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Summary: Background: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events. Methods: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance. Findings: The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m2; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8–22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5–17%). No sphingolipids mediated the association between eGFR and ischemic stroke. Interpretation: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD. Funding: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

Background: The function of exosomes, small extracellular vesicles (sEV) secreted from human adipose-derived stem cells (ADSC), is becoming increasingly recognized as a means of transferring the regenerative power of stem cells to injured cells in wound healing. Exosomes are rich in ceramides and long noncoding RNA (lncRNA) like metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). We identified putative ceramide responsive cis-elements (CRCE) in MALAT1. We hypothesized that CRCE respond to cellular ceramide levels to regulate sEV MALAT1 packaging. MALAT1 levels by many cells exceed those of protein coding genes and it's expression is equally high in exosomes. Ceramide also regulates exosome synthesis, however, the contents of exosome cargo via sphingomyelinase and ceramide synthase pathways has not been demonstrated. Methods: ADSC were treated with an inhibitor of sphingomyelinase, GW4869, and stimulators of ceramide synthesis, C2- and C6-short chain ceramides, prior to collection of conditioned media (CM). sEV were isolated from CM, and then used to treat human dermal fibroblast (HDF) cultures in cell migration scratch assays, and mitochondrial stress tests to evaluate oxygen consumption rates (OCR). Results: Inhibition of sphingomyelinase by treatment of ADSC with GW4869 lowered levels of MALAT1 in small EVs. Stimulation of ceramide synthesis using C2- and C6- ceramides increased cellular, EVs levels of MALAT1. The functional role of sEV MALAT1 was evaluated in HDF by applying EVs to HDF. Control sEV increased migration of HDF, and significantly increased ATP production, basal and maximal respiration OCR. sEV from GW4869-treated ADSC inhibited cell migration and maximal respiration. However, sEV from C2- and C6-treated cells, respectively, increased both functions but not significantly above control EV except for maximal respiration. sEV were exosomes except when ADSC were treated with GW4869 and C6-ceramide, then they were larger and considered microvesicles. Conclusions: Ceramide synthesis regulates MALAT1 EV content. Sphingomyelinase inhibition blocked MALAT1 from being secreted from ADSC EVs. Our report is consistent with those of MALAT1 increasing cell migration and mitochondrial MALAT1 altering maximal respiration in cells. Since MALAT1 is important for exosome function, it stands that increased exosomal MALAT1 should be beneficial for wound healing as shown with these assays. 8tyb17USzV7szeprSwPAz5 Video Abstract [ABSTRACT FROM AUTHOR]

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER stress and UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non‐autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non‐autonomous signals to propagate UPR activation in target cells and tissues. [ABSTRACT FROM AUTHOR]

Prior evidence indicates the potential central role of the acid sphingomyelinase (ASM)/ceramide system in the infection of cells with SARS-CoV-2. We conducted a multicenter retrospective observational study including 72,105 adult patients with laboratory-confirmed SARS-CoV-2 infection who were admitted to 36 AP-HP (Assistance Publique–Hôpitaux de Paris) hospitals from 2 May 2020 to 31 August 2022. We examined the association between the ongoing use of medications functionally inhibiting acid sphingomyelinase (FIASMA), which reduces the infection of cells with SARS-CoV-2 in vitro, upon hospital admission with 28-day all-cause mortality in a 1:1 ratio matched analytic sample based on clinical characteristics, disease severity and other medications (N = 9714). The univariate Cox regression model of the matched analytic sample showed that FIASMA medication use at admission was associated with significantly lower risks of 28-day mortality (HR = 0.80; 95% CI = 0.72–0.88; p < 0.001). In this multicenter observational study, the use of FIASMA medications was significantly and substantially associated with reduced 28-day mortality among adult patients hospitalized with COVID-19. These findings support the continuation of these medications during the treatment of SARS-CoV-2 infections. Randomized clinical trials (RCTs) are needed to confirm these results, starting with the molecules with the greatest effect size in the study, e.g., fluoxetine, escitalopram, and amlodipine. [ABSTRACT FROM AUTHOR]

Acid sphingomyelinase (ASMase) serves as one of the most remarkable enzymes in sphingolipid biology. ASMase facilitates the hydrolysis of sphingomyelin, yielding ceramide and phosphorylcholine via the phospholipase C signal transduction pathway. Owing to its prominent intervention in apoptosis, ASMase, and its product ceramide is now at the bleeding edge of lipid research due to the coalesced efforts of several research institutions over the past 40 years. ASMase-catalyzed ceramide synthesis profoundly alters the physiological properties of membrane structure in response to a broad range of stimulations, orchestrating signaling cascades for endoplasmic reticulum stress, autophagy, and lysosomal membrane permeabilization, which influences the development of hepatic disorders, such as steatohepatitis, hepatic fibrosis, drug-induced liver injury, and hepatocellular carcinoma. As a result, the potential to modulate the ASMase action with appropriate pharmaceutical antagonists has sparked a lot of curiosity. This article emphasizes the fundamental mechanisms of the systems that govern ASMase aberrations in various hepatic pathologies. Furthermore, we present an insight into the potential therapeutic agents used to mitigate ASMase irregularities and the paramountcy of such inhibitors in drug repurposing. [ABSTRACT FROM AUTHOR]

Psoriasis is a complex chronic immunologically mediated disease that may involve skin, nails, and joints. It is characterized by hyperproliferation, deregulated differentiation, and impaired apoptosis of keratinocytes. Sphingolipids, namely ceramide, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate, are signal molecules that may regulate cell growth, immune reactions, and apoptosis. Fifteen patients with psoriasis and seventeen healthy persons were enrolled in the study. Skin samples were taken from psoriatic lesions and non-lesional areas. Tissue concentration of ceramides, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate was measured by liquid chromatography. We assessed that all levels of ceramides, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate were higher in lesioned psoriatic skin than in non-affected skin. The profile of bioactive lipids in the lesional skin of patients with psoriasis differed significantly from non-involved psoriatic skin and skin in healthy subjects. [ABSTRACT FROM AUTHOR]

Chlorogenic acid (CGA), a dietary natural phenolic acid, has been widely reported to regulate glucose and lipid metabolism. However, the protective effects and the underlying mechanisms of CGA on glucagon-induced hepatic glucose production remain largely uncharacterized. Herein, we investigated the efficacy of CGA on hepatic gluconeogenesis both in vivo and in vitro. The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered with CGA. Furthermore, chronic CGA treatment ameliorated the accumulation of glucose and ceramide in high-fat diet (HFD)-fed mice. CGA also attenuated HFD-fed-induced inflammation response. The protective effect of CGA on glucose production was further confirmed in primary mouse hepatocytes by inhibiting accumulation of ceramide and expression of p38 MAPK. Moreover, CGA administration in HFD-fed mice preserved the decreased phosphorylation of Akt in the liver, resulting in the inhibition of FoxO1 activation and, ultimately, hepatic gluconeogenesis. However, these protective effects were significantly attenuated by the addition of C2 ceramide. These results suggest that CGA inhibits ceramide accumulation to restrain hepatic glucagon response. [ABSTRACT FROM AUTHOR]

Sphingolipids are a diverse family of complex lipids typically composed of a sphingoid base bound to a fatty acid via amide bond. The metabolism of sphingolipids has long remained out of focus of biochemical studies. Recently, it has been attracting an increasing interest of researchers because of different and often multidirectional effects demonstrated by sphingolipids with a similar chemical structure. Sphingosine, ceramides (N-acylsphingosines), and their phosphorylated derivatives (sphingosine-1-phosphate and ceramide-1-phosphates) act as signaling molecules. Ceramides induce apoptosis and regulate stability of cell membranes and cell response to stress. Ceramides and sphingoid bases slow down anabolic and accelerate catabolic reactions, thus suppressing cell proliferation. On the contrary, their phosphorylated derivatives (ceramide-1-phosphate and sphingosine-1-phosphate) stimulate cell proliferation. Involvement of sphingolipids in the regulation of apoptosis and cell proliferation makes them critically important in tumor progression. Sphingolipid metabolism enzymes and sphingolipid receptors can be potential targets for antitumor therapy. This review describes the main pathways of sphingolipid metabolism in human cells, with special emphasis on the properties of this metabolism in tumor cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Interleukin 24 is a pleiotropic immunomodulatory cytokine. Numerous studies have shown that enhancing or inhibiting the expression of Interleukin 24 has a beneficial effect in animal models and clinical trials in different pathologies. We and others have already demonstrated the therapeutic utility of Interleukin 24 as an anticancer therapy and in autoimmune diseases and inflammation. Successful drug targeting will require a deeper understanding of the downstream signaling pathways. In this review, we discuss the signaling pathway triggered by Interleukin 24. Interleukin 24 is a member of the IL-10 family with crucial roles in antitumor, wound healing responses, host defense, immune regulation, and inflammation. Interleukin 24 is produced by both immune and nonimmune cells. Its canonical pathway relies on recognition and interaction with specific Interleukin 20 receptors in the plasma membrane and subsequent cytoplasmic Janus protein tyrosine kinases (JAK)/signal transducer and activator of the transcription (STAT) activation. The identification of noncanonical JAK/STAT-independent signaling pathways downstream of IL-24 relies on the interaction of IL-24 with protein kinase R in the cytosol, respiratory chain proteins in the inner mitochondrial membrane, and chaperones such as Sigma 1 Receptor in the endoplasmic reticulum. Numerous studies have shown that enhancing or inhibiting the expression of Interleukin 24 has a therapeutic effect in animal models and clinical trials in different pathologies. Successful drug targeting will require a deeper understanding of the downstream signaling pathways. In this review, we discuss the signaling pathway triggered by IL-24. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a heterogenous group of neoplasms showing a variety of clinical and pathological features depending on their anatomical location. Sphingolipids are involved in the formation and progression of cancers, and their changes are an important part of the abnormalities observed during carcinogenesis. Because the course of rectal and colonic cancer differs, the aim of the study was to assess whether the sphingolipid profile is also different in tumors of these two regions. Using a combination of ultra-high-performance liquid chromatography combined with triple quadrupole mass spectrometry, differences in the amounts of cellular sphingolipids were found in colorectal cancer. Sphingosine content was higher in rectal cancer than in adjacent healthy tissue, while the content of two ceramides (C18:0-Cer and C20:0-Cer) was lower. In colon cancer, a higher content of sphingosine, sphinganine, sphingosine-1-phosphate, and two ceramides (C14:0-Cer and C24:0-Cer) was found compared to healthy tissue, but there was no decrease in the amount of any of the assessed sphingolipids. In rectal cancer, the content of sphinganine and three ceramides (C16:0-Cer, C22:0-Cer, C24:0-Cer), as well as the entire pool of ceramides, was significantly lower compared to colon cancer. The S1P/Cer ratio in rectal cancer (S1P/C18:1-Cer, S1P/C20:0-Cer, S1P/C22:0-Cer, S1P/C24:1-Cer) and in colon cancer (S1P/C18:0-Cer, S1P/C18:1-Cer, S1P/C20:0-Cer) was higher than in adjacent healthy tissue and did not differ between the two sites (rectal cancer vs. colonic cancer). It seems that the development of colorectal cancer is accompanied by complex changes in the metabolism of sphingolipids, causing not only qualitative shifts in the ceramide pool of cancer tissue but also quantitative disturbances, depending on the location of the primary tumor. [ABSTRACT FROM AUTHOR]

Wickerhamomyces ciferrii is a non-conventional yeast strain characterized by the production of large amounts of tetraacetylphytosphingosine (TAPS). TAPS is an industrially valuable substance that can be converted into bioactive ceramide through deacetylation. TAPS-overproducing W. ciferrii is typically cultured in complex media, but there have been no systematic studies on the development of a defined medium for TAPS production. In this study, the composition of a defined medium for W. ciferrii strain was systematically investigated to increase the TAPS production. Among the defined medium components tested, Zn2+ significantly influenced TAPS production. The modified defined medium devoid of ZnSO 4 , with 40 g/L glycerol as a carbon source, increased TAPS production by 35% (1.16 ± 0.04 g/L, 0.039 g-TAPS/OD 600) compared to the control defined medium (0.8 ± 0.01 g/L, 0.022 g-TAPS/OD 600) in flask cultures. In batch bioreactor fermentation using the modified defined medium (40 g/L glycerol), 1.85 ± 0.1 g/L of TAPS (0.046 g-TAPS/g-glycerol, 0.044 g-TAPS/OD 600) was achieved, which was 28% higher than 1.45 ± 0.02 g/L of TAPS (0.036 g-TAPS/g-glycerol, 0.027 g-TAPS/OD 600) with the complex medium. Therefore, the modified defined medium developed in this study has the potential to serve as a base medium for large- scale TAPS production and for physiological and metabolic engineering studies. [Display omitted] • A defined medium was developed to increase tetraacetyl phytosphingosine (TAPS). • Omission of Zn2+ in a defined medium increased the TAPS production. • TAPS in the defined medium was 28% higher than with the complex medium. [ABSTRACT FROM AUTHOR]

Background: Moisturizers are first‐line therapy for treatment of atopic dermatitis (AD). Although there are multiple types of moisturizers available, head‐to‐head trials between different moisturizers are limited. Objective: To evaluate if a paraffin‐based moisturizer is as effective as ceramide‐based moisturizer in children with AD. Materials and Methods: In this double‐blind, randomized comparative trial of pediatric patients with mild to moderate AD, subjects applied either a paraffin‐based or ceramide‐based moisturizer twice daily. Clinical disease activity using SCOring Atopic Dermatitis (SCORAD), quality of life using Children/Infants Dermatology Life Quality Index (CDLQI/IDLQI), and transepidermal water loss (TEWL) were measured at baseline and at follow‐up at 1, 3, and 6 months. Results: Fifty‐three patients were recruited (27 ceramide group and 26 paraffin group) with a mean age of 8.2 years and mean disease duration of 60 months. The mean change in SCORAD at 3 months in the ceramide‐based and paraffin‐based moisturizer groups was 22.1 and 21.4, respectively (p =.37). The change in CDLQI/IDLQI, TEWL over forearm and back, amount and days of topical corticosteroid required, median time to remission and disease‐free days at 3 months were similar in both groups. As the 95% confidence interval (CI) of mean change in SCORAD at 3 months in both groups (0.78, 95% CI: −7.21 to 7.52) was not within the predefined margin of equivalence (−4 to +4), the conclusion of equivalence could not be proven. Conclusion: Both the paraffin‐based and ceramide‐based moisturizers were comparable in improving the disease activity in children with mild to moderate AD. [ABSTRACT FROM AUTHOR]

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder associated with peroxisomal dysfunction. Patients with this rare disease accumulate very long-chain fatty acids (VLCFAs) in their bodies because of impairment of peroxisomal VLCFA ß-oxidation. Several clinical types of X-ALD, ranging from mild (axonopathy in the spinal cord) to severe (cerebral demyelination), are known. However, the molecular basis for this phenotypic variability remains largely unknown. In this study, we determined plasma ceramide (CER) profile using liquid chromatography-tandem mass spectrometry. We characterized the molecular species profile of CER in the plasma of patients with mild (adrenomyeloneuropathy; AMN) and severe (cerebral) X-ALD. Eleven X-ALD patients (five cerebral, five AMN, and one carrier) and 10 healthy volunteers participated in this study. Elevation of C26: 0 CER was found to be a common feature regardless of the clinical types. The level of C26: 1 CER was significantly higher in AMN but not in cerebral type, than that in healthy controls. The C26: 1 CER level in the cerebral type was significantly lower than that in the AMN type. These results suggest that a high level of C26: 0 CER, along with a control level of C26: 1 CER, is a characteristic feature of the cerebral type X-ALD. [ABSTRACT FROM AUTHOR]

Introduction: There is an urgent need for biomarkers identifying individuals at risk of early‐stage cognitive impairment. Using cross‐sectional data from The Maastricht Study, this study included 197 individuals with mild cognitive impairment (MCI) and 200 cognitively unimpaired individuals aged 40 to 75, matched by age, sex, and educational level. Methods: We assessed the association of plasma sphingolipid and ceramide transfer protein (CERT) levels with MCI and adjusted for potentially confounding risk factors. Furthermore, the relationship of plasma sphingolipids and CERTs with magnetic resonance imaging brain volumes was assessed and age‐ and sex‐stratified analyses were performed. Results: Associations of plasma ceramide species C18:0 and C24:1 and combined plasma ceramide chain lengths (ceramide risk score) with MCI were moderated by sex, but not by age, and higher levels were associated with MCI in men. No associations were found among women. In addition, higher levels of ceramide C20:0, C22:0, and C24:1, but not the ceramide risk score, were associated with larger volume of the hippocampus after controlling for covariates, independent of MCI. Although higher plasma ceramide C18:0 was related to higher plasma CERT levels, no association of CERT levels was found with MCI or brain volumes. Discussion: Our results warrant further analysis of plasma ceramides as potential markers for MCI in middle‐aged men. In contrast to previous studies, no associations of plasma sphingolipids with MCI or brain volumes were found in women, independent of age. These results highlight the importance of accounting for sex‐ and age‐related factors when examining sphingolipid and CERT metabolism related to cognitive function. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an antibody‐mediated autoimmune disorder characterized by fluctuation of fatigue and weakness of muscle. Due to the heterogeneity of the course of MG, available biomarkers for prognostic prediction are urgently needed. Ceramide (Cer) was reported to participate in immune regulation and many autoimmune diseases, but its effects on MG remain undefined. This study aimed to investigate the ceramides expression levels in MG patients and their potential as novel biomarkers of disease severity. Levels of plasma ceramides were determined by ultra performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS). Severity of disease was assessed by quantitative MG scores (QMGs), MG‐specific activities of daily living scale (MG‐ADLs) and 15‐item MG quality of Life (MG‐QOL15). The concentrations of serum interleukin‐1β (IL‐1β), IL‐6, IL‐17A, and IL‐21 were determined by enzyme‐linked immunosorbent assay (ELISA), and the proportions of circulating memory B cells and plasmablasts were detected by flow‐cytometry assay. Four plasma ceramides levels we studied were detected higher in MG patients. And three of them (C16:0‐Cer, C18:0‐Cer, and C24:0‐Cer) were positively associated with QMGs. In addition, receiver operating characteristic (ROC) analysis suggested that plasma ceramides have a good ability of differentiating MG from HCs. Importantly, only C18:0‐Cer was shown to be positively associated with the concentration of serum IL and circulating memory B cells, and the decrease in plasma C18:0‐Cer paralleled the clinical improvement of patients with MG. All together, our data suggest that ceramides may play an important role in the immunopathological mechanism of MG, and C18:0‐Cer has the potential to be a novel biomarker for disease severity in MG. [ABSTRACT FROM AUTHOR]

We developed a new method to isolate small extracellular vesicles (sEVs) from male and female wild-type and 5xFAD mouse brains to investigate the sex-specific functions of sEVs in Alzheimer's disease (AD). A mass spectrometric analysis revealed that sEVs contained proteins critical for EV formation and Aβ. ExoView analysis showed that female mice contained more GFAP and Aβ-labeled sEVs, suggesting that a larger proportion of sEVs from the female brain is derived from astrocytes and/or more likely to bind to Aβ. Moreover, sEVs from female brains had more acid sphingomyelinase (ASM) and ceramide, an enzyme and its sphingolipid product important for EV formation and Aβ binding to EVs, respectively. We confirmed the function of ASM in EV formation and Aβ binding using co-labeling and proximity ligation assays, showing that ASM inhibitors prevented complex formation between Aβ and ceramide in primary cultured astrocytes. Finally, our study demonstrated that sEVs from female 5xFAD mice were more neurotoxic than those from males, as determined by impaired mitochondrial function (Seahorse assays) and LDH cytotoxicity assays. Our study suggests that sex-specific sEVs are functionally distinct markers for AD and that ASM is a potential target for AD therapy. [ABSTRACT FROM AUTHOR]

Ceramide, a bioactive sphingolipid, serves as an important second messenger in cell signal transduction. Under stressful conditions, it can be generated from de novo synthesis, sphingomyelin hydrolysis, and/or the salvage pathway. The brain is rich in lipids, and abnormal lipid levels are associated with a variety of brain disorders. Cerebrovascular diseases, which are mainly caused by abnormal cerebral blood flow and secondary neurological injury, are the leading causes of death and disability worldwide. There is a growing body of evidence for a close connection between elevated ceramide levels and cerebrovascular diseases, especially stroke and cerebral small vessel disease (CSVD). The increased ceramide has broad effects on different types of brain cells, including endothelial cells, microglia, and neurons. Therefore, strategies that reduce ceramide synthesis, such as modifying sphingomyelinase activity or the ratelimiting enzyme of the de novo synthesis pathway, serine palmitoyltransferase, may represent novel and promising therapeutic approaches to prevent or treat cerebrovascular injury-related diseases. [ABSTRACT FROM AUTHOR]

Natural ceramide, a biologically active compound present in plants, has been used widely in food, cosmetics, and pharmaceutical industries. Abundant ceramide has been detected in sewage sludge, which has inspired the idea to recycle ceramide from it. Therefore, the methods of extracting, purifying, and detecting ceramides from plants were reviewed, with the aim to establish methods to get condensed ceramide from sludge. Ceramide extraction methods include traditional methods (maceration, reflux, and Soxhlet extraction) and green technologies (ultrasound-assisted, microwave-assisted, and supercritical fluid extraction). In the past two decades, more than 70% of the articles have used traditional methods. However, green extraction methods are gradually improved and showed high extraction efficiency with lower solvent consumed. The preferred technique for ceramide purification is chromatography. Common solvent systems include chloroform–methanol, n-hexane–ethyl acetate, petroleum ether-ethyl acetate, and petroleum ether-acetone. For structural determination of ceramide, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry are used in combination. Among quantitative analysis methods for ceramide, liquid chromatography–mass spectrometry was the most accurate. This review concludes that with our prilemenary experiment results it is feasible to apply the plant "extraction + purification" process of ceramide to sludge, but more optimization need to be performed to get better results. [ABSTRACT FROM AUTHOR]

ESB1609 is a small‐molecule sphingosine‐1‐phosphate‐5 receptor–selective agonist designed to restore lipid homeostasis by promoting cytosolic egress of sphingosine‐1‐phosphate to reduce abnormal levels of ceramide and cholesterol in disease. A phase 1 study was conducted in healthy volunteers to determine the safety, tolerability, and pharmacokinetics of ESB1609. Following single oral doses, ESB1609 demonstrated linear pharmacokinetics in plasma and cerebrospinal fluid (CSF) for formulations containing sodium laurel sulfate. Plasma and CSF median time to maximum drug concentration (tmax) were reached by 4–5 hours and 6–10 hours, respectively. The delay in achieving tmax in CSF relative to plasma, likely due to the high protein binding of ESB1609, was also observed in 2 rat studies. Continuous CSF collection via indwelling catheters confirmed that a highly protein‐bound compound is measurable and established the kinetics of ESB1609 in human CSF. Mean plasma terminal elimination half‐lives ranged from 20.2 to 26.8 hours. The effect of either a high‐fat or standard meal increased maximum plasma concentration and area under the concentration‐time curve from time 0 to infinity compared to the fasted state by 2.42–4.34‐fold higher, but tmax and half‐life remained the same irrespective of fed state. ESB1609 crosses the blood‐brain barrier with CSF:plasma ratios ranging between 0.04% and 0.07% across dose levels. ESB1609 demonstrated a favorable safety and tolerability profile at exposures expected to be efficacious. [ABSTRACT FROM AUTHOR]

The multiple protective functions of the skin derive from the interactions between epithelial skin and immune cells as well as the commensal microbiota. Developed in the last trimester of intra‐uterine life, the skin barrier adapts dynamically after birth. Specific differences in the structure and physiology have been disclosed between infant and adult skin. The stratum corneum of infants is thinner and structured by thicker corneocytes with a more anisotropic surface in comparison to adult skin. Lower levels of the natural moisturizing factor and its constituents, together with the increased protease activity in the epidermis result in dry baby skin and ongoing adaptation of the desquamation to the extra‐uterine environment. Infant epidermis is characterized by an accelerated proliferation rate and clinically competent permeability barrier in term neonates, despite the higher baseline values of transepidermal water loss in infants. The skin surface of newborns is less acidic, which could increase susceptibility to diaper and atopic dermatitis. Immediately after birth, skin is colonized by commensal bacteria—a process dependent on the mode of delivery and of major importance for the maturation of the immune system. Skin bacterial diversity and dysbiosis have been related to different pathology such as atopic and seborrheic dermatitis. This paper focuses on the ongoing structural, functional and biochemical adaptation of the human skin barrier after birth. We discuss the interactions on the 'skin barrier/ microbiota/ immune system' axis and their role in the development of competent functional integrity of the epidermal barrier. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is increasing interest in the development of oleogel‐based emulsions. However, they usually contained surfactants for stabilization, especially small‐molecular weight surfactants, which may have adverse health impacts. RESULTS: Herein, a surfactant‐free oleogel‐based emulsion stabilized by co‐assembled ceramide/lecithin (CER/LEC) crystals was developed. The formation and stabilization mechanisms were explored. The different molar ratios of gelator (LEC and CER) in emulsions resulted in different crystal morphology, crystallinity as well as different emulsion properties. This suggested that appropriate crystallinity, crystal size, and interfacial distribution of these crystals provided higher surface coverage against droplets coalescence, thus better emulsion stabilization. Both X‐ray diffractograms and contact angle results confirmed that the crystals which were primarily responsible for emulsion stabilization, are co‐assembled crystals consisted of both gelators (CER and LEC). Furthermore, the percentage of free fatty acids (FFAs%) results revealed a negative relationship between lipid digestibility and crystal concentration. CONCLUSIONS: This strategy greatly enriched surfactant‐free oleogel‐based emulsion formulations, as well as their potential applications in healthy lipid‐based products and novel food delivery systems with controlled lipid digestibility. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The utilization of ceramides, which are members of the sphingolipid family, has been widely acknowledged in the cosmetic and pharmaceutical industries, along with various other applications as therapeutic agents. Most ceramides currently available on the market are synthetic ceramides created through chemical reactions with precursors resembling the natural precursor of sphingolipid production by living organisms. In fact, many organisms ranging from microbes to higher-order mammals natively use metabolism to produce sphingolipids, including ceramides and their derivatives, to support cell molecular functions. Sphingolipids, for instance, are present in the cell membranes of mammals, plants, and yeast to maintain membrane morphology. As a green alternative to the chemical synthesis method, many studies have been carried out to reveal the diversity and characteristics of biologically produced ceramide derivatives. In this review, we summarized the most important aspects of ceramide biosynthesis in general and provide a quick overview of the common organisms producing ceramides. In addition, a brief discussion regarding the role of ceramides in cells and their risks was included. As the biosynthesis of ceramides is an attractive alternative to current commercial methods, the advances reviewed herein demonstrate the untapped potential for the further development of synthetic pathways to enhance biobased-ceramide production. [ABSTRACT FROM AUTHOR]

Abstract Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle‐stimulating hormone. Though POI affects many aspects of women's health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch‐chain amino acid (BCAA) insufficiency‐related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57BL/6J mice. A mechanism study revealed that the BCAA insufficiency‐induced POI is associated with abnormal activation of the ceramide‐reactive oxygen species (ROS) axis and consequent impairment of ovarian granulosa cell function. Significantly, the dietary supplement of BCAA prevented the development of ROS‐induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI.

Abstract Background Increased acid sphingomyelinase (ASMase) activity is associated with insulin resistance and cardiac dysfunction. However, the effects of ASMase on diabetic cardiomyopathy (DCM) and the molecular mechanism(s) underlying remain to be elucidated. We here investigated whether ASMase caused DCM through NADPH oxidase 4-mediated apoptosis. Methods and results We used pharmacological and genetic approaches coupled with study of murine and cell line samples to reveal the mechanisms initiated by ASMase in diabetic hearts. The protein expression and activity of ASMase were upregulated, meanwhile ceramide accumulation was increased in the myocardium of HFD mice. Inhibition of ASMase with imipramine (20 mg Kg−1 d−1) or siRNA reduced cardiomyocyte apoptosis, fibrosis, and mitigated cardiac hypertrophy and cardiac dysfunction in HFD mice. The similar effects were observed in cardiomyocytes treated with high glucose (HG, 30 mmol L−1) + palmitic acid (PA, 100 μmol L−1) or C16 ceramide (CER, 20 μmol L−1). Interestingly, the cardioprotective effect of ASMase inhibition was not accompanied by reduced ceramide accumulation, indicating a ceramide-independent manner. The mechanism may involve activated NADPH oxidase 4 (NOX4), increased ROS generation and triggered apoptosis. Suppression of NOX4 with apocynin prevented HG + PA and CER incubation induced Nppb and Myh7 pro-hypertrophic gene expression, ROS production and apoptosis in H9c2 cells. Furthermore, cardiomyocyte-specific ASMase knockout (ASMaseMyh6KO) restored HFD-induced cardiac dysfunction, remodeling, and apoptosis, whereas NOX4 protein expression was downregulated. Conclusions These results demonstrated that HFD-mediated activation of cardiomyocyte ASMase could increase NOX4 expression, which may stimulate oxidative stress, apoptosis, and then cause metabolic cardiomyopathy.

Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin condition that recurs frequently and has diverse clinical features. The main mechanism of AD is the dysfunction of the skin-epidermal barrier. One of the causes of stratum corneum (SC) structural integrity disruption is the decreased production of ceramide, an important lipid component in SC. The latest generation of moisturisers contain ceramide to help replace this lipid deficit. This study aimed to compare the efficacy of moisturisers containing ceramide with other moisturisers for AD management. Searches were conducted systematically on PubMed, the Cochrane Library, ScienceDirect, Clinicaltrials.gov, and Google Scholar for studies published from January 2012 to July 2022. Interventions and outcomes were compared in this study. Statistical analysis was performed with ReviewManager 5.4 software. Five articles met the eligibility and inclusion criteria. Three articles were meta-analyses on trans-epidermal water loss (TEWL) outcomes and two articles were meta-analyses on SCORing Atopic Dermatitis (SCORAD) outcomes. A meta-analysis of TEWL results found that TEWL values were not significantly different in subjects treated with ceramide-containing moisturisers (mean difference: −3.56, 95% CI [−8.63, 1.52], P = 0.17) with high heterogeneity (I2 = 92%) compared to other treatments. The change in SCORAD was significantly higher in moisturisers containing ceramide (mean difference: −0.98, 95% CI [−1.63, −0.33], P = 0.003) with low heterogeneity (I2 = 0%). Moisturisers containing ceramide improve SCORAD and TEWL; however only the changes in SCORAD in moisturisers containing ceramide is superior to other moisturisers.

In Alzheimer’s disease, the transporter P-glycoprotein is responsible for the clearance of amyloid-β in the brain. Amyloid-β correlates with the sphingomyelin metabolism, and sphingomyelin participates in the regulation of P-glycoprotein. The amyloid cascade hypothesis describes amyloid-β as the central cause of Alzheimer’s disease neuropathology. Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-β and their potential association in the pathological process of Alzheimer’s disease is critical. Herein, we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age. The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age. Decreased sphingomyelin levels, increased ceramide levels, and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice. Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1–42 and human cerebral microvascular endothelial cells treated with amyloid-β1–42. In human cerebral microvascular endothelial cells, neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1–42 treatment. Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide. Together, these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway. These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.

We attempted to use tobiko powder, a byproduct of the konjac cake production, to rear the 5th-instar silkworms by mixing it in the artificial diet, and found that tobiko powder was usable up to the mixing ratio of 20 wt%. Even when the content of mulberry leaf powder in the diet was decreased down to 10 wt% with inversely increasing the tobiko powder up to 20 wt%, the 5th-instar silkworms yielded cocoons comparable to the conventional rearing. However, the spinning habit of the silkworm was a little modified probably by the bioactive chemicals contained in the tobiko powder. Further, yellowing occurred on the surface of the trial raw silk fibers, suggesting that some substances contained in the tobiko powder were excreted in the sericin layer of the cocoon threads. Such change in the composition of sericin layer effectively promoted the enzymatically degumming and then, a glossiness of the degummed fibers was enhanced due to the formation of the fibrillary lines passing along the fiber axis on the fiber surface. In addition, WAXD analysis revealed that the crystallinity of the trial fibers was a little superior to that of the conventional fibers.

Abstract Background Pyroptosis of endothelial cells is a new cause of endothelial dysfunction in multiple diseases. Ceramide acts as a potential bioactive mediator of inflammation and increases vascular endothelial permeability in many diseases, whether it can aggravate vascular endothelial injury by inducing cell pyroptosis remains unknown. This study was established to explore the effects of C8-ceramide (C8-Cer) on human umbilical vein vascular endothelial cells (HUVECs) and its possible underlying mechanism. Methods HUVECs were exposed to various concentrations of C8-Cer for 12 h, 24 h, 48 h. The cell survival rate was measured using the cell counting kit-8 assay. Western blotting and Real-time polymerase chain reaction (RT-PCR) were used to detect the pyroptosis-releated protein and mRNA expressions, respectively. Caspase-1 activity assay was used to detect caspase-1 activity. Hoechst 33342/propidium iodide double staining and flow cytometry were adopted to measure positive staining of cells. Lactate dehydrogenase release assay and enzyme-linked immunosorbent assay were adopted to measure leakage of cellular contents. FITC method was used to detect the permeability of endothelial cells. ROS fluorescence intensity were detected by flow cytometry. Results The viability of HUVECs decreased gradually with the increase in ceramide concentration and time. Ceramide upregulated the expression of thioredoxin interacting protein (TXNIP), NLRP3, GSDMD, GSDMD-NT, caspase-1 and Casp1 p20 at the protein and mRNA level in a dose-dependent manner. It also enhanced the PI uptake in HUVECs and upregulated caspase-1 activity. Moreover, it promoted the release of lactate dehydrogenase, interleukin-1β, and interleukin-18. Meanwhile, we found that ceramide led to increased vascular permeability. The inhibitor of NLRP3 inflammasome assembly, MCC950, was able to disrupt the aforementioned positive loop, thus alleviating vascular endothelial cell damage. Interestingly, inhibition of TXNIP either chemically using verapamil or genetically using small interfering RNA (siRNA) can effectively inhibit ceramide-induced pyroptosis and improved cell permeability. In addition, ceramide stimulated reactive oxygen species (ROS) generation. The pretreatment of antioxidant N-acetylcysteine (NAC), ROS scavenger, blocked the expression of pyroptosis markers induced by C8-cer in HUVECs. Conclusion The current study demonstrated that C8-Cer could aggravate vascular endothelial cell damage and increased cell permeability by inducing cell pyroptosis. The results documented that the ROS-dependent TXNIP/NLRP3/GSDMD signalling pathway plays an essential role in the ceramide-induced pyroptosis in HUVECs.

Levocetirizine hydrochloride (LVC) is an antihistaminic drug that is repurposed for the treatment of alopecia. This investigation is targeted for formulating LVC into cationic ceramide/phospholipid composite (CCPCs) for the management of alopecia. CCPCs were fabricated by ethanol-injection approach, through a central composite experiment. CCPCs were evaluated by inspecting their entrapment efficiency (EE%), polydispersity index (PDI), particle size (PS), and zeta potential (ZP). The optimum CCPCs were additionally studied by in-vitro, ex-vivo, in-silico, and in-vivo studies. The fabricated CCPCs had acceptable EE%, PS, PDI, and ZP values. The statistical optimization elected optimum CCPCs composed of 5 mg hyaluronic acid, 10 mg ceramide III, and 5 mg dimethyldidodecylammonium bromide employing phytantriol as a permeation enhancer. The optimum CCPCs had EE%, PS, PDI, and ZP of 88.36 ± 0.34%, 479.00 ± 50.34 nm, 0.377 ± 0.0035, and 20.20 ± 1.13 mV, respectively. The optimum CCPC maintained its stability for up to 90 days. It also viewed vesicles of tube shape via transmission electron microscope. The in-silico assessment resulted in better interaction and stability between LVC and vesicle components in water. The ex-vivo and in-vivo assessments showed satisfactory skin retention of LVC from optimum CCPCs. The histopathological assessment verified the safety of optimum CCPCs to be topically applied. Overall, the optimum CCPCs could be utilized as a potential system for the topical management of alopecia, with a prolonged period of activity, coupled with reduced LVC shortcomings.

Abstract Many cardiovascular disorders, including atherosclerosis, hypertension, coronary heart disease, diabetes, etc., are characterized by endothelial cell dysfunction. Endothelial cell function is closely related to sphingolipid metabolism, and normal sphingolipid metabolism is critical for maintaining endothelial cell homeostasis. Sphingolipid metabolites or key enzymes in abnormal situation, including sphingosine, ceramide (Cer), sphingosine-1-phosphate (S1P), serine, sphingosine kinase (SPHK), ceramide kinase (Cerk), sphingosine-1-phosphate lyase (S1PL) etc., may have a protective or damaging effect on the function of endothelial cells. This review summarizes the effects of sphingolipid metabolites and key enzymes disordering in sphingolipid metabolism on endothelial cells, offering some insights into further research on the pathogenesis of cardiovascular diseases and corresponding therapeutic targets.

Ceramidases (CDases) are vital sphingolipid enzymes involved in organismal growth and development. They have been reported as key mediators of thermal stress response. However, whether and how CDase responds to heat stress in insects remain unclear. Herein, we identified two CDase genes, C. lividipennis alkaline ceramidase (ClAC) and neutral ceramidase (ClNC), by searching the transcriptome and genome databases of the mirid bug, Cyrtorhinus lividipennis, an important natural predator of planthoppers. Quantitative PCR (qPCR) analysis showed that both ClNC and ClAC were highly expressed in nymphs than in adults. ClAC was especially highly expressed in the head, thorax, and legs, while ClNC was widely expressed in the tested organs. Only the ClAC transcription was significantly affected by heat stress. Knocking down ClAC increased the C. lividipennis nymph survival rate under heat stress. The transcriptome and lipidomics data showed that the RNA interference-mediated suppression of ClAC significantly upregulated the transcription level of catalase (CAT) and the content of long-chain base ceramides, including C16-, C18-, C24-, and C31-ceramides. In C. lividipennis nymphs, ClAC played an important role in heat stress response, and the upregulation of nymph survival rate might be caused by variation in the ceramide levels and transcriptional changes in CDase downstream genes. This study improves our understanding of the physiological functions of insect CDase under heat stress and provides valuable insights into the nature enemy application. [ABSTRACT FROM AUTHOR]

Simple Summary: CERS6 is known to be associated with metastasis and poor prognosis in non-small cell lung cancer (NSCLC) patients because of C16 ceramide production, though the underlying mechanism remains largely unelucidated. In this study, CERS6 binding partners were identified by co-immunoprecipitation, as well as liquid chromatography and tandem mass spectrometry analysis. LASP1, one of the leading candidates, was found to play a role in cell migration, while CERS6 and LASP1 were shown to co-localize on lamellipodia and interact with actin. Silencing of CERS6 and/or LASP1 led to reduced levels of lamellipodia formation and cell migration. Furthermore, interaction of CERS6 or LASP1 with actin was dramatically decreased when the partner was depleted. Based on these findings, it is proposed that LASP1–CERS6 interaction promotes cancer cell migration. CERS6 is associated with metastasis and poor prognosis in non-small cell lung cancer (NSCLC) patients through d18:1/C16:0 ceramide (C16 ceramide)-mediated cell migration, though the detailed mechanism has not been elucidated. In the present study, examinations including co-immunoprecipitation, liquid chromatography, and tandem mass spectrometry analysis were performed to identify a novel binding partner of CERS6. Among the examined candidates, LASP1 was a top-ranked binding partner, with the LIM domain possibly required for direct interaction. In accord with those findings, CERS6 and LASP1 were found to co-localize on lamellipodia in several lung cancer cell lines. Furthermore, silencing of CERS6 and/or LASP1 significantly suppressed cell migration and lamellipodia formation, whereas ectopic addition of C16 ceramide partially rescued those phenotypes. Both LASP1 and CERS6 showed co-immunoprecipitation with actin, with those interactions markedly reduced when the LASP1–CERS6 complex was abolished. Based on these findings, it is proposed that LASP1–CERS6 interaction promotes cancer cell migration. [ABSTRACT FROM AUTHOR]

Maintaining the integrity of the nuclear envelope (NE) is essential for preventing genomic DNA damage. Recent studies have shown that enzymes that catalyze lipid synthesis are involved in NE maintenance, but the underlying mechanism remains unclear. Here, we found that the ceramide synthase (CerS) homolog in the fission yeast Schizosaccharomyces pombe Tlc4 (SPAC17A2.02c) suppressed NE defects in cells lacking the NE proteins Lem2 and Bqt4. Tlc4 possesses a TRAM/LAG1/CLN8 domain that is conserved in CerS proteins and functions through its non-catalytic activity. Tlc4 was localized at the NE and endoplasmic reticulum, similar to CerS proteins, and also showed unique additional localization at the cisand medial-Golgi cisternae. Growth and mutation analyses revealed that Golgi localization of Tlc4 was tightly linked to its activity of suppressing the defects in the double-deletion mutant of Lem2 and Bqt4. Our results suggest that Lem2 and Bqt4 control the translocation of Tlc4 from the NE to the Golgi, which is necessary for maintaining NE integrity. [ABSTRACT FROM AUTHOR]

Currently, there are no animal models for studying both specific social fear and social fear with comorbidities. Here, we investigated whether social fear conditioning (SFC), an animal model with face, predictive and construct validity for social anxiety disorder (SAD), leads to the development of comorbidities at a later stage over the course of the disease and how this affects the brain sphingolipid metabolism. SFC altered both the emotional behavior and the brain sphingolipid metabolism in a time-point-dependent manner. While social fear was not accompanied by changes in non-social anxiety-like and depressive-like behavior for at least two to three weeks, a comorbid depressive-like behavior developed five weeks after SFC. These different pathologies were accompanied by different alterations in the brain sphingolipid metabolism. Specific social fear was accompanied by increased activity of ceramidases in the ventral hippocampus and ventral mesencephalon and by small changes in sphingolipid levels in the dorsal hippocampus. Social fear with comorbid depression, however, altered the activity of sphingomyelinases and ceramidases as well as the sphingolipid levels and sphingolipid ratios in most of the investigated brain regions. This suggests that changes in the brain sphingolipid metabolism might be related to the short- and long-term pathophysiology of SAD. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) has been the standard of care for treating a multitude of cancer types. However, ionizing radiation has adverse short and long-term side effects which have resulted in treatment complications for decades. Thus, advances in enhancing the effects of RT have been the primary focus of research in radiation oncology. To avoid the usage of high radiation doses, treatment modalities such as high-intensity focused ultrasound can be implemented to reduce the radiation doses required to destroy cancer cells. In the past few years, the use of focused ultrasound (FUS) has demonstrated immense success in a number of applications as it capitalizes on spatial specificity. It allows ultrasound energy to be delivered to a targeted focal area without harming the surrounding tissue. FUS combined with RT has specifically demonstrated experimental evidence in its application resulting in enhanced cell death and tumor cure. Ultrasound-stimulated microbubbles have recently proved to be a novel way of enhancing RT as a radioenhancing agent on its own, or as a delivery vector for radiosensitizing agents such as oxygen. In this mini-review article, we discuss the bio-effects of FUS and RT in various preclinical models and highlight the applicability of this combined therapy in clinical settings. [ABSTRACT FROM AUTHOR]

Type III secretion systems are found in many Gram-negative pathogens and symbionts of animals and plants. Salmonella enterica has two type III secretion systems associated with virulence, one involved in the invasion of host cells and another involved in maintaining an appropriate intracellular niche. SrfJ is an effector of the second type III secretion system. In this study, we explored the biochemical function of SrfJ and the consequences for mammalian host cells of the expression of this S. enterica effector. Our experiments suggest that SrfJ is a glucosylceramidase that alters the lipidome and the transcriptome of host cells, both when expressed alone in epithelial cells and when translocated into macrophages in the context of Salmonella infection. We were able to identify seventeen lipids with higher levels and six lipids with lower levels in the presence of SrfJ. Analysis of the forty-five genes, the expression of which is significantly altered by SrfJ with a fold-change threshold of two, suggests that this effector may be involved in protecting Salmonella from host immune defenses. [ABSTRACT FROM AUTHOR]

Introduction: Insulin resistance (IR) is one of the common chronic metabolic disorders in Africa and elsewhere. Accumulation of lipids in the body may be due to an imbalance in the metabolism of lipids, glucose and proteins. Ceramides are a sphingolipid class of lipids that are biologically active and vital in the production of more complex lipids. Circulating ceramides are thought to have a role in the development of obesity‐related IR, although the precise involvement remains unclear. Aim: To investigate the impact of circulating ceramide on IR and body adiposity in people with and without type 2 diabetes mellitus (T2DM). Methodology: The study was observational and cross‐sectional. There were a total of 84 volunteers with T2DM and 75 nondiabetics (control). The participants' ages, body mass indexes (BMI), waist circumferences, and blood pressure (BP) were among the clinical parameters assessed. Ceramide levels, fasting plasma glucose (FPG), lipids, basal insulin levels and glycated haemoglobin (HbA1c) were also measured. Additionally, the homeostatic model assessment for IR (HOMA‐IR) and beta cell function (HOMA‐β) were computed. Results: T2DM and control participants had different mean values for anthropometric parameters, BP, FPG, HbA1c, lipids, insulin, HOMA‐IR, HOMA‐β and ceramide levels (p <.05 for all). HOMA‐IR, HOMA‐β and cardiovascular risk were significant correlates with ceramide levels in the T2DM group (r = 0.24; −0.34; 0.24, p <.05, respectively). Further, FPG (OR = 1.83, p =.01) and ceramide (OR = 1.05, p =.01) levels were significant predictors of IR in the case group. Conclusion: Patients with T2DM exhibited high ceramide concentrations, which, when combined with high FPG, were associated with IR. The consequences of circulating ceramides in health and disease; however, merit further research. The exact role of circulating ceramides in obesity‐related insulin resistance remains elusive. In this study patients with type 2 diabetes exhibited higher ceramide concentrations, which, when combined with elevations in blood glucose, were associated with insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Myricetin, a type of flavonol commonly found in fruits and herbs, has demonstrated anticancer properties by triggering the process of apoptosis or programmed cell death in tumor cells. Despite the absence of mitochondria and nuclei, erythrocytes can undergo programmed cell death, also known as eryptosis.This process is characterized by cell shrinkage, externalization of phosphatidylserine (PS) on the cell membrane, and the formation of membrane blebs. The signaling of eryptosis involves Ca2+ influx, the formation of reactive oxygen species (ROS), and the accumulation of cell surface ceramide. The present study explored the effects of myricetin on eryptosis. Methods and results: Human erythrocytes were exposed to various concentrations of myricetin (2–8 µM) for 24 h. Flow cytometry was used to assess the markers of eryptosis, including PS exposure, cellular volume, cytosolic Ca2+ concentration, and ceramide accumulation. In addition, the levels of intracellular ROS were measured using the 2',7'-dichlorofluorescin diacetate (DCFDA) assay. The myricetin-treated (8 µM) erythrocytes significantly increased Annexin-positive cells, Fluo-3 fluorescence intensity, DCF fluorescence intensity, and the accumulation of ceramide. The impact of myricetin on the binding of annexin-V was significantly reduced, but not completely eliminated, by the nominal removal of extracellular Ca2+. Conclusion: Myricetin triggers eryptosis, which is accompanied and, at least in part, caused by Ca2+ influx, oxidative stress and increase of ceramide abundance. [ABSTRACT FROM AUTHOR]

The maintenance of diminished acid ceramidase (ASAH1) gene expression leading to the accumulation of antiproliferative intracellular ceramides in oral squamous cell carcinoma (OSCC) has emerged as a prospective oral cancer therapeutic regimen. Our published study demonstrated that the key periodontal pathogen Porphyromonas gingivalis downregulates the expression patterns of ASAH1 mRNA in normal epithelial cells in vitro. Therefore, P. gingivalis may also beneficially diminish the expression of ASAH1 in OSCC. Because a uniquely structured P. gingivalis‐derived phosphoethanolamine dihydroceramide (PEDHC) inhibits the proliferation of normal human fibroblasts, this study aimed to test the effect of PEDHC on the survival of human oral squamous OECM‐1 cells in vitro. We demonstrated that the P. gingivalis dihydroceramide‐null (ΔPG1780) strain upregulates the expression of ASAH1 mRNA and promotes aggressive proliferation and migration of OECM‐1 cells compared to the parent P. gingivalis‐W83 strain. In addition, the intracellular concentration of ceramides was dramatically elevated in OECM‐1 cells exposed to PEDHC in vitro. Furthermore, PEDHC inhibited expression patterns of ASAH1 mRNA as well as some genes associated with degradation of the basement membranes and extracellular matrix, for example, MMP‐2, ADAM‐17 and IL‐6, in OECM‐1 cells. Altogether, these data indicated that PEDHC produced by P. gingivalis inhibits acid ceramidase expression, promotes intracellular ceramide accumulation and suppresses the survival and migration of OSCC cells in vitro. Further studies are needed to determine molecular mechanisms of PEDHC‐mediated inhibitory effect(s) on OSCC using in vivo models of oral cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: In human cancers, there are molecular changes associated with their development and responses to therapy. These include changes in molecules in their membranes called sphingolipids. Understanding why and how these lipids are altered may lead to new therapies targeting these changes. Unfortunately, as in other areas of modern cancer research, we lack an understanding of how these molecules are altered in tumors of Black Americans, or whether these changes have different impacts than in White Americans. As an important first step, we used mass spectrometry to profile the sphingolipids in tumors of the colon, liver, lung, head and neck, and endometrial cancers of Black and White Americans. We found that sphingolipids with known roles in how tumors grow and respond to therapy are differentially altered in Black and White Americans. These results strongly support further research designed to determine if Black Americans may benefit from therapies that target these alterations. In the US, the incidence and mortality of many cancers are disproportionately higher in African Americans (AA). Yet, AA remain poorly represented in molecular studies investigating the roles that biological factors might play in the development, progression, and outcomes of many cancers. Given that sphingolipids, key components of mammalian cellular membranes, have well-established roles in the etiology of cancer progression, malignancy, and responses to therapy, we conducted a robust mass spectrometry analysis of sphingolipids in normal adjacent uninvolved tissues and tumors of self-identified AA and non-Hispanic White (NHW) males with cancers of the lung, colon, liver, and head and neck and of self-identified AA and NHW females with endometrial cancer. In these cancers, AA have worse outcomes than NHW. The goal of our study was to identify biological candidates to be evaluated in future preclinical studies targeting race-specific alterations in the cancers of AA. We have identified that various sphingolipids are altered in race-specific patterns, but more importantly, the ratios of 24- to 16-carbon fatty acyl chain-length ceramides and glucosylceramides are higher in the tumors of AA. As there is evidence that ceramides with 24-carbon fatty acid chain length promote cellular survival and proliferation, whereas 16-carbon chain length promote apoptosis, these results provide important support for future studies tailored to evaluate the potential roles these differences may play in the outcomes of AA with cancer. [ABSTRACT FROM AUTHOR]

Background: Tocotrienol, a type of vitamin E, is well known for its anti-cancer and other biological activities. This systematic review aims to summarize the involvement of endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) as the underlying molecular mechanisms for the anticancer properties of tocotrienol. Method: A comprehensive literature search was performed in March 2023 using the PubMed, Scopus, Web of Science, and EMBASE databases. In vitro, in vivo, and human studies were considered. Result: A total of 840 articles were retrieved during the initial search, and 11 articles that fit the selection criteria were included for qualitative analysis. The current mechanistic findings are based solely on in vitro studies. Tocotrienol induces cancer cell growth arrest, autophagy, and cell death primarily through apoptosis but also through paraptosis-like cell death. Tocotrienol-rich fractions, including α-, γ- and δ-tocotrienols, induce ERS, as evidenced by upregulation of UPR markers and/or ERS-related apoptosis markers. Early endoplasmic reticulum calcium ion release, increased ceramide level, proteasomal inhibition, and upregulation of microRNA-190b were suggested to be essential in modulating tocotrienol-mediated ERS/UPR transduction. Nevertheless, the upstream molecular mechanism of tocotrienol-induced ERS is largely unknown. Conclusion: ERS and UPR are essential in modulating tocotrienol-mediated anti-cancer effects. Further investigation is needed to elucidate the upstream molecular mechanism of tocotrienol-mediated ERS. [ABSTRACT FROM AUTHOR]