcholines and sterol esters), while wild corals were characterised by a greater relative abundance of fatty acids and classes involved in immunoregulation. Comparing eggs from different origins, nursery offspring were richer in energy-storing triacylglycerols, as well as ceramides and phosphatidylcholines essential for membrane structure, while wild eggs had a greater relative abundance of wax ester species also important for energy storage. No differences were found in total protein abundance (adult or eggs) or egg physical characteristics (count and size) between nursery and wild origins. Variations in lipid profiles are consistent with differences in environmental conditions between reef sites and origin (nursery versus wild), highlighting the need to consider site selection and propagation conditions when planning restoration projects. Importantly, these findings demonstrate that the lipid classes with the highest relative abundance in A. millepora nursery and wild eggs differed from those in adults from the same origin, suggesting that propagation origin is more important for driving lipid profiles in coral eggs compared to parental effects. [ABSTRACT FROM AUTHOR]

Employing lipidomics, this study investigated the lipid composition of seabuckthorn fruit oil processed via supercritical CO2 extraction and centrifugal separation. Qualitative analysis showed that a total of 2861 lipid molecules were identified in seabuckthorn fruit oil. Quantitative analysis showed that the content of lipids in seabuckthorn fruit oil extracted by supercritical CO2 extraction (927,539.84 µg/mL) was significantly higher than that in centrifugal‐separated seabuckthorn fruit oil (735,717.63 µg/mL), with 17 distinct lipid classes and 215 lipid molecules differentiated through multivariate statistical analysis. Lipid molecules, such as diacylglycerol (DG), ceramides (Cer), monohexosyl ceramide, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, and monogalactosyl DG, were predominantly found in the oil extracted using supercritical CO2. In contrast, monogalactosyl monoacylglycerol, diglycosyl ceramide, and Cer phosphate were significantly present in the oil extracted by centrifugal separation. These findings contribute new insights into how processing methods affect the quality and composition of seabuckthorn fruit oil and provide a basis for detecting oil adulteration. [ABSTRACT FROM AUTHOR]

Background: Observational studies have suggested that plasma lipidome play a pivotal role in the occurrence of Parkinson's disease (PD). However, it remains unknown which lipids among plasma lipidome affect PD and how they exert their influence. Clarity is lacking regarding the causal relationship between plasma lipidome and PD, as well as whether circulating inflammatory proteins serve as mediators. Methods: Single nucleotide polymorphisms (SNPs) significantly associated with 179 plasma lipidome were selected as instrumental variables to assess their causal impact on PD. PD data, serving as the outcome, were sourced from the International Parkinson's Disease Genomics Consortium, which boasts the largest sample size to date. The inverse variance weighted (IVW), Weighted median method, MR-Egger method, Simple mode method, Weighted mode method and MR-PRESSO were employed to evaluate the influence of the 179 plasma lipidome on PD. Heterogeneity, pleiotropy tests, and reverse causality analyses were conducted accordingly. Additionally, we analyzed the causal relationship between 91 circulating inflammatory proteins and PD, exploring whether these proteins serve as mediators in the pathway from plasma lipidome to PD. Results: Among the 179 plasma lipidome, three were found to be associated with a reduced risk of PD: Phosphatidylcholine (14:0_18:2) (IVW, OR = 0.877; 95%CI, 0.787-0.978; p = 0.018), Phosphatidylcholine (16:0_16:1) levels (IVW, OR = 0.835; 95%CI, 0.717-0.973; p = 0.021), and Phosphatidylcholine (O-17:0_17:1) levels (IVW, OR = 0.854; 95%CI, 0.779-0.936; p = 0.001). Meanwhile, Sphingomyelin (d38:1) was linked to an increased risk of PD (IVW, OR = 1.095; 95%CI, 1.027-1.166; p = 0.005). Among the 91 circulating inflammatory proteins, three were associated with a lower PD risk: Fibroblast growth factor 21 levels (IVW, OR = 0.817; 95%CI, 0.674-0.990; p = 0.039), Transforming growth factor-alpha levels (IVW, OR = 0.825; 95%CI, 0.683-0.998; p = 0.048), and Tumor necrosis factor receptor superfamily member 9 levels (IVW, OR = 0.846; 95%CI, 0.744-0.963; p = 0.011). Two were associated with a higher risk of PD: Interleukin-17A levels (IVW, OR = 1.285; 95%CI, 1.051-1.571; p = 0.014) and TNF-beta levels (IVW, OR = 1.088; 95%CI, 1.010-1.171; p = 0.026). Additionally, a positive correlation was observed between Phosphatidylcholine (14:0_18:2) levels and Fibroblast growth factor 21 levels (IVW, OR = 1.125; 95%CI, 1.006-1.257; p = 0.038), suggesting that Fibroblast growth factor 21 levels may serve as a mediating factor in the pathway between Phosphatidylcholine (14.0_18.2) levels and PD. The mediation effect was estimated to be -0.024, accounting for approximately 18% of the total effect. Conclusion: Both plasma lipidome and circulating inflammatory proteins demonstrate a causal relationship with PD. Additionally, circulating inflammatory proteins may serve as mediators in the pathway from plasma lipidome to PD. These findings may contribute to the prediction and diagnosis of PD and potentially pave the way for targeted therapies in the future. [ABSTRACT FROM AUTHOR]

The tumor-suppressor sphingolipid ceramide is recognized as a key participant in the cytotoxic mechanism of action of many types of chemotherapy drugs, including anthracyclines, Vinca alkaloids, the podophyllotoxin etoposide, taxanes, and the platinum drug oxaliplatin. These drugs can activate de novo synthesis of ceramide or stimulate the production of ceramide via sphingomyelinases to limit cancer cell survival. On the contrary, dysfunctional sphingolipid metabolism, a prominent factor in cancer survival and therapy resistance, blunts the anticancer properties of ceramide-orchestrated cell death pathways, especially apoptosis. Although P-glycoprotein (P-gp) is famous for its role in chemotherapy resistance, herein, we propose alternate interpretations and discuss the capacity of this multidrug transporter as a "ceramide neutralizer", an unwelcome event, highlighting yet another facet of P-gp's versatility in drug resistance. We introduce sphingolipid metabolism and its dysfunctional regulation in cancer, present a summary of factors that contribute to chemotherapy resistance, explain how P-gp "neutralizes" ceramide by hastening its glycosylation, and consider therapeutic applications of the P-gp-ceramide connection in the treatment of cancer. [ABSTRACT FROM AUTHOR]

The human heart is subject to highly variable amounts of strain during day‐to‐day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro‐ and anti‐arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano‐electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole‐heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin‐bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch‐activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin‐bound calcium and stretch‐activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano‐electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate. Key points: The electrophysiological and mechanical function of the heart are tightly interrelated by excitation–contraction coupling (ECC) in the forward direction and mechano‐electric feedback (MEF) in the reverse direction.While ECC is considered in many state‐of‐the‐art computational models of cardiac electromechanics, less is known about the effect of different MEF mechanisms.Accounting for calcium bound to troponin increases stroke volume and delays repolarization. Geometry‐mediated MEF leads to more heterogeneous activation and repolarization with steeper gradients. Both effects combine in an additive way.Non‐selective stretch‐activated channels as an additional MEF mechanism lead to heterogeneous diastolic transmembrane voltage, higher developed tension and delayed repolarization or afterdepolarizations in highly stretched parts of the atria.The differential and combined effects of these three MEF mechanisms during sinus rhythm activation in a human four‐chamber heart model may have implications for arrhythmogenesis, both in terms of substrate (repolarization gradients) and triggers (ectopy). [ABSTRACT FROM AUTHOR]

The transient receptor potential melastatin 4 (TRPM4) channel contributes extensively to cardiac electrical activity, especially cardiomyocyte action potential formation. Mechanical stretch can induce changes in heart rate and rhythm, and the mechanosensitive channel Piezo1 is expressed in many cell types within the myocardium. Our previous study showed that TRPM4 and Piezo1 are closely co‐localized in the t‐tubules of ventricular cardiomyocytes and contribute to the Ca2+‐dependent signalling cascade that underlies hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. In the present study, we employed the HL‐1 mouse atrial myocyte‐like cell line as an in vitro model to investigate whether Piezo1–TRPM4 coupling can affect action potential properties. We used the small molecule Piezo1 agonist, Yoda1, as a surrogate for mechanical stretch to activate Piezo1 and detected the action potential changes in HL‐1 cells using FluoVolt, a fluorescent voltage sensitive dye. Our results demonstrate that Yoda1‐induced activation of Piezo1 changes the action potential frequency in HL‐1 cells. This change in action potential frequency is reduced by Piezo1 knockdown using small intefering RNA. Importantly knockdown or pharmacological inhibition of TRPM4 significantly affected the degree to which Yoda1‐evoked Piezo1 activation influenced action potential frequency. Thus, the present study provides in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte‐like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+‐activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction. Key points: The transient receptor potential melastatin 4 (TRPM4) and Piezo1 channels have been confirmed to contribute to the Ca2+‐dependent signalling cascade that underlies cardiac hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ.We employed the HL‐1 mouse atrial myocyte‐like cell line as an in vitro model to investigate the effect of Piezo1–TRPM4 coupling on cardiac electrical properties.The results show that both pharmacological and genetic inhibition of TRPM4 significantly affected the degree to which Piezo1 activation influenced action potential frequency in HL‐1 cells.Our findings provide in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte‐like cell line.The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+‐activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction in various (patho)physiological processes. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death in the USA and is known to be exacerbated by elevated mechanical stress from hypertension. Caveolae are plasma membrane structures that buffer mechanical stress but have been found to be reduced in pathological conditions associated with chronically stretched myocardium. To explore the physiological implications of the loss of caveolae, we used human engineered cardiac tissue (ECT) constructs, composed of human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes and hiPSC‐derived cardiac fibroblasts, to develop a long‐term cyclic stretch protocol that recapitulates the effects of hypertension on caveolae expression, membrane tension, and the β‐adrenergic response. Leveraging this new stretch protocol, we identified neutral sphingomyelinases (nSMase) as mechanoregulated mediators of caveolae loss, ceramide production and the blunted β‐adrenergic response in this human cardiac model. Specifically, in our ECT model, nSMase inhibition via GW4869 prevented stretch‐induced loss of caveolae‐like structures, mitigated nSMase‐dependent ceramide production, and maintained the ECT contractile kinetic response to isoprenaline. These findings are correlated with a blood lipidomic analysis in middle‐aged and older adults, which revealed an increase of the circulating levels of ceramides in adults with hypertension. Furthermore, we found that conduction slowing from increased pressure loading in mouse left ventricle was abolished in the context of nSMase inhibition. Collectively, these findings identify nSMase as a potent drug target for mitigating stretch‐induced effects on cardiac function. Key points: We have developed a new stretch protocol for human engineered cardiac tissue that recapitulates changes in plasma membrane morphology observed in animal models of pressure/volume overload.Stretch of engineered cardiac tissue induces activation of neutral sphingomyelinase (nSMase), generation of ceramide, and disassembly of caveolae.Activation of nSMase blunts cardiac β‐adrenergic contractile kinetics and mediates stretch‐induced slowing of conduction and upstroke velocity.Circulating ceramides are increased in adults with hypertension, highlighting the clinical relevance of stretch‐induced nSMase activity. [ABSTRACT FROM AUTHOR]

The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected. [ABSTRACT FROM AUTHOR]

Background/Objectives: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition linked to the ongoing obesity pandemic, is rapidly increasing worldwide. In turn, its multifactorial etiology is consistently associated with low dietary quality. Changing dietary macronutrient and phytochemical quality via incorporating cooked common bean into an obesogenic diet formulation has measurable health benefits on the occurrence of both obesity and hepatic steatosis in C57BL/6 mice. Methods: A cohort of C57BL/6 mice were randomized into experimental diets containing multiple dietary concentrations of common bean. The primary endpoint of this study was comparing metabolomic analyses from liver and plasma of different treatment groups. Additionally, RNA sequencing and protein expression analysis via nanocapillary immunoelectrophoresis were used to elucidate signaling mediators involved. Results: Herein, global metabolomic profiling of liver and plasma identified sphingolipids as a lipid subcategory on which bean consumption exerted significant effects. Of note, C16 and C18 ceramides were significantly decreased in bean-fed animals. Hepatic RNAseq data revealed patterns of transcript expression of genes involved in sphingolipid metabolism that were consistent with metabolite profiles. Conclusions: Bean incorporation into an otherwise obesogenic diet induces effects on synthesis, biotransformation, and degradation of sphingolipids that inhibit the accumulation of ceramide species that exert pathological activity. These effects are consistent with a mechanistic role for altered sphingolipid metabolism in explaining how bean inhibits the development of MASLD. [ABSTRACT FROM AUTHOR]

Sphingolipids (SLs) are bioactive signaling molecules essential for various cellular processes, including cell survival, proliferation, migration, and apoptosis. Key SLs such as ceramides, sphingosine, and their phosphorylated forms play critical roles in cellular integrity. Dysregulation of SL levels is implicated in numerous diseases, notably chronic kidney disease (CKD). This review focuses on the role of SLs in CKD, highlighting their potential as biomarkers for early detection and prognosis. SLs maintain renal function by modulating the glomerular filtration barrier, primarily through the activity of podocytes. An imbalance in SLs can lead to podocyte damage, contributing to CKD progression. SL metabolism involves complex enzyme-catalyzed pathways, with ceramide serving as a central molecule in de novo and salvage pathways. Ceramides induce apoptosis and are implicated in oxidative stress and inflammation, while sphingosine-1-phosphate (S1P) promotes cell survival and vascular health. Studies have shown that SL metabolism disorders are linked to CKD progression, diabetic kidney disease, and glomerular diseases. Targeting SL pathways could offer novel therapeutic approaches for CKD. This review synthesizes recent research on SL signaling regulation in kidney diseases, emphasizing the importance of maintaining SL balance for renal health and the potential therapeutic benefits of modulating SL pathways. [ABSTRACT FROM AUTHOR]

Background: Male androgenetic alopecia (MAA) is a multifactorial disease, with patients presenting at a younger age, which is a risk factor for many metabolic diseases. Aims: To explore the risk factors associated with early‐onset of MAA and its metabolic characteristics. Methods: Forty patients with MAA and 45 healthy controls were collected. The serum levels of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), total testosterone (TT), uric acid (UA), and 25‐hydroxyvitamin D (25(OH)D) were measured. Meanwhile, lipid metabolites were detected by ultra‐high‐performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). Results: 37.50% MAA patients had metabolic syndrome, compared to 17.78% in control group (p < 0.05). The levels of HDL‐C, UA, and 25(OH)D were decreased in patients with MAA compared to healthy controls (p < 0.05). However, there was no significant difference in the level of TT between the two groups. Additionally, there were no significant differences in the levels of HDL‐C, UA, 25(OH)D, and TT among different grades of hair loss (p > 0.05). The lipid profile of early‐onset MAA differed significantly from healthy controls. In early‐onset MAA, the levels of ceramide (Cer) and sphingomyelin (SM) were significantly lower. Cer(d38:5) and TG(15:0/18:1/18:1) may be the biomarkers. Conclusion: Low HDL‐C, UA, and 25(OH)D may be the independent risk factors for early‐onset MAA. Abnormal lipid metabolism was observed in early‐onset MAA, wherein Cer and SM may serve as protective factors. [ABSTRACT FROM AUTHOR]

Objective of this study was to ascertain metabolic biomarkers and investigate the metabolic alterations associated with aqueous humor (AH) in wet age-related macular degeneration (AMD). Methods: AH samples were collected from a total of 20 participants, including 10 individuals diagnosed with wet AMD and 10 individuals undergoing cataract surgery, serving as the control group. Metabolomics analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify and quantify metabolites. Results: A total of 155 metabolites were identified in the AH samples. Among them, 10 metabolites emerged as potential biomarkers capable of differentiating patients with wet AMD from the control group. In the AH of wet AMD patients, there was increased expression of Cardiolipin (CL) (72:5), Diglyceride (DG) (18:3_18:2), DG (36:5e) and Triglyceride (TG) (24:7), while the expression of Ceramides (Cer) (d32:0), Cer (d34:0), Cer (d36:0), Monogalactosyldiacylglycerol (MGDG) (16:1_18:3), Sphingosine (SPH) (d18:0) and TG (16:0_10:4_16:0) was down regulated. Conclusion: Through metabolomics analysis of AH, this study successfully uncovered valuable metabolic biomarkers linked to wet AMD. These findings contribute to a more comprehensive understanding of the pathogenesis of wet AMD and offer potential avenues for the development of innovative treatment strategies for this condition. [ABSTRACT FROM AUTHOR]

Abnormalities in lipid homeostasis have been associated with many human diseases, and the interrelation between lipotoxicity and cellular dysfunction has received significant attention in the past two decades. Ceramides (Cers) are bioactive lipid molecules that serve as precursors of all complex sphingolipids. Besides their function as structural components in cell and mitochondrial membranes, Cers play a significant role as key mediators in cell metabolism and are involved in numerous cellular processes, such as proliferation, differentiation, inflammation, and induction of apoptosis. The accumulation of various ceramides in tissues causes metabolic and cellular disturbances. Recent studies suggest that Cer lipotoxicity has an important role in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, and cardiovascular diseases (CVDs). In humans, elevated plasma ceramide levels are associated with insulin resistance and impaired cardiovascular and metabolic health. In this review, we summarize the role of ceramides as key mediators of lipotoxicity in obesity, diabetes, cardiovascular diseases, and inflammation and their potential as a promising diagnostic tool. [ABSTRACT FROM AUTHOR]

Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2-/- mice. Compared to wild-type mice, female Asah2-/- mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.

Abstract Background Ceramides have recently been identified as novel biomarkers associated with diabetes mellitus (DM) and major adverse cardiac and cerebrovascular events (MACCE). This study aims to explore their utility in diagnosing microvascular disease. Methods This study prospectively enrolled 309 patients from 2018 to 2020 into three groups: healthy controls (Group 1, N = 51), DM patients without acute myocardial infarction (AMI) (Group 2, N = 150), and DM patients with AMI (Group 3, N = 108). We assessed outcomes using stress perfusion cardiac magnetic resonance (CMR) imaging for coronary microvascular disease (CMD) (Outcome 1), retinography for retinal microvascular disease (RMD) (Outcome 2), both CMD and RMD (Outcome 3), and absence of microvascular disease (w/o MD) (outcome 4). We evaluated the classification performance of ceramides using receiver operating characteristic (ROC) analysis and multiple logistic regression. 11-ceramide panel previously identified by our research group as related to macrovascular disease were used. Results Average glycated hemoglobin (HbA1c) values were 5.1% in Group 1, 8.3% in Group 2, and 7.6% in Group 3. Within the cohort, CMD was present in 59.5% of patients, RMD in 25.8%, both CMD and RMD in 18.8%, and w/o MD in 38.5%. The AUC values for the reference ceramide ratios were as follows: CMD at 0.66 (p = 0.012), RMD at 0.61 (p = 0.248), CMD & RMD at 0.64 (p = 0.282), and w/o MD at 0.67 (p = 0.010). In contrast, the AUC values using 11-ceramide panel showed significant improvement in the outcomes prediction: CMD at 0.81 (p = 0.001), RMD at 0.73 (p = 0.010), CMD & RMD at 0.73 (p = 0.04), and w/o MD at 0.83 (p = 0.010). Additionally, the plasma concentration of C14.0 was notably higher in the w/o MD group (p

Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.

Abstract Background Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia. Methods Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n = 10 without cachexia, n = 20 cachectic without inflammation (CRP

Abstract Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 adults with PTSD and 40 trauma-exposed non-PTSD individuals (n = 20/sex/condition; 19–39 years old). Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ~ 90 measures were collected, on sleep, and mental and physical health indices. Poorer sleep quality was associated with greater PTSD severity in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 lipid subclasses. After adjusting for BMI and sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The correlations between triglycerides and ceramide metabolites with cholesterol metabolites and systolic blood pressure were dependent upon sex and PTSD status. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher body mass may have contributed to changes in the lipidome found in PTSD.

Abstract Background COVID-19 is primarily considered a respiratory tract infection, but it can also affect the central nervous system (CNS), which can result in long-term sequelae. In contrast to CNS infections by classic neurotropic viruses, SARS-CoV-2 is usually not detected in cerebrospinal fluid (CSF) from patients with COVID-19 with neurological involvement (neuro-COVID), suggesting fundamental differences in pathogenesis. Methods To assess differences in CNS metabolism in neuro-COVID compared to CNS infections with classic neurotropic viruses, we applied a targeted metabolomic analysis of 630 metabolites to CSF from patients with (i) COVID-19 with neurological involvement [n = 16, comprising acute (n = 13) and post-COVID-19 (n = 3)], (ii) viral meningitis, encephalitis, or myelitis (n = 10) due to herpes simplex virus (n = 2), varicella zoster virus (n = 6), enterovirus (n = 1) and tick-borne encephalitis virus (n = 1), and (iii) aseptic neuroinflammation (meningitis, encephalitis, or myelitis) of unknown etiology (n = 21) as additional disease controls. Results Standard CSF parameters indicated absent or low neuroinflammation in neuro-COVID. Indeed, CSF cell count was low in neuro-COVID (median 1 cell/µL, range 0–12) and discriminated it accurately from viral CNS infections (AUC = 0.99) and aseptic neuroinflammation (AUC = 0.98). 32 CSF metabolites passed quality assessment and were included in the analysis. Concentrations of differentially abundant (fold change ≥|1.5|, FDR ≤ 0.05) metabolites were both higher (9 and 5 metabolites) and lower (2 metabolites) in neuro-COVID than in the other two groups. Concentrations of citrulline, ceramide (d18:1/18:0), and methionine were most significantly elevated in neuro-COVID. Remarkably, triglyceride TG(20:1_32:3) was much lower (mean fold change = 0.09 and 0.11) in neuro-COVID than in all viral CNS infections and most aseptic neuroinflammation samples, identifying it as highly accurate biomarker with AUC = 1 and 0.93, respectively. Across all samples, TG(20:1_32:3) concentration correlated only moderately with CSF cell count (ρ = 0.65), protein concentration (ρ = 0.64), and Q-albumin (ρ = 0.48), suggesting that its low levels in neuro-COVID CSF are only partially explained by less pronounced neuroinflammation. Conclusions The results suggest that CNS metabolite responses in neuro-COVID differ fundamentally from viral CNS infections and aseptic neuroinflammation and may be used to discover accurate diagnostic biomarkers in CSF and to gain insights into differences in pathophysiology between neuro-COVID, viral CNS infections and aseptic neuroinflammation.

Abstract Elevated concentrations of palmitate in serum of obese individuals can impair endothelial function, contributing to development of cardiovascular disease. Although several molecular mechanisms of palmitate-induced endothelial dysfunction have been proposed, there is no consensus on what signaling event is the initial trigger of detrimental palmitate effects. Here we report that inhibitors of ER stress or ceramid synthesis can rescue palmitate-induced autophagy impairment in macro- and microvascular endothelial cells. Furthermore, palmitate-induced cholesterol synthesis was reverted using these inhibitors. Similar to cell culture data, autophagy markers were increased in serum of obese individuals. Subsequent lipidomic analysis revealed that palmitate changed the composition of membrane phospholipids in endothelial cells and that these effects were not reverted upon application of above-mentioned inhibitors. However, ER stress inhibition in palmitate-treated cells enhanced the synthesis of trilglycerides and restored ceramide levels to control condition. Our results suggest that palmitate induces ER-stress presumably by shift in membrane architecture, leading to impaired synthesis of triglycerides and enhanced production of ceramides and cholesterol, which altogether enhances lipotoxicity of palmitate in endothelial cells.

BACKGROUND RESULTS CONCLUSION Repeated exposure to ultraviolet A (UVA) irradiation, which can penetrate the epidermis and reach the dermis, is one of the major causes of skin photoaging. Photoaged skin is characterized clinically by generalized wrinkling, a dry and loose appearance, and seborrheic keratoses, along with skin barrier dysfunction. Fucoxanthin, a xanthophyll carotenoid with a specific allenic bond and 5,6‐monoepoxide in its structure, has been found to serve various functions as a food supplement. In the present study, the protective effects of orally administered fucoxanthin at relatively low concentrations (0.001% and 0.01%) against UVA induced photoaging were evaluated in vivo using hairless mice.Oral supplementation of 0.001% fucoxanthin was sufficient for its metabolites to accumulate in the skin, thereby inhibiting pathological changes induced by UVA irradiation, including impaired skin barrier function and accelerated wrinkle formation. Analysis of gene expression revealed that dietary fucoxanthin exerted antiphotoaging effects, possibly by modulating natural moisturizing factor (NMF) synthesis, desquamation, and ceramide composition in the epidermis, and by inhibiting the UVA induced degradation of collagen fibers and inflammation in the dermis.Taken together, our data indicate the potential application of dietary fucoxanthin as a novel ingredient in nutricosmetics for skin care against photoaging. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

To broadly measure the spectrum of cellular self-antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self-lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d autoreactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the "sphingomyelin cycle" that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions. [ABSTRACT FROM AUTHOR]

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant and a potent aryl hydrocarbon receptor (AHR) ligand, causes delayed intestinal motility and affects the survival of enteric neurons. In this study, we investigated the specific signaling pathways and molecular targets involved in TCDD-induced enteric neurotoxicity. Immortalized fetal enteric neuronal (IM-FEN) cells treated with 10 nM TCDD exhibited cytotoxicity and caspase 3/7 activation, indicating apoptosis. Increased cleaved caspase-3 expression with TCDD treatment, as assessed by immunostaining in enteric neuronal cells isolated from WT mice but not in neural crest cell-specific Ahr deletion mutant mice (Wnt1Cre+/−/Ahrb(fl/fl)), emphasized the pivotal role of AHR in this process. Importantly, the apoptosis in IM-FEN cells treated with TCDD was mediated through a ceramide-dependent pathway, independent of endoplasmic reticulum stress, as evidenced by increased ceramide synthesis and the reversal of cytotoxic effects with myriocin, a potent inhibitor of ceramide biosynthesis. We identified Sptlc2 and Smpd2 as potential gene targets of AHR in ceramide regulation by a chromatin immunoprecipitation (ChIP) assay in IM-FEN cells. Additionally, TCDD downregulated phosphorylated Akt and phosphorylated Ser9-GSK-3β levels, implicating the PI3 kinase/AKT pathway in TCDD-induced neurotoxicity. Overall, this study provides important insights into the mechanisms underlying TCDD-induced enteric neurotoxicity and identifies potential targets for the development of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Abnormal production of reactive oxygen species (ROS) has been implicated in the physiopathology of neuronal cell death. Increased ROS levels are associated with exacerbated peptide aggregation, inflammation, and mitochondrial dysfunction, which facilitate the triggering of specific cell death pathways. Antioxidant molecules are potentially useful in the amelioration of neurodegeneration. In this regard, natural products are an invaluable source of antioxidants. Therefore, we investigate the antioxidant and neuroprotective activities of four Colombian angiosperm extracts. Antioxidant activity was evaluated by phytochemical assays using TLC techniques with Dragendorff reagent, ninhydrin, and chloranil in dioxane, NH3, Fast Blue, and FeCl3, together with bioautography using DPPH and β-carotene. In vitro neuroprotective activity, cell death, and ROS accumulation were evaluated by MTT and flow cytometry in the SH-SY5Y cell line exposed to paraquat and C2-ceramide. We found that Zanthoxylum rhoifolium Lam, Zanthoxylum martinicense, Nectandra membranacea, and Nectandra reticulata extracts have antioxidant activity higher than quercetin under a β-carotene bleaching assay and protect SH-SY5Y cells against paraquat and C2-ceramide associated with a reduction in ROS. In conclusion, these extracts have a strong neuroprotective potential, and the precise mechanism requires more evaluation. [ABSTRACT FROM AUTHOR]

Obligate intracellular protozoan parasite, Leishmania donovani, causative agent of visceral leishmaniasis, led to impaired macrophage functions. It is well documented that many of these changes were induced by parasite‐mediated reduction in macrophage cholesterol content. Leishmania‐mediated alteration in the other lipids has not been explored in detail yet. Here, we found that the expression of key cholesterol biosynthetic genes and total cellular cholesterol were reduced during L. donovani infection. Further, we have also identified that this reduction in the cholesterol led to increased membrane fluidity and inhibition of antigen‐presenting potential of macrophages. In addition to this, we studied the relative changes in different lipids in THP‐1‐derived macrophages during L. donovani infection through liquid chromatography‐mass spectrometry. We found that Sphingomyelin (16:0) and ceramide (20:1, 26:0 and 26:1) were significantly reduced in infected macrophages. We further observed that the majority of different sub‐classes of phospholipids were downregulated significantly. Overall ratio of phosphatidylcholine versus phosphotidylethanolamine was decreased which indicated the compensatory mechanism of cell in response to cholesterol reduction. The observed Leishmania‐mediated alteration in macrophage‐lipidome provided the novel insights into mechanism of host‐pathogen interactions. [ABSTRACT FROM AUTHOR]

Like 'influencers' who achieve fame and power through social media, ceramides are low abundance members of communication platforms that have a mighty impact on their surroundings. Ceramide microdomains form within sphingolipid-laden lipid rafts that confer detergent resistance to cell membranes and serve as important signaling hubs. In cells exposed to excessive amounts of saturated fatty acids (e.g. in obesity), the abundance of ceramide-rich microdomains within these rafts increases, leading to concomitant alterations in cellular metabolism and survival that contribute to cardiometabolic disease. In this mini-review, we discuss the evidence supporting the formation of these ceramide microdomains and describe the spectrum of harmful ceramide-driven metabolic actions under the context of an evolutionary theory. Moreover, we discuss the proximal 'followers' of these ceramide media stars that account for the diverse intracellular actions that allow them to influence obesity-linked disease. [ABSTRACT FROM AUTHOR]

Ceramide 2 is the main lipid of stratum corneum and a popular component in skin healthcare products. But developing ceramide 2 based corneal protecting product is troublesome due to its insoluble feature in water. In this work, a novel type of inclusion nanoparticle was developed to solubilize and enhance the corneal repair effect of ceramide 2 by the anti-solvent method. It was revealed that the types of solvents and cyclodextrins influenced the precipitation rate as well as the stability of intermediate clusters of ceramide 2, where DMSO with moderate supersaturation promoted the formation of inclusion complex with β-cyclodextrins. The ceramide-cyclodextrin inclusion complex had an amphiphilic structure, which could self-assemble into nanoparticles in water, as evidenced by disappeared endothermic peaks of ceramide (78°C) and cyclodextrin (120°C), as well as appearance of two endothermic peaks corresponding to nanoparticle transition (45°C) and dissociation of cyclodextrin inclusion complex (102°C). Upon treating rat damaged skins with ceramide 2 inclusion nanoparticles, the cumulative permeation of indomethacin (IND, a model drug for skin permeability) were found to be 330.80 ± 54.86 μg/cm2, which was significantly lower than the control group (472.47 ± 154.83 μg/cm2). In comparison, water suspensions of ceramide 2 showed no corneal repair effect. [ABSTRACT FROM AUTHOR]

Endometriosis is a prevalent chronic inflammatory disease characterized by a considerable delay between initial symptoms and diagnosis through surgery. The pressing need for a timely, non-invasive diagnostic solution underscores the focus of current research efforts. This study examines the diagnostic potential of the menstrual blood lipidome. The lipid profile of 39 samples (23 women with endometriosis and 16 patients in a control group) was acquired using reverse-phase high-performance liquid chromatography–mass spectrometry with LipidMatch processing and identification. Profiles were normalized based on total ion counts. Significant differences in lipids were determined using the Mann–Whitney test. Lipids for the diagnostic model, based on logistic regression, were selected using a combination of variance importance projection filters and Akaike information criteria. Levels of ceramides, sphingomyelins, cardiolipins, triacylglycerols, acyl- and alkenyl-phosphatidylethanolamines, and alkenyl-phosphatidylcholines increased, while acyl- and alkyl-phosphatidylcholines decreased in cases of endometriosis. Plasmenylphosphatidylethanolamine PE P-16:0/18:1 and cardiolipin CL 16:0_18:0_22:5_22:6 serve as marker lipids in the diagnostic model, exhibiting a sensitivity of 81% and specificity of 85%. The diagnostic approach based on dried spots of menstrual blood holds promise as an alternative to traditional non-invasive methods for endometriosis screening. [ABSTRACT FROM AUTHOR]

Various lipid transfer proteins (LTPs) mediate the inter‐organelle transport of lipids. By working at membrane contact zones between donor and acceptor organelles, LTPs achieve rapid and accurate inter‐organelle transfer of lipids. This article will describe the emerging paradigm that the action of LTPs at organelle contact zones generates metabolic channeling events in lipid metabolism, mainly referring to how ceramide synthesized in the endoplasmic reticulum is preferentially metabolized to sphingomyelin in the distal Golgi region, how cholesterol and phospholipids receive specific metabolic reactions in mitochondria, and how the hijacking of host LTPs by intracellular pathogens may generate new channeling‐like events. In addition, the article will discuss how the function of LTPs is regulated, exemplified by a few representative LTP systems, and will briefly touch on experiments that will be necessary to establish the paradigm that LTP‐mediated inter‐organelle transport of lipids is one of the mechanisms of compartmentalization‐based metabolic channeling events. [ABSTRACT FROM AUTHOR]

Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth hormone‐releasing hormone knockout (GHRH‐KO) female mice and their littermate controls. Employing a targeted lipidomic approach, we specifically investigated ceramide levels in GHRH‐KO mice, a well‐established model of enhanced longevity. While younger GHRH‐KO mice did not exhibit notable differences in serum lipids, older counterparts demonstrated significant reductions in over one‐third of the evaluated lipids. In employing the same analysis in liver tissue, GHRH‐KO mice showed pronounced downregulation of numerous ceramides and hexosylceramides, which have been shown to elicit many of the tissue defects that accompany aging (e.g., insulin resistance, oxidative stress, and cell death). Additionally, gene expression analysis in the liver tissue of adult GHRH‐KO mice identified substantial decreases in several ceramide synthesis genes, indicating that these alterations are, at least in part, attributed to GHRH‐KO‐induced transcriptional changes. These findings provide the first evidence of disrupted ceramide metabolism in a long‐lived mammal. This study sheds light on the intricate connections between GH deficiency, ceramide levels, and the molecular mechanisms influencing lifespan extension. [ABSTRACT FROM AUTHOR]

Elevated skeletal muscle diacylglycerols (DAGs) and ceramides can impair insulin signaling, and acylcarnitines (acylCNs) reflect impaired mitochondrial fatty acid oxidation, thus, the intramuscular lipid profile is indicative of insulin resistance. Acute (i.e., postprandial) hyperinsulinemia has been shown to elevate lipid concentrations in healthy muscle and is an independent risk factor for type 2 diabetes (T2D). However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to or exacerbating insulin resistance. We therefore investigated the impact of acute hyperinsulinemia on the skeletal muscle lipid profile to help characterize the physiological basis in which hyperinsulinemia elevates T2D risk. In a cross-sectional comparison, endurance athletes (n = 12), sedentary lean adults (n = 12), and individuals with obesity (n = 13) and T2D (n = 7) underwent a hyperinsulinemic-euglycemic clamp with muscle biopsies. Although there were no significant differences in total 1,2-DAG fluctuations, there was a 2% decrease in athletes versus a 53% increase in T2D during acute hyperinsulinemia (P = 0.087). Moreover, C18 1,2-DAG species increased during the clamp with T2D only, which negatively correlated with insulin sensitivity (P < 0.050). Basal muscle C18:0 total ceramides were elevated with T2D (P = 0.029), but not altered by clamp. Acylcarnitines were universally lowered during hyperinsulinemia, with more robust reductions of 80% in athletes compared with only 46% with T2D (albeit not statistically significant, main effect of group, P = 0.624). Similar fluctuations with acute hyperinsulinemia increasing 1,2 DAGs in insulin-resistant phenotypes and universally lowering acylcarnitines were observed in male mice. In conclusion, acute hyperinsulinemia elevates muscle 1,2-DAG levels with insulin-resistant phenotypes. This suggests a possible dysregulation of intramuscular lipid metabolism in the fed state in individuals with low insulin sensitivity, which may exacerbate insulin resistance. NEW & NOTEWORTHY: Postprandial hyperinsulinemia is a risk factor for type 2 diabetes and may increase muscle lipids. However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to insulin resistance. We observed that acute hyperinsulinemia elevates muscle 1,2-DAGs in insulin-resistant phenotypes, whereas ceramides were unaltered. Insulin-mediated acylcarnitine reductions are also hindered with high-fat feeding. The postprandial period may exacerbate insulin resistance in metabolically unhealthy phenotypes. [ABSTRACT FROM AUTHOR]

Limited or absent activity of the enzyme α-galactosidase A (α-Gal A), due to mutation in the related gene on the X chromosome, leads to the development of a rare hereditary and genetic disease known as Fabry disease (FD). This pathology involves a progressive accumulation in various organs of the substrates of the enzyme e.g., globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (Lyso-Gb3), suggesting these molecules as biomarkers of Fabry disease. The present paper describes the development of an analytical strategy for the identification and quantification of Gb3 and Lyso-Gb3, in serum and blood samples by using liquid chromatography (LC) coupled to mass spectrometry in multiple reaction monitoring (MRM/MS) ion mode. The best experimental conditions were obtained by extracting the glycolipids with chloroform/methanol/H2O (2/1/0.3) and by separating them on a C4 column with a linear gradient (A: H2O with 2 mM ammonium formate. B: methanol with 1 mM ammonium formate, both acidified with 0.2% formic acid). The best transitions (a combination of precursor and fragment ions—m/z) were 786.8 m/z > 268.3 m/z for Lyso-GB3, 1137.3 m/z > 264.3 m/z for Gb3, 1039.3 m/z > 264.4 m/z for N-heptadecanoyl-ceramide trihexoside, and 843.5 m/z > 264.3 m/z for N-glycinated lyso-ceramide trihexoside, the latter being used as an internal standard. The developed method provided a reliable, fast, and effective procedure for direct measurements of GB3 and Lyso-GB3 in serum and blood for diagnosis of Fabry disease, suggesting this method as a complementary assay to the current enzymatic test. Therefore, this approach could open new insights into the clinical diagnostics of lysosomal storage disorders. [ABSTRACT FROM AUTHOR]

The central nervous system continuously detects circulating concentrations of lipids such as fatty acids and troglycerides. Once information has been detected, the central nervous system can in turn participate in the control of energy balance and blood sugar levels and in particular regulate the secretion and action of insulin. Neurons capable of detecting circulating lipid variations are located in the hypothalamus and in other regions such as the nucleus accumbens, the striatum or the hippocampus. An excess of lipids will have deleterious effects and may induce central lipotoxicity, in particular following local production of ceramides and the appearance of neuroinflammation which may lead to metabolic diseases such as obesity and type 2 diabetes. • Both specialized neurons and non-neuronal cells can sense circulating lipids. • lipoprotein lipase in neurons and astrocytes sense triglycerides-enriched lipoproteins. • Ceramides can induce brain lipotoxicity associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

Ceramides are a family of lipids constituted by a sphingoid base and a fatty acid. In the skin, they are mainly present in the stratum corneum where, with cholesterol and free fatty acids, they constitute the inter‐corneocyte lipids. With the other lipid groups, they play a key role in the formation of dense lamellar structures between adjacent corneocytes, collectively ensuring the vital efficient barrier to water evaporation and protection from foreign agents´ penetration. Changes in ceramide level and relative composition, with potential impairment of lipid arrangement, have been evidenced in different skin conditions and skin diseases. Therefore, use of suitably formulated ceramides has been proposed for topical treatment to help re‐structure damaged lipid arrangement and repair impaired skin barrier function. Nonetheless, the formulation of ceramides in products necessitates specific processes such as heating to high temperature before their introduction in the final formula. In this review on the structure, the role and the potential of ceramides for skincare, we point out the necessity of rigorous process when formulating ceramides into the final product. We demonstrate the counterproductive effects of undissolved ceramides on skin barrier repair capacity of the formulas, when assessed in different in vitro models of disrupted skin barrier. [ABSTRACT FROM AUTHOR]

Over the past 50 years there have been great strides made in the discovery of the composition and relevance of the total stratum corneum (SC) ceramide matrix. However, the focus of this review is on the free intercellular class of ω‐linoleoyloxyacylceramides, corneocyte‐bound ceramides and associated lipids known as the corneocyte lipid envelope (CLE) together with their processing enzymes involved in aiding ceramide attachment the corneocyte protein envelope (CPE). Two structural models and partially shared biosynthetic pathways have been proposed for the attachment of CPE‐bound O‐ceramides (ω‐hydroxyceramides attached to glutamate residues of proteins in the (CPE) using the 12R‐lipoxygenase (12R‐LOX)/epidermal lipoxygenase‐3 (eLOX3)/epoxide hydrolase‐3 (EPHX3)/unknown esterase/ transglutaminase‐1 (TG1) attachment pathway) and CPE‐bound EO‐ceramides (epoxy‐enone ceramides attached to cysteine residues of proteins in the CPE using the 12R‐LOX/eLOX3/short chain dehydrogenase/reductase family 9C member 7 (SDR9C7)/non‐enzymatic attachment pathway), i.e. there is a bifurcation step beyond epidermal eLOX3. Their formation and structures will be discussed as well as their relevance in compromised skin barrier conditions together with our own work on SC maturation examined by proteomics, lipidomics, enzyme immunolocalization studies, mechanical fragility assays and Nile red staining of corneocyte envelopes (CE). Reduced levels of 12R‐LOX, eLOX3, SDR9C7 and TG1 were observed in photodamaged skin of the cheeks that were associated with reduced SC maturation as evidenced by Nile red staining and increased CE fragility. In the severely photodamaged cheeks of Albino African SC we also observed increased levels of acylceramides. Concomitantly by reducing the activity of 12R‐LOX by antibody inhibition and TG1 inhibition with a known chemical inhibitor, we demonstrated in a humidity‐based ex vivo SC maturation model that these enzymes contributed to increased CE hydrophobicity and mechanical integrity. We hypothesize that at least the CPE‐bound O‐ceramide pathway is operational in the SC. Nevertheless, our understanding of the full complexity of ω‐linoleoyloxyacylceramides and the composition of the CLE is limited particularly on cosmetically relevant body sites such as the face. [ABSTRACT FROM AUTHOR]

Anthony V. Rawlings has had 30+ years of experience in the general area of skin science. He has many scientific publications, and his work has been highly cited. He has made major contributions to our understanding of skin physiology, including xerosis and hydration, barrier function, desquamation, the corneocyte envelope, physical chemistry of stratum corneum lipids, photodamage and ethnic variation. He has held management positions with several companies in the US and UK, established AVR Consulting in 2002 and maintained a long‐standing relationship with colleagues at University College London. His time as the Editor in Chief of the International Journal of Cosmetic Science was pivotal in the development of the journal. He worked hard and succeeded in getting the IJCS included in the PubMed database. [ABSTRACT FROM AUTHOR]

Ceramides are essential lipids for skin barrier function, and various classes and species exist in the human stratum corneum (SC). To date, the relationship between skin conditions and ceramide composition in healthy individuals has remained largely unclear. In the present study, we measured six skin condition parameters (capacitance, transepidermal water loss, scaliness, roughness, multilayer exfoliation, and corneocyte cell size) for the SC of the cheeks and upper arms of 26 healthy individuals and performed correlation analyses with their SC ceramide profiles, which we measured via liquid chromatography–tandem mass spectrometry. In the cheeks, high levels and/or ratios of two free ceramide classes containing an extra hydroxyl group in the long-chain moiety and a protein-bound ceramide class containing 6-hydroxysphingosine correlated with healthy skin conditions. In contrast, the ratios of two other free ceramide classes, both containing sphingosine, and a protein-bound ceramide class containing 4,14-sphingadiene correlated with unhealthy skin conditions, as did shortening of the carbon chain of the fatty acid portion of two ceramide classes containing non-hydroxy fatty acids. Thus, our findings help to elucidate the relationship between skin conditions and ceramide composition. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme is the most common and fatal brain tumor among human cancers. Ceramide (Cer) and Sphingosine 1-phosphate (S1P) have emerged as bioeffector molecules that control several biological processes involved in both cancer development and resistance. Cer acts as a tumor suppressor, inhibiting cancer progression, promoting apoptosis, enhancing immunotherapy and sensitizing cells to chemotherapy. In contrast, S1P functions as an onco-promoter molecule, increasing proliferation, survival, invasiveness, and resistance to drug-induced apoptosis. The pro-survival PI3K/Akt pathway is a recognized downstream target of S1P, and we have previously demonstrated that in glioma cells it also improves Cer transport and metabolism towards complex sphingolipids in glioma cells. Here, we first examined the possibility that, in T98G glioma cells, S1P may regulate Cer metabolism through PI3K/Akt signaling. Our research showed that exogenous S1P increases the rate of vesicular trafficking of Cer from the endoplasmic reticulum (ER) to the Golgi apparatus through S1P receptor-mediated activation of the PI3K/Akt pathway. Interestingly, the effect of S1P results in cell protection against toxicity arising from Cer accumulation in the ER, highlighting the role of S1P as a survival factor to escape from the Cer-generating cell death response. [ABSTRACT FROM AUTHOR]

Background: There is a dearth of effective treatments to counter retinol‐induced skin irritation. Objective: This study aimed to investigate the efficacy of three potential mitigants: (i) phytosteryl/octyldodecyl lauroyl glutamate (PLG), (ii) a physiologic lipid mixture (PLM) comprised of ceramide three and cholesterol, and (iii) niacinamide, in ameliorating irritation instigated by retinol. Methods: An occlusive human patch test, spanning 5 days, was undertaken on 18 Chinese participants aged between 23 and 40. It was designed as a randomized, double‐blind, and vehicle‐controlled study. Clinician erythema assessment (CEA) and instrumental evaluations were employed pre and post‐test. Subsequently, a 4‐week consumer in‐use test, randomized and double‐blind in nature, was executed to substantiate the soothing effects of PLG. Results: Data from CEA and bioengineering assessments revealed that, in comparison to the vehicle control, both 2% PLG and 5% PLM notably curbed retinol‐induced skin erythema and inflammation. Notably, PLG outperformed PLM. Conversely, 3% niacinamide did not offer relief against retinol‐induced discomfort. The subsequent consumer in‐use test affirmed that treatments with 2% PLG were better tolerated than those with the vehicle alone. Conclusion: To the best of our knowledge, this study represents the first confirmation that physiologic lipids effectively mitigate retinol‐induced irritation. Given their capacity to counter retinol‐induced irritation, physiologic lipids, particularly PLG, are recommended for incorporation in retinol regimens. Additionally, the Visia‐CR a* value can serve as a robust objective measure for interpreting patch test outcomes. [ABSTRACT FROM AUTHOR]

Lipids are emerging as important potential targets for the early diagnosis and prognosis of several inflammatory diseases. Studying the lipid profiles is important for understanding cellular events such as low-grade inflammation, a condition common to many human diseases, including cancer, neurodegenerative diseases, diabetes, and obesity. This work aimed to explore lipid signatures in an inflammation cellular model using an advanced bioanalytical approach complemented by Machine Learning techniques. Analyses based on the high-resolution mass spectrometry of extracted lipids in TNF-α inflamed cells (R3/1 NF-κB reporter cells) versus lipids in control cells resulted in 469 quantified lipids, of which 20% were phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs), 10% were sphingomyelins (SMs), 6% were phosphatidylinositols (PIs), 7% were ceramides (Cer), 6% were phosphatidylglycerols (PGs), and 5% were phosphatidylserines (PSs). TNF-α induced a significant alteration compared to the control, with a fold change higher than 1.5; of the 88 lipids, 71 were upregulated and 17 were downregulated, impacting various pathways as revealed by network analyses. To validate the inflammation model, the TNF-α induced cells were treated with polyphenols from thinned young apples (TAPs), which are known to have anti-inflammatory properties. The dysregulation of ceramides (Cer(d18:1/23:0), Cer(d18:1/23:0), and Cer(d18:1/22:0)) observed in TNF-α inflamed cells was completely reverted after TAP treatment. Network analyses showed the alteration of arachidonic acid and TNF signaling, which were modulated by polyphenols from thinned young apples. The results highlighted the potentiality of the inflammatory model and the bioanalytical approach to describe lipid profiles in complex biological matrices and different states. In addition, the quantified lipids were interpreted by an Artificial Intelligence approach to identify relevant signatures and clusters of lipids that can impact cellular states. Lastly, this study underlines both the potential applications of lipidomics combined with Machine Learning and how to build and validate Machine Learning models to predict inflammation based on lipid-related pattern signatures. [ABSTRACT FROM AUTHOR]