Pathophysiological changes associated with Alzheimer's disease (AD) begin decades before dementia onset, with age and APOE ε4 genotype as major risk factors [1-4]. Primary risk factors for developing AD include aging and number of copies of the apolipoprotein E (APOE) ε4 allele. Altered sphingolipid metabolism is increasingly implicated in early AD. However, the relationship between early plasma and brain sphingolipid changes-particularly in the context of APOE genotype-remains poorly defined. In this study, we analyzed plasma and brain sphingolipid profiles in transgenic AD mice carrying human APOE3 or APOE4 variants, with or without familial AD mutations (E3FAD and E4FAD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we assessed 110 sphingolipid species across four major classes (ceramides (Cers), hexosylceramides (HexCers), lactosylceramides (LacCers), and sphingomyelins (SMs)) at 2, 4, and 6 months in plasma and at 6 months in brain tissue in the cortex, hippocampus, striatum, and cerebellum. Our results demonstrate that early plasma sphingolipid alterations are largely driven by APOE genotype rather than AD pathology. Specifically, APOE4 carriers showed significant increases in SM species and reductions in Cer species compared to APOE3 carriers, independent of age or AD genotype. Brain lipid profiles showed minimal changes across genotypes after region correction. However, combined p-value analyses revealed APOE- and EFAD-dependent differences in the composition of primarily cortical sphingolipids. ROC analyses demonstrated high discriminative power of plasma sphingolipids for APOE, but not for AD genotype. These findings suggest that early plasma lipid profiles in female 5xFAD mice are more strongly influenced by APOE genotype than by overt AD pathology, potentially reflecting systemic pathways linked to APOE4-associated AD risk, while early disease-associated changes in the brain appear to be subtle and region-specific. These results underscore the importance of accounting for APOE genotype in early-stage AD lipidomic studies and in the interpretation of peripheral lipid biomarkers.

Venous thromboembolism (VTE) is a significant global health burden, and metabolic alterations play a key role in its pathogenesis. However, previous studies have been constrained by several limitations, hindering clarification of the causal role of metabolites.

To comprehensively evaluate the causal roles of metabolites in the pathogenesis of VTE and determine whether metabolites mediate the relationships between modifiable risk factors and VTE.

Genetic associations involving 690 plasmas and 211 urinary metabolites were analyzed as exposures, while the outcomes for VTE were derived from a large-scale meta-analysis of genome-wide association studies. Metabolome-wide Mendelian randomization and colocalization analyses were performed to assess the causal role of metabolites in VTE. Metabolic pathway analysis was performed using MetOrigin, and druggability assessments were conducted to prioritize potential therapeutic targets. Additionally, a 2-step Mendelian randomization framework was employed to elucidate the mediating effects of metabolites on the relationships between modifiable risk factors and VTE.

After Bonferroni correction, 51 plasma metabolites and 18 urinary metabolites were significantly associated with VTE risk. Colocalization evidence supported causal relationships for 37 metabolites with VTE. Eleven metabolic pathways were identified for VTE-related metabolites, and 6 metabolites were prioritized as potential therapeutic targets. Twenty-four modifiable risk factors were associated with 28 VTE-related metabolites, 7 of which were linked to VTE risk. Mediation analyses further revealed significant mediating effect of 8 metabolites on how 6 modifiable factors influenced VTE.

This study identifies potential metabolite biomarkers associated with VTE risk and uncovered the metabolic mediators between modifiable risk factors and VTE, offering new insights for future prevention and treatment strategies.

The neurotoxic effects of fungal toxins in both humans and animals have been well documented. Fumonisin B1 (FB1), a mycotoxin produced by fungi of the Fusarium species, is the most toxic fumonisin variant whose neurotoxic effect is still being elucidated. This review highlights the biochemical aspects of FB1 neurotoxicity, such as its mechanisms of action as well as therapeutic strategies. Both in vitro and in vivo studies have demonstrated that alteration in sphingolipid metabolism is a major event in FB-induced neurotoxicity. Studies have also shown that neurotoxicity due to FB1 involves dysregulation of several biochemical events in the brain, such as induction of oxidative stress and inflammation, mitochondrial dysfunction and associated programmed cell death, inhibition of acetylcholinesterase and alteration of neurotransmitter levels, decreased activity of Na+K+ ATPase, as well as disruption of blood-brain barrier. This review highlights the potential public health effects of FB1-induced neurotoxicity and the need to limit human and animal exposure to FB1in order to prevent its neurotoxic effect. Moreover, it is hoped that this review would stimulate studies aimed at filling the current research gaps such as delineating the effect of FB1 on the blood-brain barrier and appropriate therapies for neurotoxicity caused by FB1.

The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis.

In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2 %, 24.0 %, and 5.7 %, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6 %), conversion from serine (45.1 %), and other sources (9.4 %). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7 %) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3 %) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100 %), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth.

By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.

Lumbar spinal canal stenosis (LSCS) plays a crucial role in neurogenic claudication and neuropathic pain. Recent studies suggest that changes in sphingolipid metabolism are linked to neuropathic pain. To explore the association between sphingolipids and LSCS, we measured the levels of sphingolipids and sphingolipid-associated molecules in an animal model of cauda equina compression (CEC), a typical type of LSCS.

By placing silicon blocks within the lumbar epidural space, CEC model were constructed in which motor disfunction had already been confirmed in our previous study. Quantitative measurements of various sphingolipids were conducted using LC-MS/MS in spinal cord and cerebrospinal fluid (CSF) samples on days 1, 7, and 28 following insertion of silicon blocks. Additionally, gene expression was analyzed in spinal cord tissue.

In the CEC model, there was a significant increase ceramide levels in the CSF with upregulation of ceramide synthase 1 in the spinal cord tissue samples on day 1. Further, S1P levels in the CSF increased on day 7 and in the spinal cord significantly increased on day 28, and there was an increase in mRNA expression levels of sphingosine kinases (SphK)1 on days 1,7, and 28, while SphK2 on days 7 and 28. Regarding S1P receptors, there was an increase in mRNA expression levels of S1P1 on days 1,7, and 28 and S1P3 on day1.

The production and activation of the sphingolipid signaling pathway could play a pivotal role in neuropathic pain related to LSCS.

Chlamydiae are obligate intracellular pathogens that utilize host cell metabolites for catabolic and anabolic processes. The bacteria replicate in epithelial cells from which they take up sphingolipids (SL) and incorporate them into the chlamydial membrane and the vacuole (termed inclusion). SL uptake is essential for Chlamydia trachomatis (Ctr) in epithelial cells; however, they can also infect phagocytes, but the consequences for the SL metabolism have not yet been investigated in these cells. We performed a quantitative sphingolipidome analysis of infected primary neutrophils, macrophages, and immortalized fallopian tube epithelial cells. Sphingosine (Sph) levels are elevated in primary M2-like macrophages and human neutrophils infected with C. trachomatis. Human neutrophils respond to the pathogen by markedly upregulating sphingosine kinase 1 (SPHK1). We show in M2-like macrophages, by RNAseq, that two counteracting pathways involving upregulation of SPHK1, but also sphingosine-1-phosphate phosphatases 1 and 2 (SGPP1 and SGPP2) and sphingosine-1-phosphate lyase (SGPL1), maintain a steady pool of S1P. Using click chemistry, we show that exogenously added sphingomyelin (SM) and ceramide (Cer) are efficiently taken up into the chlamydial inclusion and are integrated into bacterial membranes in infected M2-like macrophages. Exogenous Sph reduces chlamydial infectivity, is transported into the inclusion lumen, and integrates into chlamydial membranes, suggesting that this particular SL species could represent a host defense mechanism. Taken together, our data indicate an important role for Sph/Sph kinase vs S1P/S1P phosphatase balance in infected phagocytes and a previously unrecognized role for sphingosine in the immune defense against chlamydial infection.IMPORTANCEChlamydia trachomatis (Ctr) is the leading cause of sexually transmitted diseases worldwide. Left untreated, it can cause severe complications such as blindness, pelvic inflammatory disease, or infertility. To date, no vaccines are available, and antibiotic treatment represents the only therapeutic approach to cure the infection. Limited access to antibiotics and displaced antibiotic intake increase the risk of developing recurring infections. Immune cells which fail to clear the infection and serve as a niche for chlamydial survival and replication, favor this outcome. Our research aims to elucidate the influence of sphingolipids (SL) during chlamydial infection, especially of phagocytic cells. Identifying relevant targets offers new strategies to develop alternative treatment methods.

Traumatic brain injury (TBI) causes neuroinflammation and can generate long-term pathological consequences, including motor and visual impairments, cognitive deficits, and depression. In our previous study, we found that Fat1+-transgenic mice with higher endogenous n-3 polyunsaturated fatty acids (n-3 PUFA) were protected from post-TBI behavioral deficits and exhibited reduced levels of TBI-induced microglial activation, inflammatory factors, and sphingolipid ceramide, a lipid mediator of inflammation and cell death. This study's objective was to evaluate if feeding n-3 PUFA (EPA and docosahexaenoic acid, DHA 2:1) could restrict the elevation of ceramide in brain tissue and prevent TBI-mediated sensory-motor and behavioral deficits. Wildtype C57/BL6 mice were gavage pre-fed with PUFA (EPA: DHA = 2:1) at 500 mg/kg body weight/week for 2 weeks before and 4 weeks after exposure to left side focal cranial air-blast (50 psi) TBI or sham-blast (0-psi). Saline-gavaged mice served as controls. Following blast injury, various motor, visual, and behavioral tests were conducted, and brain tissues were collected for histological and biochemical assays. Lipidomics analysis confirmed a significant elevation of EPA in the plasma and brain tissue of PUFA-fed mice. TBI-Blast brain tissues were found to have elevated ceramide levels in control mice but not in PUFA-fed mice. Moreover, PUFA-fed mice demonstrated protection against motor impairment, photoreceptor dysfunction, depression, oculomotor nerve degeneration, and microglia activation in the optic tract. Our results demonstrate that EPA-mediated suppression of ceramide biosynthesis and neuroinflammatory factors in PUFA-fed mice is associated with significant protection against the visual, motor, and emotional deficits caused by TBI.

Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.

Rheumatoid arthritis (RA) is an autoimmune disease primarily manifested by insistent proliferative synovitis, joint degradation, and bone erosions with no targeted therapy yet. Spirulina platensis serves as a treasure house of bioactive compounds with potential significance against different inflammatory ailments. Inspired by the potentiating biological attributes of S. platensis, the current investigation is concerned with dissecting the mechanistic basis of S. platensis against rheumatoid arthritis (RA) through a series of biochemical and histopathological assessments integrated with a serum metabolomics strategy to explore more efficacious and safe alternative therapies to rectify RA. Firstly, a rat model of RA was established using complete Freund's adjuvant (CFA), and RA-related biochemical and histopathological scores were determined as monitoring indexes for control efficiency of S. platensis against RA. Serum metabolomics was adopted to profile the potential biomarkers and their corresponding metabolic pathways modulated by Spirulina through UPLC-MS/MS analysis integrated with chemometrics and MetaboAnalyst 5.0 pathway analysis. The results demonstrated that Spirulina exerted significantly modulatory effects in the CFA model by reducing systemic manifestations of oxidative stress, inflammation, and impaired liver and kidney functions typically exemplified by catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), rheumatoid factor (RF), monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and urea. Histopathological investigations have revealed that Spirulina intervention causes moderately lower inflammatory cells infiltrations, synovial hyperplasia, and cartilage destruction. Regarding serum metabolomics, Spirulina could remarkably reverse disordered RA-associated metabolites, namely glutamic acid, arachidonic acid, 5-hydroxyeicosatetraenoic acid, (20:4/18:0) phosphatidylcholine, and citric acid, to a normal-like state through modulating arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, and citrate cycle pathways putatively implicated in inflammation and joint damage. Our findings provide compelling evidence that S. platensis possesses a broad spectrum of mechanisms to restore the disrupted homeostasis in RA by multi-targeted, synergistic actions.

This study explored the immunomodulatory effects of Rehmanniae Radix Praeparata polysaccharides (RP) on LPS-induced immune activation. RP, characterized as a heteropolysaccharide (6.34 kDa and 4.63 kDa) rich in galactose and glucose, was administered to LPS-challenged BALB/c mice at 25 mg/kg and 50 mg/kg doses. Results showed RP significantly reduced pro-inflammatory cytokines (TNF-α, IL-6), lowered oxidative stress (MDA), and boosted antioxidant enzymes (SOD, GSH-Px). It restored splenic structure, mitigated apoptosis, and suppressed the TNF-α/NF-κB/IL-6 pathway. Metabolomics linked RP to sphingolipid metabolism, while gut microbiota analysis revealed increased beneficial bacteria and elevated SCFAs. Transcriptomics confirmed RP's immune regulation via TNF signaling. These findings demonstrate RP's potential in alleviating immune overactivation by modulating inflammation, gut microbiota, and SCFA production, suggesting therapeutic promise for immune-related diseases.

Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.

Sphingolipids (SPLs) are essential membrane lipids with significant bioactive roles involved in various cellular processes, and their alterations have been found to be linked to many diseases, including age-related diseases. However, comprehensive studies on the association of plasma sphingolipids with aging in large, diverse cohorts remain limited. The objective of this study was to investigate the relationship between plasma sphingolipid levels and aging in a cohort of 240 normoglycemic, biracial individuals (Black and White), aged 19-65 years. Using a targeted lipidomics approach, we measured 76 sphingolipid species using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in picomole/mL and determined changes in their levels with age and their correlations with aging. We found significant age-related changes in several sphingolipid species, including ceramide C18:1 and several very long-chain sphingomyelins (VLC SMs), such as C28:1 and C30:1, increases with age, showing a positive correlation. On the other hand, glycosphingolipids (monohexosylceramide, MHC; lactosylceramide, LacCer) and sphingosine (So) showed strong negative correlations with aging. A significant correlation was also observed between the ratios of saturate/monosaturated sphingolipid species with aging. In conclusion, our findings provide novel insights into the dynamic changes of circulating sphingolipids with aging. Specific sphingolipid species, such as Ceramide C18:1 and SM, accumulate with age, while others, including MHC, LacCer, and So decrease. These results suggest that the plasma SPL profile may provide valuable information about healthy aging and age-associated disease conditions.

Ceramides, which are recognized as pivotal signaling agents in cell differentiation and proliferation, elicit apoptosis in response to anticancer drugs and stress. Although the 1-hydroxy group of ceramide is considered to play an important role in inducing apoptosis, the detailed mechanism underlying ceramide-induced apoptosis remains elusive. We previously synthesized ceramide derivatives by transforming the 1-hydroxy group into amino and carboxy groups, and assessed their ability to form domains in artificial membranes. In this study, we evaluated the apoptotic activities of these derivatives against living cells. Surprisingly, despite the lack of the 1-hydroxy group, most of the derivatives exhibited apoptotic activity, with some being more active than ceramide. Confocal microscopy using fluorescent-ceramide and coherent anti-Stokes Raman scattering microscopy utilizing deuterated ceramide suggested the formation of large domains on living cell membranes. These findings suggest a potential relationship between domain formation and apoptotic activity. Liquid chromatography-mass spectrometry showed that the differences in apoptotic activity among the derivatives were unlikely attributed to variations in cellular uptake. Consequently, we propose that these ceramide derivatives accumulate and form distinct domains within the cellular membranes, inducing apoptosis. Intracellular ceramides synthesized in response to external stimuli may trigger apoptosis through the same mechanism.

Neurodevelopment is a multifaceted and tightly regulated process essential for the formation, maturation, and functional specialization of the nervous system. It spans critical stages, including cellular proliferation, differentiation, migration, synaptogenesis, and synaptic pruning, which collectively establish the foundation for cognitive, behavioral, and emotional functions. Metabolism serves as a cornerstone for neurodevelopment, providing the energy and substrates necessary for biosynthesis, signaling, and cellular activities.

Key metabolic pathways, including glycolysis, lipid metabolism, and amino acid metabolism, support processes such as cell proliferation, myelination, and neurotransmitter synthesis. Crucial signaling pathways, such as insulin, mTOR, and AMPK, further regulate neuronal growth, synaptic plasticity, and energy homeostasis. Dysregulation of these metabolic processes is linked to a spectrum of neurodevelopmental disorders, including autism spectrum disorders (ASDs), intellectual disabilities, and epilepsy.

This review investigates the intricate interplay between metabolic processes and neurodevelopment, elucidating the molecular mechanisms that govern brain development and the pathogenesis of neurodevelopmental disorders. Additionally, it highlights potential avenues for the development of innovative strategies aimed at enhancing brain health and function.

Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify formyl peptide receptor 2 (FPR2) as a membrane receptor that specifically binds long-chain ceramides (C14 to C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis through Gi cyclic adenosine monophosphate signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo-electron microscopy structures of FPR2 in complex with Gi trimers bound to C16:0, C18:0, and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.

The brain is rich in lipids, and disorders or abnormalities in lipid metabolism can induce neurotoxicity. Ceramides are the central intermediates of sphingolipid metabolism. This study was designed to investigate the potential lipotoxicity of ceramides in brain ischemia. First, a pseudo-targeted lipidomics analysis of plasma samples from stroke patients found significantly elevated levels of long-chain ceramides. A similar observation was made in mice subjected to permanent middle cerebral artery occlusion (pMCAO) surgery. In cultured cells, it was found that the altered ceramides were mainly derived from astrocytes via de novo pathway, and SPTLC2 was a key regulator because Sptlc2 knockdown largely blocked ceramide production. Ceramides induced astrocyte activation and triggered oxidative stress to impair mitochondrial homeostasis by increasing mitochondrial permeabilization. Moreover, ceramides triggered the formation of voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane, through which mtDNA was released into the cytoplasm. Similar to oxygen and glucose depletion treatment, ceramides also increased cGAS activity and STING protein expression. However, this activity was diminished in the presence of the mitochondrial ROS scavenger SKQ1, indicating the involvement of oxidative stress in ceramide action. By facilitating cGAS/STING signaling cascades, ceramides resultantly induced interferon response to aggravate inflammatory damage in the ischemic brain. To address the impact of ceramides on brain ischemic injury in vivo, ceramide generation was blocked in the brain by injection of AAV9-Sptlc2 shRNA in pMCAO mice. Sptlc2 knockdown in the brain reduced ceramide generation and attenuated brain ischemic damage with astrocyte inactivation. As expected, Sptlc2 deficiency effectively blocked cGAS/STING pathway-dependent interferon responses. Together, these findings suggest a new therapeutic strategy for pharmacological intervention to attenuate neuroinflammation.

We aimed to evaluate the associations of hexosylceramides (HexCers) and their ratio with incident type 2 diabetes mellitus (T2DM) and explore underlying mechanisms.

We conducted a nested case-control study using the Suzhou chronic disease cohort including 234 T2DM cases and 468 controls, 1:2 matched on age (±2 y) and sex. HexCer(d18:1/16:1) and HexCer(d18:1/24:1) were measured by targeted UPLC-MS/MS. Multivariable conditional logistic regression was used to estimate the associations of these HexCer species and their ratio with T2DM risk.

After adjustment for potential confounders, compared with the lowest quartile, the highest quartile of HexCer(d18:1/24:1) was positively associated with T2DM risk (OR: 1.91; 95%CI, 1.12, 3.26; P-trend <0.05). The ratio of HexCer(d18:1/24:1) to HexCer(d18:1/16:1) showed a positive association with T2DM risk (OR: 1.89; 95%CI, 1.13, 3.18; P-trend <0.05). On the natural log scale, each SD increases in HexCer(d18:1/24:1) and its ratio to HexCer(d18:1/16:1) increased by 29% and 30%, respectively. No significant association for HexCer(d18:1/16:1) was found. Additive value of HexCer(d18:1/24:1) or HexCer(d18:1/24:1)/HexCer(d18:1/16:1) ratio for prediction of T2DM above traditional risk factors.

HexCer(d18:1/24:1) and its ratio to HexCer(d18:1/16:1) are positively associated with incident T2DM in a community-based Chinese population. Future studies are warranted to confirm our findings.

The median lethal concentration value of alkalinity tolerance for Macrobrachium nipponense over 96 h is only 14.42 mmol/L with a safety value of 4.71 mmol/L, which is insufficient to perform the aquaculture program in a water environment with high alkalinity. Thus, the present study aims to explore the effects of alkalinity exposure on the gills of M. nipponense through identifying the changes in antioxidant enzymes, morphology, and gene expressions after 1 day, 4 days, and 7 days of exposure under an alkalinity of 10 mmol/L. The activities of MDA, GSH-PX, CAT, T-AOC, and Ca2+Mg2+-ATPase are significantly stimulated by 62.6%, 6.57%, 32.1%, 33.3%, and 14.9%, compared to those from Day 0 (control group), indicating that these antioxidant enzymes play essential roles in the protection of prawns from the damage of reactive oxygen species caused by alkalinity exposure. In addition, alkalinity exposure results in an increase in the hemolymph vessels, affecting the normal respiratory function of the gills. Transcriptome profiling analysis reveals that short-term alkali exposure (4 days) does not result in significant changes in gene expression in the present study. Furthermore, metabolic pathways, biosynthesis of amino acids, amino sugar and nucleotide sugar metabolism, lysosomes, glycolysis/gluconeogenesis, and phagosomes represent the main enriched metabolic pathways of differentially expressed genes (DEGs) between Day 4 and Day 7. Biosynthesis of amino acids, lysosomes, and phagosomes are immune-related metabolic pathways, while amino sugar and nucleotide sugar metabolism and glycolysis/gluconeogenesis are energy metabolism-related metabolic pathways, indicating that the processes of immune response and energy metabolism play essential roles in the response to alkalinity exposure in M. nipponense. Thus, the DEGs from these metabolic pathways are considered as candidate genes involved in the regulation of alkaline acclimation in M. nipponense. The present study provides valuable evidence for analysis of the adaptive mechanism when exposed to alkalinity, contributing to the survival rate and aquaculture of this species under water environments with high alkalinity.

Higher blood pressure in early life may signal cardiovascular disease over the life course, but determinants of blood pressure in early life are poorly understood.

To examine the association of maternal cardiometabolic risk factors during pregnancy with offspring blood pressure from age 2 to 18 years and explore whether the association is modified by offspring sex and race and ethnicity.

This cohort study analyzed data from the Environmental Influences on Child Health Outcomes program between January 1, 1994, and March 31, 2023. Three common maternal cardiometabolic risk factors during pregnancy were examined: prepregnancy obesity, gestational diabetes, and hypertensive disorders of pregnancy (HDP).

Maternal cardiometabolic risk factors were retrieved and harmonized from medical records and questionnaires.

Offspring systolic blood pressure (SBP) and diastolic blood pressure (DBP) percentiles adjusted for age, sex, and height were calculated.

Among 12 480 mother-offspring pairs (mean [SD] maternal age during pregnancy, 29.9 [6.4] years; 856 of 12 303 identifying as Asian [7.0%]; 1908 as Black [15.5%]; 2305 as Hispanic [18.7%]; 6522 as White [52.3%], and 712 as other [5.8%] race and ethnicity), at least 1 maternal cardiometabolic risk factor was present in 5537 (44.4%), with prepregnancy obesity being the most prevalent (3072 [24.6%]), followed by HDP (1693 [13.6%]) and gestational diabetes (805 [6.5%]). Offspring born to mothers with any cardiometabolic risk factors had higher SBP (4.88 percentile points; 95% CI, 3.97-5.82 percentile points) and higher DBP (1.90 percentile points; 95% CI, 1.15-2.64 percentile points) at their first blood pressure measurement, after adjusting for potential confounders, compared with their counterparts without any risk factors. Hypertensive disorders of pregnancy, alone or with either prepregnancy obesity or gestational diabetes, was significantly associated with higher offspring blood pressure. These associations were generally more significant among female compared with male offspring and among Black compared with other racial and ethnic groups. Among 6015 offspring who had 2 or more blood pressure measures, maternal cardiometabolic risk factors were associated with an increased rate of blood pressure change from age 2 to 18 years (SBP percentile, 0.5 [95% CI, 0.2-0.8] per year; DBP percentile, 0.7 [95% CI 0.5-1.0] per year).

These findings suggest that protecting pregnant individuals from cardiometabolic risk factors may promote healthier blood pressure in the next generation.

Sphingolipids are crucial for vascular integrity and cellular homeostasis, with recent studies highlighting their role in viral diseases.

The study aimed to assess the plasma levels of sphingolipids, specifically Sphingosine-1-phosphate (S1P) and the key enzymes of sphingolipid metabolism: Sphingomyelin synthase (SMS1), Ceramide Kinase (CERK) and acid ceramidase (ASAH1) and its association with clinical outcomes of dengue.

This prospective cohort study had 102 dengue cases with 17 severe dengue (SD), 33 dengue with warning signs (DWW), 52 dengue without warning signs (DWOW) along with 10 each from other febrile illnesses and healthy controls. Blood was collected across febrile, defervescence, and convalescence phases. Plasma levels of S1P and the enzymes were measured using ELISA, mRNA using qRT-PCR. Predictive efficacy was determined using Support vector machine (SVM) models.

Study showed a significant reduction in S1P levels across all dengue forms during febrile phases, with further decline in SD during the critical phase (P < 0.05).mRNA levels of the enzymes were increasing during critical phase (P ≤ 0.001) with no significant difference noted in their respective protein levels. S1P and SMS1 levels correlated significantly with clinical severity indicators, including hematocrit, albumin, platelet count, and liver enzymes. SVM analysis identified CERK levels along with platelet count, HCT, and ALT as markers with high predictive accuracy for dengue severity.

The study reports an association of sphingolipids with dengue virulence, emphasizing the role of S1P metabolism in disease progression and plasma leakage, and highlighting the potential of targeting sphingolipids in managing severe dengue.

While several hypotheses have been proposed to explain the underlying mechanisms of Alzheimer's disease, none have been entirely satisfactory. Both genetic and non-genetic risk factors, such as infections, metabolic disorders and psychological stress, contribute to this debilitating disease. Multiple lines of evidence indicate that ceramides may be central to the pathogenesis of Alzheimer's disease. Tumor necrosis factor-α, saturated fatty acids and cortisol elevate the brain levels of ceramides, while genetic risk factors, such as mutations in APP, presenilin, TREM2 and APOE ε4, also elevate ceramide synthesis. Importantly, ceramides displace sphingomyelin and cholesterol from lipid raft-like membrane patches that connect the endoplasmic reticulum and mitochondria, disturbing mitochondrial oxidative phosphorylation and energy production. As a consequence, the flattening of lipid rafts alters the function of γ-secretase, leading to increased production of Aβ42. Moreover, ceramides inhibit the insulin-signaling cascade via at least three mechanisms, resulting in the activation of glycogen synthase kinase-3 β. Activation of this kinase has multiple consequences, as it further deteriorates insulin resistance, promotes the transcription of BACE1, causes hyperphosphorylation of tau and inhibits the transcription factor Nrf2. Functional Nrf2 prevents apoptosis, mediates anti-inflammatory activity and improves blood-brain barrier function. Thus, various seemingly unrelated Alzheimer's disease risk factors converge on ceramide production, whereas the elevated levels of ceramides give rise to the well-known pathological features of Alzheimer's disease. Understanding and targeting these mechanisms may provide a promising foundation for the development of novel preventive and therapeutic strategies.

Mas, a newly identified G-protein-coupled receptor, is prevalent in myeloid-derived immune cells and plays a key role in inflammation. This study investigates Mas signaling and neutrophil extracellular traps (NETs) in acute liver failure (ALF), aiming to elucidate their mechanisms. Male Mas1-/- and wild-type mice, aged 6-8 weeks, receive intraperitoneally injected with lipopolysaccharide (LPS)/D-galactosamine (D-Gal) (L/G) to study NETs formation. Hepatic Mas expression increases in WT-L/G mice, whereas systemic Mas1 knockout significantly reduces L/G-induced NETs and hepatotoxicity. Antibiotics treatment and co-housing (Mas1-/--L/G and WT-L/G mice) experiments show that gut flora influences the disease phenotype in Mas1-/--L/G mice. Fecal metabolite analysis suggests that mice may be protected by reduced deoxycholic acid (DCA) production in Mas1-/- activated hepatic farnesoid X receptor (FXR), suppressing sphingosine-1-phosphate (S1P)-dependent NETs. Additionally, Mas1-/- also activates the FXR-S1P-NETs axis in the liver by inhibiting SHP2. Single-cell sequencing shows decreased interaction between endothelial cells and Cldn1+CD177+ senescent neutrophils through Col4a1-CD44. This inhibits S1P-induced Raf signaling pathway activation and NETs formation. Mas signaling significantly impacts NETs formation, highlighting its potential as an anti-inflammatory therapeutic target for ALF.

Cardiovascular disease (CVD) is a significant cause of mortality worldwide. Preventive programs are trying to reduce the burden of the disease. Recent advances in metabolomics profiling open a new avenue for developing complementary CVD evaluation strategies.

The aim of the study was to investigate whether a metabolomic profile can provide an additional characterisation of individuals with coronary artery disease (CAD).

The study included 167 participants with CAD aged 41-79 years. A control group was formed of 166 individuals without CAD, gender- and age-matched to the study group. A total of 188 metabolites were profiled in serum by liquid chromatography-tandem mass spectrometry. After clearing the data, associations between 132 metabolites and CAD presence were analysed using multiple linear regression models.

We observed significant differences in serum metabolic profiles between analysed groups on various levels. However, a deeper analysis revealed sphingomyelin 41:1 (SM 41:1) as the main metabolite independently associated with CAD after correction for classical CV risk factors. Its concentration was lower in the CAD group (median 9.79 µmol/L, interquartile range (IQR) 7.92-12.23) compared to control one (median 13.60 µmol/L, IQR 11.30-16.15) (p < 0.001). Further analysis showed that SM 41:1 concentration was inversely correlated with CAD, current smoking, and hypertension; and positively associated with female gender and non-HDL level.

CAD patients present lower plasma concentrations of SM 41:1 than healthy subjects. A better understanding of the biological function of sphingomyelin in CAD patients may help develop therapeutic approaches and risk stratification in this group.

Polycystic ovary syndrome (PCOS) is a pivotal cause of anovulatory infertility and the pathogenesis remains elusive. Cellular senescence and sphingolipid metabolism disorder are closely intertwined, and both have been demonstrated present within the granulosa cells of PCOS, while research on the combined impact of senescence and sphingolipids on PCOS-related anovulation is scarce.

Here, we leveraged four datasets of PCOS and executed differential gene expression analysis, engaged in WGCNA, and harnessed machine learning algorithms-including RF, SVM-RFE, and LASSO-to deeply explore the key genes that interact with senescence and sphingolipid metabolism in granulosa cells of PCOS. These key genes were subjected to further analysis to construct a diagnostic model, forecast immune cell infiltration, and identify potential agents. Additionally, within the testosterone-stimulated granulosa cells, we validated the expression of key genes, confirmed senescence and sphingolipids dysregulation, and evaluated the therapeutic efficacy of the candidate agent.

Our research pinpointed a set of genes (LYN, PLCG2, STAT5B, MMP9, and IL6R) that showed promise as biomarkers for PCOS-related anovulation and the diagnostic nomogram was developed. These biomarkers were linked to various immune cell types infiltration. In testosterone-stimulated granulosa cells, we observed increased expression of these biomarkers, accompanied by signs of senescence and changes in sphingolipids. Importantly, the potential agent aspirin displayed the ability to ameliorate these two processes.

This study highlighted the important value of genes associated with senescence and sphingolipids dysregulation in PCOS. Aspirin targeting senescence could be a promising therapeutic drug for addressing anovulation associated with PCOS.

Intramuscular fat (IMF) is a key determinant of meat quality enhancement in pigs. However, its correlation with subcutaneous fat (SCF) deposition presents a challenge. The precise regulation of IMF lipogenesis, without impacting SCF deposition, is a critical issue in the pig industry. To investigate this, our study examined the lipid profiles of longissimus dorsi (LD) muscle and subcutaneous adipose tissue in high IMF (IMFH) and low IMF (IMFL) Chinese Erhualian pigs using lipidomics techniques.

We identified 112 differentially abundant lipids (DALs) in the muscle and 101 DALs in the adipose tissue. Notably, 105 specific DALs associated with IMF, including various candidate markers like upregulated lipids of PS (19:2/18:1), TG (14:2/4:0/4:0), PS (17:1/18:2), FA(10:0) + COOH:(s), CL (20:4/18:2/18:2/18:2), and downregulated lipids of FA (20:4), SM (d43:5), TG (38:1/22:6), PC (22:3/20:3), and PC (18:2/24:8), were identified. These specific DALs were implicated in the regulation of linoleic, arachidonic, and alpha-linolenic acid metabolism, and choline metabolism in cancer. We further discovered that the lysophosphlipase 1 (LYPLA1) gene promotes differentiation and lipid deposition of intramuscular pre-adipocytes by affecting the phosphatidylcholine (PC) content.

Our findings identify specific lipids associated with IMF accumulation in both skeletal muscle and subcutaneous adipose depots, thereby offering valuable insights into the lipid composition of porcine IMF and new avenues for targeted IMF deposition.

This review summarizes the recently published scientific evidence regarding the role of enzymes engaged in de novo anabolic biosynthesis, catabolic, and salvage pathways of ceramide bioactive sphingolipids in bone dynamics and skeletal health.

Ceramides are precursors for bioactive sphingolipids, including sphingosine, sphingosine-1-phosphate, and others. Studies of bone metabolism and bone-related cells demonstrated that ceramide and sphingosine-1-phosphate control levels of bone remodeling and resorption generated by osteoblasts and osteoclasts. Multiple published studies demonstrated the critical role of enzymes in regulating the ceramide/sphingosine-1-phosphate ratio relative to bone physiology and the promotion of inflammatory osteolysis. Accordingly, emerging evidence suggests that targeting sphingolipid metabolism has the potential to alleviate inflammatory osteolysis and accelerate bone regeneration. Therefore, this study aimed to discuss current knowledge about crosstalk between sphingolipids and their metabolic enzymes within osteoclast and osteoblast coupling in bone remodeling and pathogenic osteolysis. This review highlights the complexity of de novo sphingolipid biosynthesis and knowledge gaps in bone physiology and pathology. We also discuss the importance of canonical and non-canonical mammalian and bacterial-derived sphingolipids relative to bone health.

Sphingolipids are essential components of cell membranes and lipoproteins. They are synthesized de novo in the endoplasmic reticulum and subsequently undergo various enzymatic modifications in different organelles, giving rise to a diverse range of biologically active compounds. These molecules play a critical role in regulating cell growth, senescence, migration, apoptosis, and signaling. In recent years, the sphingolipid metabolic pathway has been recognized as a key factor in heart failure (HF) pathophysiology. Abnormal levels of sphingolipid metabolites, such as ceramide (Cer) and sphingomyelin (SM), contribute to oxidative stress and inflammatory responses, ultimately promoting cardiomyocyte apoptosis. Conversely, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) regulate vascular function and influence cardiac remodeling. Additionally, enzymes such as diacylglycerol acyltransferase 1 (DGAT1) and sphingosine-1-phosphate lyase 1 (SGPL1) modulate cardiac lipid metabolism. Given their role in HF progression, monitoring sphingolipid alterations offers potential as valuable biomarkers for assessing disease severity, prognosis, and diagnosis. Given the complexity of sphingolipid metabolism and its involvement in diverse regulatory biological processes, a comprehensive understanding of its roles at both the cellular and organismal levels in physiopathology remains incomplete. Therefore, this review aims to explore the physiological functions, regulatory mechanisms, and therapeutic potential of sphingolipid metabolism. It will summarize the specific molecular mechanisms driving key pathological processes in HF, including ventricular remodeling, myocardial fibrosis, vascular dysfunction, and metabolic disorders. Finally, the review will highlight targeted sphingolipid metabolites as potential therapeutic strategies, offering new insights into HF diagnosis and treatment, with the goal of advancing adjunctive clinical therapies.

Sarcopenia, closely associated with other diseases such as diabetes, metabolic syndrome, and osteoporosis, significantly impacts aging populations. It is characterized by muscle atrophy, increased intramuscular adipose tissue, impaired myogenesis, chronic low-grade inflammation, and reduced muscle function. The mechanisms behind aging muscle remain incompletely understood. This study aims to elucidate the role of Sirt2 in the aging process of skeletal muscles and enhance our understanding of the underlying mechanisms. Sirt2 expression was reduced in aging muscle of male mice by 40%, compared to young muscle. Aged male Sirt2 knockout mice exhibit increased intramuscular adipose tissue infiltration by 8.5-fold changes. Furthermore, the deletion of Sirt2 exacerbated myogenesis impairment in aged muscle by decreasing the expression of Pax7 (50%) and NogoA (80%), compared to age- and sex- matched counterparts, emphasizing the role of Sirt2 in pathology of aging muscle. Additionally, long-term Sirt2 deletion affected other Sirtuin subfamily members, with decreased expressions of Sirt1 (65%), Sirt4 (94%), and Sirt5 (71%), and increased expressions of Sirt6 (4.6-fold) and Sirt7 (2.8-fold) in old male Sirt2 knockout mice, while there was no difference of these gene expression in young male mice. This study underscores the critical need for a deeper investigation into Sirt2, promising new insights that could lead to targeted therapies for sarcopenia, ultimately improving the quality of life in the elderly.

Sphingolipids and glycosphingolipids are among the most structurally diverse and complex compounds in the mammalian metabolome. They are well known to play important roles in biological architecture, cell-cell communication and cellular regulation, and for many biological processes, multiple sphingolipids are involved. Thus, it is not surprising that untargeted genetic/transcriptomic/pharmacologic/metabolomic screens have uncovered changes in sphingolipids and sphingolipid genes/proteins while studying physiological and pathological processes. Consequently, with increasing frequency, both targeted and untargeted mass spectrometry methodologies are being used to conduct sphingolipidomic analyses. Interpretation of such large data sets and design of follow-up experiments can be daunting for investigators with limited expertise with sphingolipids (and sometimes even for someone well-versed in sphingolipidology). Therefore, this review gives an overview of essential elements of sphingolipid structure and analysis, metabolism, functions, and roles in disease, and discusses some of the items to consider when interpreting lipidomics data and designing follow-up investigations.

Although α-synuclein pathology is typically associated with Lewy body diseases and multiple systems atrophy, increasing evidence indicates that it also occurs in a group of lysosomal storage disorders termed sphingolipidoses caused by the incomplete degradation, and subsequent accumulation, of a class of lipids termed sphingolipids. Notably, a number of genes that cause sphingolipidoses are also risk genes for Lewy body diseases, suggesting aetiological links between these distinct disorders. In the present review, we discuss the sphingolipidoses in which α-synuclein pathology has been reported: Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease and Anderson-Fabry disease, and describe the characteristic clinical and pathological features of these disorders, in addition to the evidence suggesting α-synuclein pathology occurs in these disorders. Finally, we evaluate the pathological mechanisms that underlie these rare disorders, with particular attention to how the enzymatic deficiency, substrate accumulation, or both, could contribute to the genesis of α-synuclein pathology and the implications of this for Lewy body diseases.

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

Stroke-associated pneumonia (SAP) represents a major complication and cause of death in patients suffering from intracerebral haemorrhage (ICH). It's urgent to develop more effective therapeutic strategies. Tongfu Xingshen capsule (TFXS) is a traditional Chinese medicine that has been utilised in clinical studies for the treatment of ICH and SAP, but the underlying mechanisms remain to be fully elucidated.

This study aims to explore the therapeutic effects and mechanisms of TFXS on SAP using an aspiration-induced Klebsiella pneumoniae infection-complicating ICH rat model and an intratracheal injection of lipopolysaccharide (LPS)-induced acute lung injury-complicating ICH rat model.

The chemical components of TFXS are characterised using ULPLC-Q Exactive-Orbitrap-MS. The therapeutic effects of TFXS are evaluated through neurological scoring, histopathology analysis, magnetic resonance imaging, immunofluorescence, Alcian blue-nuclear fast red staining, myeloperoxidase activity assessment, leukocyte counting, and ELISA. To investigate the underlying mechanisms, faecal microbiota transplantation, 16S rRNA sequencing, untargeted metabolomics, and Spearman correlation analyses are performed.

A total of 60 compounds are identified in TFXS. Pharmacological analysis reveals that TFXS significantly mitigates neurological deficits, enhances haematoma absorption, attenuates brain damage and neuroinflammation, and improves pneumonia and pulmonary injury by reducing the infiltration of leukocytes and lymphocytes, as well as suppressing the infiltration and overactivation of neutrophils. TFXS also alleviates intestinal lesions and barrier damage by increasing acidic mucins and the expression of the tight junction protein zonula occludens-1 (ZO-1). Mechanistically, TFXS ameliorates pneumonia and pulmonary injury in a gut microbiota-dependent manner. It reverses sphingolipid metabolism disorders and ceramide accumulation by modulating SAP-induced gut microbiota dysbiosis and enhancing the abundance of probiotics, including Lactobacillus, Allobaculum and Enterococcus.

TFXS exerts anti-inflammatory and protective effects on the brain, lung, and gut by alleviating gut microbiota dysbiosis and sphingolipid metabolism disorders. These findings highlight TFXS as a promising therapeutic candidate for the treatment of SAP.

This patent highlights novel pyrazolo[1,5-a]pyrimidine-3,5-diamines as neutral sphingomyelinase 2 (nSMase2) inhibitors. It provides detailed information on pyrazolo[1,5-a]pyrimidine-3,5-diamine compounds, their pharmaceutical composition, use, and potential therapeutic applications for nSMase2-related diseases.

The translation of biomedical devices and drug research is an expensive and long process with a low probability of receiving FDA approval. Developing physiologically relevant in vitro models with human cells offers a solution to not only improving the odds of FDA approval but also to expand our ability to study complex in vivo systems in a simpler fashion. Animal models remain the standard for pre-clinical testing; however, the data from animal models is an unreliable extrapolation when anticipating a human response in clinical trials, thus contributing to the low rates of translation. In this review, we focus on in vitro vascular or angiogenic models because of the incremental role that the vascular system plays in the translation of biomedical research. The first section of this review discusses the most common angiogenic cytokines that are used in vitro to initiate angiogenesis, followed by angiogenic inhibitors where both initiators and inhibitors work to maintain vascular homeostasis. Next, we evaluate previously published in vitro models, where we evaluate capturing the physical environment for biomimetic in vitro modeling. These topics provide a foundation of parameters that must be considered to improve and achieve vascular biomimicry. Finally, we summarize these topics to suggest a path forward with the goal of engineering human in vitro models that emulate the in vivo environment and provide a platform for biomedical device and drug screening that produces data to support clinical translation.

Although effective as a chemotherapeutic, the utility of Doxorubicin (Dox) is hampered by cardiotoxicity. Despite this, the ability to predict and guide monitoring of patients receiving Dox is hampered by a lack of effective biomarkers to identify susceptible patients and detect early signs of subclinical cardiotoxicity. Based on their well-established roles in the response to Dox and other chemotherapies, we performed a retrospective analysis of serum and plasma sphingolipids (SLs) from female patients with breast cancer (BC) undergoing anthracycline-containing therapy, correlating with cardiac parameters assessed by echocardiography. Results showed substantial changes in both plasma and serum SL species during therapy including ceramide (Cer), deoxydihydroCer, and dihydrosphingosine with reversion toward baseline after treatment. Linear mixed-effects model analysis revealed that baseline levels of a number of SLs correlated with adverse cardiac outcomes. Here, serum sphingosine-1-phosphate (S1P), dihydroS1P, and plasma Cer performed comparably to the prognostic value of pro-NT-BNP, an established biomarker of cardiotoxicity. Intriguingly, while pro-NT-BNP had no predictive value at mid- and post-therapy timepoints, serum S1P and dihydroS1P, and plasma Cer levels showed a correlation with adverse outcomes, particularly at the post-therapy timepoint. Finally, analysis of plasma and serum C16:C24-Cer ratios-previously linked with adverse cardiac outcomes-showed no correlation in the context of chemotherapy treatment. Overall, this pilot study provides initial evidence that plasma and serum SLs may have benefits as both prognostic and diagnostic biomarkers for female BC patients undergoing anthracycline-containing chemotherapy. Consequently, diagnostic SL measurements-recently implemented for metabolic-associated cardiac disorders-could have wider utility.

This study aimed to elucidate the antiobesity mechanisms of sweet potato extract (SPE) through biochemical, gut microbiome, liver transcriptome, and metabolome analyses. Administration of SPE to high-fat-diet-fed mice significantly reduced body weight gain, serum low-density lipoprotein cholesterol, hepatic lipid accumulation, and adipocyte hypertrophy, which were closely linked to gut microbiome composition. SPE notably increased the abundance of Eubacterium_coprostanoligenes_group_unclassified and decreased that of Kineothrix, both of which were strongly associated with short-chain fatty acid (SCFA) production. LC-QTOF-MS analysis identified resin glycoside compounds from SPE with reduced levels in mouse feces, suggesting their utilization in vivo. SPE also promoted dietary fat excretion. Liver transcriptomic and metabolomic profiling revealed that SPE may exert antiobesity effects by modulating the bile-sphingolipid metabolism, which was closely correlated with the reshaped gut microbiomes and SCFAs. These findings provide new insights into the antiobesity effects and mechanisms of SPE.

Idiopathic pulmonary fibrosis (IPF) is a lung disease with an unknown etiology and a short survival rate. There is no accurate method of early diagnosis, and it involves computed tomography (CT) or lung biopsy. Since diagnostic methods are not accurate due to their similarity to other lung pathologies, discovering new biomarkers is a key issue for diagnosticians. Currently, the use of ccf-DNA (circulating cell-free deoxyribonucleic acid) is an important focus due to its association with IPF-induced alterations in metabolic pathways, such as amino acid metabolism, energy metabolism, and lipid metabolism pathways. Other biomarkers associated with metabolic changes have been found, and they are related to changes in type II/type I alveolar epithelial cells (AECs I/II), changes in extracellular matrix (ECM), and inflammatory processes. Currently, IPF pathogenetic treatment remains unknown, and the mortality rates are increasing, and the patients are diagnosed at a late stage. Signaling pathways and metabolic dysfunction have a significant role in the disease occurrence, particularly the transforming growth factor-β (TGF-β) signaling pathway, which plays an essential role. TGF-β, Wnt, Hedgehog (Hh), and integrin signaling are the main drivers of fibrosis. These pathways activate the transformation of fibroblasts into myofibroblasts, extracellular matrix (ECM) deposition, and tissue remodeling fibrosis. Therapy targeting diverse signaling pathways to slow disease progression is crucial in the treatment of IPF. Two antifibrotic medications, including pirfenidone and nintedanib, are Food and Drug Administration (FDA)-approved for treatment. ccf-DNA could become a new biomarker for IPF diagnosis to detect the disease at the early stage, while FDA-approved therapies could help to prevent late conditions from forming and decrease mortality rates.

There is an urgent need for antiviral compounds effective against currently known and future viral threats. The development of host-targeting antivirals (HTAs) appears as an alternative strategy to fight viral infections minimizing the potential of resistant mutant development and potentially leading to the identification of broad-spectrum antiviral agents. Among the host factors explored for HTA strategy, lipids constitute an attractive target as many viruses, even genetically diverse, hijack specific lipids during their lifecycle. Multiple repurposing efforts have been performed to analyze the antiviral properties of lipid-targeting compounds. These studies include the analysis of the effects of cholesterol lowering drugs such as statins, cholesterol transport inhibitors, sphingolipid modulators, de novo lipogenesis inhibitors blocking fatty acid synthesis, compounds targeting glycerophospholipids or drugs interfering with lipid droplet metabolism. This review is focused on the current status of lipid-based or lipid-targeting antiviral strategies and their potential for the development of antiviral therapies, with special emphasis on those studies that have reached advanced stages of development such as efficacy studies in animal models or clinical trials. Whereas there is still a long way to go, multiple proof-of-concept studies and clinical evidence reinforce the therapeutic potential of these strategies warranting their further development into effective antiviral therapies.

Centenarians and their relatives possess a notable survival advantage, with higher longevity and reduced susceptibility to major age-related diseases. To date, characteristic omics profiles of centenarians have been described, demonstrating that these individuals with exceptional longevity regulate their metabolism to adapt and incorporate more resilient biomolecules into their cells. Among these adaptations, the lipidomic profile stands out. However, it has not yet been determined whether this lipidomic profile is specific to centenarians or is the consequence of extreme longevity genetics and is also present in centenarians' offspring. This distinction is crucial for defining potential therapeutic targets that could help delay the aging process and associated pathologies. We applied mass-spectrometry-based techniques to quantify 569 lipid species in plasma samples from 39 centenarians, 63 centenarians' offspring, and 69 noncentenarians' offspring without familial connections. Based on this profile, we calculated different indexes to characterize the functional and structural properties of plasma lipidome. Our findings demonstrate that extreme longevity genetics (centenarians and centenarians' offspring) determines a specific lipidomic signature characterized by (i) an enrichment of hexosylceramides, (ii) a decrease of specific species of ceramides and sulfatides, (iii) a global increase of ether-PC and ether-LPC, and (iv) changes in the fluidity and diversity of specific lipid classes. We point out the conversion of ceramides to hexosylceramides and the maintenance of the levels of the ether-linked PC as a phenotypic trait to guarantee extreme longevity. We propose that this molecular signature is the result of an intrinsic adaptive program that preserves protective mechanisms and cellular identity.