Reproduction is a fundamental biological process for the survival and continuity of species. Examining changes in reproductive strategies offers valuable insights into how animals have adapted their life histories to different environments. Since reproduction is one of the most energy-intensive processes in female animals, nutrient scarcity is expected to interfere with the ability to invest in gametes. Lately, a new model to study adaptation to nutrient limitation has emerged; the Mexican tetra Astyanax mexicanus. This fish species exists as two different morphs, a surface river morph and a cave-dwelling morph. The cave-dwelling morph has adapted to the dark, lower biodiversity, and nutrient-limited cave environment and consequently evolved an impressive starvation resistance. However, how reproductive strategies have adapted to nutrient limitations in this species remains poorly understood. Here, we compared breeding activities and maternal contributions between laboratory-raised surface fish and cavefish. We found that cavefish produce different clutch sizes of eggs with larger yolk compared to surface fish, indicating a greater maternal nutrient deposition in cavefish embryos. To systematically characterize yolk compositions, we used untargeted proteomics and lipidomics approaches to analyze protein and lipid profiles in 2-cell stage embryos and found an increased proportion of sphingolipids in cavefish compared to surface fish. Additionally, we generated transcriptomic profiles of surface fish and cavefish ovaries using a combination of single cell and bulk RNA sequencing to examine differences in maternal contribution. We found that genes essential for hormone regulation were upregulated in cavefish follicular somatic cells compared to surface fish. To evaluate whether these differences contribute to their reproductive abilities under natural-occurring stress, we induced breeding in starved female fish. Remarkably, cavefish maintained their ability to breed under starvation, whereas surface fish largely lost this ability. We identified insulin-like growth factor 1a receptor (igf1ra) as a potential candidate gene mediating the downregulation of ovarian development genes, potentially contributing to the starvation-resistant fertility of cavefish. Taken together, we investigated the female reproductive strategies in Astyanax mexicanus, which will provide fundamental insights into the adaptations of animals to environments with extreme nutrient deficit.

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.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer caused by mutagenesis resulting from excess UVR or other types of oxidative stress. These stressors also upregulate the production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), through endoplasmic reticulum stress-initiated, sphingosine-1-phosphate (S1P) signaling pathway. Although CAMP has beneficial antimicrobial activities, it also can be proinflammatory and procarcinogenic. We addressed whether and how S1P-induced CAMP production leads to cSCC development. Our study demonstrated that (i) CAMP expression is increased in cSCC cells and skin from patients with cSCC; (ii) S1P levels are elevated in cSCC cells, whereas inhibition of S1P production attenuates CAMP-stimulated cSCC growth; (iii) exogenous CAMP stimulates cSCC but not normal human keratinocyte growth; (iv) blockade of FPRL1 protein, a CAMP receptor, attenuates cSCC growth as well as the growth and invasion of cSCC cells mediated by CAMP into an extracellular matrix-containing fibroblast substrate; (v) FOXP3+ regulatory T-cell (which decreases antitumor immunity) levels increase in cSCC skin; and (vi) CAMP induces endoplasmic reticulum stress in cSCC cells. Together, the endoplasmic reticulum stress-S1P-CAMP axis forms a vicious circle, creating a favorable environment for cSCC development, that is, cSCC growth and invasion impede anticancer immunity.

Adipose tissue (AT) inflammation, a hallmark of the metabolic syndrome, is triggered by overburdened adipocytes sending out immune cell recruitment signals during obesity development. An AT immune landscape persistent throughout weight loss and regain constitutes an immune-obesogenic memory that hinders long-term weight loss management. Lipid-associated macrophages (LAMs) are emerging as major players in diseased, inflamed metabolic tissues and may be key contributors to an obesogenic memory in AT. Our previous study found that LAM abundance increases with weight loss via intermittent fasting (IF) in obese mice, which is driven by adipocyte p53 signalling. However, the specific signals causing LAM accumulation in AT under IF remain unknown. In this piece, we hypothesise on a range of adipocyte-secreted signals that can harbor immune-attractive features upon fasting/refeeding cycles. We highlight possible mechanisms including cell death signalling, matrikines, and other damage-associated molecular patterns (DAMPs), as well as adipo(-cyto)kines, lipid mediators, metabolites, extracellular vesicles, and epigenetic rewiring. Finally, we consider how advances in mechanisms of AT LAM recruitment gleaned from preclinical models might be translatable to long-term weight management in humans. Thus, we provide vantage points to study signals driving monocyte recruitment, polarisation towards LAMs, and LAM retention, to harness the therapeutic potential of modulating AT LAM levels by impacting the immune-obesogenic memory in metabolic disease.

Carbon nanotubes (CNTs), an extensively applied nanomaterial, can cause damage to the liver in fish. However, the underlying lipotoxic modes of CNTs exposure have not been studied. In the present study, juvenile Cyprinus carpio was exposed via water to various doses of multi-walled CNTs (MWCNTs) (0, 0.25, and 2.5 mg L-1) for a consecutive 28-day period. Our results showed elevated hepatosomatic index (HSI) and aspartate aminotransferase (AST) activities in plasma in all exposure groups, indicating that MWCNTs exposure induced liver dysfunction. Significantly increased low-density lipoprotein (LDL) and total cholesterol (CHO) levels along with significantly decreased triglyceride (TG) levels were observed in fish of HSC (2.5 mg L-1 MWCNTs), indicating abnormal lipid metabolism. Subsequently, the livers of fish in the HSC group were harvested for LC-MS/MS-based targeted lipidomic analysis. Changes in the lipid profiles showed 87 and 92 lipids significant up-regulated and down-regulated, respectively. These significantly altered lipids were classed into 20 lipid classes. Among them, Cer, Hex1Cer, CerG2GNAc1, SM, SPH, and phSM belong to sphingolipid. Taken together with our previous findings, these results suggested that the dysregulation of sphingolipid metabolism may be associated with oxidative stress and apoptosis induced by MWCNTs exposure in C. carpio. This study provides new insights into the potential mechanism of MWCNTs in fish, especially from the aspect of lipid metabolism.

Breast milk storage provides flexibility for working mothers, though its effects on milk fat globule membrane (MFGM) lipids are not fully understood. This study examined breast milk stored under refrigerated (2 and 4 days) and frozen (7, 14, and 21 days) conditions, finding that these storage durations preserved similar structural characteristics during in vitro gastrointestinal digestion. The analysis focused on MFGM lipid composition under various storage conditions using non-targeted lipidomics. Results revealed that freezing for 14 days reduced phosphatidylserine (PS) levels by 64.55%, while 21 days of freezing significantly decreased both PS (74.59%) and sphingomyelin (SM) (43.85%). Examination of MFGM lipid species indicated that refrigeration for 4 days and freezing for 21 days led to notable reductions in key MFGM lipid species. Thus, breast milk should be refrigerated for up to 4 days to minimize nutrient depletion or frozen for no more than 7 days.

Artemisia species have been regarded as an important source of ethnic medicinal plants, such as A. annua and A. capillaris, both of which are widely used in clinical treatment. The clinical efficacy of A. japonica is similar to that of A. capillaris, but fewer pharmaceutical studies have been reported. Given that the extracts of A. japonica were observed to reduce the rectal temperature of febrile rats induced by LPS, this study was designed to demonstrate this regulatory effect of the extracts, with a particular focus on the lipidomic profiling of the febrile rat hypothalamus. A total of 72 differential metabolites were filtered out and the association between lipid profiling and potential mechanism was explored. Sphingolipid, glycerophospholipid, arachidonic acid and ether lipid metabolism pathways were significantly enriched. TNF-α, IL-6 and PGE2 cytokines in the hypothalamus were significantly downregulated by the intervention of the extracts of A. japonica. Enzymatic reaction enrichment analysis suggested that PEMT and COX-2 might be potential targets of the efficacy, and which were testified to be downregulated by the ELISA assay under the extracts intervention.

Globally, an estimated 2.1 billion malaria cases and 11.7 million malaria deaths were averted in the period 2000-2022. Noticeably, despite effective control measurements, in 2022 there were an estimated 249 million malaria cases in 85 malaria-endemic countries and an increase of 5 million cases compared with 2021. Further understanding the biology, epidemiology, and pathogenesis of human malaria is therefore essential for achieving malaria elimination. Extracellular vesicles (EVs) are membrane-enclosed nanoparticles pivotal in intercellular communication and secreted by all cell types. Here, we will review what is currently known about EVs in malaria, from biogenesis and cargo to molecular insights of pathophysiology. Of relevance, a meta-analysis of proteomics cargo, and comparisons between in vitro and in vivo human studies revealed striking differences with those few studies reported from patients. Thus, indicating the need for rigor standardization of methodologies and for transitioning to human infections to elucidate their physiological role. We conclude with a focus on translational aspects in diagnosis and vaccine development and highlight key gaps in the knowledge of EVs in malaria research.

A comprehensive understanding of the molecular pathogenesis of chronic pancreatitis (CP), a fibroinflammatory disorder of the pancreas, is warranted for the development of targeted therapies. The current study focused on comparing the transcriptomes of pancreatic tissues obtained from patients with CP with those of two rodent models of chemically induced CP to identify dysregulated genes/signaling pathways.

Pancreatitis was induced in mice using cerulein and L-arginine. Pancreatic tissues were obtained from humans and mice. The RNA was isolated, and the transcriptomes were generated using the GeneChip Human Transcriptome Array 2.0 and Clariom D Mouse Array respectively. Differentially expressed genes with log2-fold changes ≥ +2 and ≤ -2 were considered for functional and signaling pathway enrichment analysis. The expression of NUCB2, which plays a role in β-cell function, was validated by ELISA in acute pancreatitis (AP) and immune cell responses in AP and CP using flow cytometry.

The current study identifies L-arginine-induced CP as a better model for investigating the pathogenesis of human CP, with greater similarity in dysregulated genes (22%), transcription factors (34%) and enriched pathways (58%) compared to cerulein model (2%, 11% and 9%) respectively. Nesfatin-1, encoded by NUCB2, was decreased in patients with AP (12% nondiabetic, 41% post pancreatitis diabetes). The Th1 immune cell response was greater in the patients with AP (44%), whereas Th17 immune response was greater in patients with CP (18%).

Our study highlights potential novel and unexplored pathways involved in inflammation, fibrosis, and pain in CP and paves the way for testing them as putative drug targets using a severe disease model.

Ceramide 1-phosphate (C1P), as a lipid mediator, specifically binds and activates cytosolic phospholipase A2α (cPLA2α). Previous findings revealed that modification of the specific hydrophobic moiety decreases the affinity with cPLA2α. However, the possible biological role of the temporal C1P-enriched domains formed in biomembranes for the molecular recognition of cPLA2α has not been fully elucidated. In this study we elucidated the properties of segregated domains formed by C1P (and its analogs) and the affinity of cPLA2α for C1P in different co-lipid environments by fluorescence spectroscopy using trans-parinaric acid and surface plasmon resonance (SPR). Fluorescence measurements suggested that the formation of C1P ordered domains is strongly influenced by interfacial 3-OH and phosphate groups of C1P, such as hydrogen-bonding and electrostatic interactions, and depends on the co-lipid composition of the host bilayer. SPR indicated that C1P under the lipid environment favorable for the formation of C1P clusters has higher affinity for cPLA2α. Thus, we speculate that C1P clusters formed under certain membrane conditions are important in specific binding with cPLA2α by increasing the interaction between the C1P headgroup and basic residues of cPLA2α. In conclusion, this study revealed that the local formation of lipid mediator-rich clusters in biomembranes likely has a significant effect on the interaction between the mediator and its receptor protein.

Inflammatory Bowel Diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract and colon affecting approximately 7 million individuals worldwide. The knowledge of specific pathology and aetiological mechanisms leading to IBD is limited, however a reduced immune system, antibiotic use and reserved diet may initiate symptoms. Dysbiosis of the gut microbiome, and consequently a varied composition of the metabolome, has been extensively linked to these risk factors and IBD. Metagenomic sequencing and liquid-chromatography mass spectrometry (LC-MS) of N = 220 fecal samples by Fransoza et al., provided abundance data on microbial genera and metabolites for use in this study. Identification of differentially abundant microbes and metabolites was performed using a Wilcoxon test, followed by feature selection of random forest (RF), gradient-boosting (XGBoost) and least absolute shrinkage operator (LASSO) models. The performance of these features was then validated using RF models on the Human Microbiome Project 2 (HMP2) dataset and a microbial community (MICOM) model was utilised to predict and interpret the interactions between key microbes and metabolites. The Flavronifractor genus and microbes of the families Lachnospiraceae and Oscillospiraceae were found differential by all models. Metabolic pathways commonly influenced by such microbes in IBD were CoA biosynthesis, bile acid metabolism and amino acid production and degradation. This study highlights distinct interactive microbiome and metabolome profiles within IBD and the highly potential pathways causing disease pathology. It therefore paves way for future investigation into new therapeutic targets and non-invasive diagnostic tools for IBD.

Both adolescents with obesity and those with type 1 diabetes (T1D) exhibit alterations in lipid profiles, but direct comparisons are limited. Comparing lipidomic profiles between obese individuals and those with T1D is crucial for identifying specific metabolic markers, informing tailored interventions, and advancing precision medicine strategies for these distinct populations. The aim of the study was to compare lipidomic profiles between adolescents with obesity and those with T1D, and to analyze associations between metabolites and clinical parameters.

We included 156 adolescents aged 11-18 years (59.6% girls) from the HEPAFIT (n=114, obesity) and Diactive-1 Cohort (n=42, T1D) studies. Clinical measures included anthropometrics, body composition, lipids, liver enzymes, glucose, and HbA1c. Lipidomic analysis of 277 serum/plasma metabolites used UHPLC-MS.

Distinct lipid profiles were seen, with higher diglycerides, triglycerides, and certain phosphatidylinositols in the obesity group, while phosphatidylcholines, phosphatidylethanolamines, cholesterol esters, sphingomyelins, and ceramides were elevated in T1D. Triglycerides acyl chain lengths and saturation levels also varied. Multivariate analysis identified seven metabolites -PC(O-18:1/18:1), PC(O-18:1/22:4), PE(O-16:0/18:1), PE(18:2e/22:6), PC(40:1), PC(O-22:1/20:4), and PE(P-18:0/18:1)- significantly associated with clinical parameters.

Distinct lipid profiles were observed among adolescents with obesity and T1D in the study, emphasizing the importance of understanding specific metabolite associations with clinical parameters for more precise health management.

Background: Sepsis, a life-threatening response to infection leading to systemic inflammation and organ dysfunction, has been hypothesized to be influenced by metabolic alterations in cerebrospinal fluid (CSF). Despite extensive research, the specific metabolic pathways contributing to sepsis remain unclear. This study aims to elucidate the causal relationships between CSF metabolites and sepsis risk using Mendelian randomization (MR), offering insights that could lead to novel therapeutic strategies. Methods: We conducted a two-sample MR analysis using genetic variants as instrumental variables (IVs) to investigate 338 CSF metabolites identified through a genome-wide association study. Data on sepsis-related outcomes were extracted from the genome-wide association study catalog encompassing 486,484 individuals of European descent. IVs were rigorously selected based on stringent genetic association and linkage disequilibrium criteria. Statistical analyses, including inverse variance weighting (IVW) and weighted median methods, were performed using the "TwoSampleMR" package in R software, supplemented by comprehensive sensitivity analyses to ensure the robustness of our findings. Results: Our analysis identified 19 CSF metabolites causally associated with sepsis risk. Notably, metabolites such as 1-palmitoyl-2-stearoyl-gpc (16:0/18:0) and 2-hydroxyglutarate showed significant negative correlations with sepsis risk. The reverse MR analysis further revealed that sepsis could negatively impact certain CSF metabolite levels, particularly ribonate, suggesting a bidirectional relationship. These relationships were substantiated by rigorous statistical testing and sensitivity analyses confirming the absence of horizontal pleiotropy and the stability of our results across various MR methods. Conclusions: This study demonstrates significant causal associations between specific CSF metabolites and the risk of developing sepsis, highlighting the potential for these metabolites to serve as biomarkers or therapeutic targets. The bidirectional nature of these findings also suggests that sepsis itself may alter metabolic profiles, offering further avenues for intervention.

Sphingolipids (SL), a class of membrane lipids, play important roles in numerous biological processes. Their significant structural diversity poses challenges for accurate quantification. To address this, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has emerged as a powerful tool for sphingolipidomics, capable of profiling these lipids comprehensively. In this study, we utilized LC-MS/MS with high-resolution mass spectrometry (MRMHR) to develop a targeted method for the identification and quantification of various SL species. This method, based on validated parameters such as precursor/fragment ions (m/z) and retention time, demonstrated high sensitivity and accuracy, successfully identifying SL species across 12 distinct classes. Its open-panel design also facilitates the analysis of new SL-species targets. Notably, using this approach, we identified 40 SL species in plasma samples from COVID-19 patients, and we determined the influence of matrix metalloproteinase-3 (MMP-3) expression on the positive downstream of SL metabolism. Beyond plasma analysis, this method has potential applications in other biomedical contexts, such as extracellular vesicles (EVs), describing the cargo of sphingosine-1-phosphate (S1P) on macrophage-derived EVs. The establishment of this targeted workflow enabling precise quantification of a wide range of SL species, holds promise for identifying novel biomarkers and therapeutic targets.

Members of the phospholipase D (PLD) superfamily found in Loxosceles spider venoms are potent toxins with inflammatory and necrotizing activities. They degrade phospholipids in cell membranes, generating bioactive molecules that activate skin cells. These skin cells, in turn, activate leukocytes involved in dermonecrosis, characterized by aseptic coagulative necrosis. Although the literature has advanced in understanding the structure-function relationship, the cell biology resulting from the interactions of these molecules with cells remains poorly understood. In this study, we show that different cells exposed to recombinant PLDs bind these molecules to their plasma membrane, leading to the subsequent organization of extracellular microvesicles/ectosomes. The binding occurs as quickly as five minutes or less after exposure, increases over time, and eventually, the PLDs are expelled from the cell surface without generating cytotoxicity. PLDs are not endocytosed, nor do they spatially colocalize with acidic organelles in the intracellular environment. At least two regions of PLDs - the domain involved in magnesium ion coordination and the choline binding site - appear to play a role in cell surface binding and ectosome organization. However, the amino acids involved in catalysis do not participate in these events. The binding of these PLDs to the cell membrane, independent of catalytic activity, is sufficient to trigger intracellular signaling and enhance the expression of the pro-inflammatory IL-8 gene. These results are supported by the observation that isoforms of PLDs lacking catalytic activity induce an inflammatory response in vivo when injected into the skin of rabbits, without causing dermonecrosis. Our data indicate that these PLDs bind to the surface of target cells, promoting the organization of extracellular vesicles/ectosomes. Subsequently, these events activate pro-inflammatory genes and induce an inflammatory response in vivo. The binding to cells is not dependent on amino acids involved in catalysis but rather on amino acids involved in magnesium coordination. The binding of PLDs to the cell surface, formation of ectosomes, and activation of cells appear to initiate signals involved in inflammatory responses that can lead to dermonecrosis in accidents. This correlation is supported by experimental observations indicating that the events of toxin binding to cells, formation of microvesicles, and inflammatory responses observed both in vitro and in vivo are interconnected.

Reproduction is a fundamental biological process for the survival and continuity of species. Examining changes in reproductive strategies offers valuable insights into how animals have adapted their life histories to different environments. Since reproduction is one of the most energy-intensive processes in female animals, nutrient scarcity is expected to interfere with the ability to invest in gametes. Lately, a new model to study adaptation to nutrient limitation has emerged; the Mexican tetra Astyanax mexicanus . This fish species exists as two different morphs, a surface river morph and a cave-dwelling morph. The cave-dwelling morph has adapted to the dark, biodiversity, and nutrient-limited cave environment and consequently evolved an impressive starvation resistance. However, how reproductive strategies have adapted to nutrient limitations in this species remains poorly understood. Here, we compared breeding activities and maternal contributions between laboratory-raised surface fish and cavefish. We found that cavefish produce different clutch sizes of eggs with larger yolk compared to surface fish, indicating a greater maternal nutrient deposition in cavefish embryos. To systematically characterize yolk compositions, we used untargeted proteomics and lipidomics approaches to analyze protein and lipid profiles in 2-cell stage embryos and found an increased proportion of sphingolipids in cavefish compared to surface fish. Additionally, we generated transcriptomic profiles of surface fish and cavefish ovaries using a combination of single cell and bulk RNA sequencing to examine differences in maternal contribution. We found that genes essential for hormone regulation were upregulated in cavefish follicular somatic cells compared to surface fish. To evaluate whether these differences contribute to their reproductive abilities under natural-occurring stress, we induced breeding in starved female fish. Remarkably, cavefish maintained their ability to breed under starvation, whereas surface fish largely lost this ability. We identified insulin-like growth factor 1a receptor ( igf1ra ) as a potential candidate gene mediating the downregulation of ovarian development genes, potentially contributing to the starvation-resistant fertility of cavefish. Taken together, we investigated the female reproductive strategies in Astyanax mexicanus , which will provide fundamental insights into the adaptations of animals to environments with extreme nutrient deficit.

The microbiota-gut-brain axis plays a pivotal role in neuropsychiatric disorders, particularly in depression. Escitalopram (ESC) is a first-line antidepressant, however, its regulatory mechanisms on the microbiota-gut-brain axis in the treatment of depression remain unclear. The antidepressant effects of ESC were evaluated using the forced swim test in Wistar-Kyoto (WKY) rats, while damage in the gut and brain regions was assessed through H&E staining and immunohistochemistry. The therapeutic mechanisms in WKY rats with depression-like behavior were investigated through 16S rRNA sequencing of the gut microbiota, serum untargeted metabolomics, and hippocampal proteomics. Results indicated that ESC intervention improved depressive-like behaviors, as evidenced by increased swimming times in WKY rats, and also restored intestinal permeability and brain tissue integrity. Significant changes in the gut microbiota composition, particularly an increase in Bacteroides barnesiae, as well as increases in serum sphingolipid metabolites (Sphinganine 1-phosphate, Sphingosine, and Sphingosine-1-phosphate) and hippocampal proteins (Sptlc1, Enpp5, Enpp2), were strongly correlated. These robust correlations suggest that ESC may exert its antidepressant effects by modulating sphingolipid metabolism through the influence of gut microbiota. Accordingly, this research elucidates novel mechanisms underlying the antidepressant efficacy of ESC and highlights the pivotal importance of the microbiota-gut-brain axis in mediating these effects.

Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.

Atherosclerosis, with its complex pathogenesis, is a leading underlying cause of many cardiovascular diseases, which are increasingly prevalent in the population. Sphingolipids play an important role in the development of atherosclerosis. Key metabolites and enzymes in sphingolipid metabolism influence the pathogenesis of atherosclerosis in a variety of ways, including inflammatory responses and oxidative stress. Thus, an investigation of sphingolipid metabolism-related metabolites and key enzymes may provide novel insights and treatment targets for atherosclerosis. This review discusses various mechanisms and research progress on the relationship between various sphingolipid metabolites, related enzymes, and atherosclerosis. Finally, we look into the future research direction of phytosphingolipids.

Immune cell-driven inflammation is a key mediator of metabolic dysfunction-associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T-cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages in the liver.

The LyzMCre approach was used to generate myeloid cell-specific knockout mice, termed S1pr1MKO. Littermate S1pr1loxp/loxp mice were used as wild-type controls. MASH was established by feeding mice a high-fat, -fructose, and -cholesterol (FFC) diet for 24 weeks, which led to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry.

Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in high-fat, -fructose, and -cholesterol-fed S1pr1MKO compared to wild-type. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of high-fat, -fructose, and -cholesterol-fed S1pr1MKO mice compared to wild-type. Gene ontology pathway analysis revealed significant suppression of the peroxisome proliferator-activated receptor gamma and mitogen-activated protein kinase pathways in S1pr1MKO consistent with attenuated MASH in mice.

Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

Dry eye disease (DED) stands as a prominent ocular condition of global prevalence, emerging as a growing concern within public health. However, the underlying mechanisms involved in its pathogenesis remain largely unknown. In recent years, with the development of metabolomics, numerous studies have reported alterations in ocular surface metabolism in DED and offered fresh perspectives on the development of DED.

The metabolic changes of the ocular surface of DED patients are closely intertwined with the cellular metabolism process and immune inflammation changes. This article expounds upon the correlation between ocular surface metabolism and immune inflammation alterations in DED in terms of glycolysis, lipid metabolism, amino acid metabolism, cellular signaling pathways, and immune inflammation regulation.

The alterations in ocular surface metabolism of patients with dry eye are closely associated with their inflammatory status. Our work contributes novel insights into the pathogenesis of dry eye diseases and offers innovative molecular targets for diagnosing, detecting, and managing DED patients.

Ulcerative colitis (UC) is a relapsing disease with an increasing morbidity and prevalence. Dietary polysaccharides have recently become a research hotspot because of their therapeutic effects and safety on UC. Our previous research elucidated that pectic polysaccharide from Phyllanthus emblica L. (PEP-1) could alleviate dextran sodium sulfate-induced UC mice. Herein, metabolomics and transcriptomics were further applied to disclose the underlying mechanisms behind PEP-1's anti-inflammatory effects. PEP-1 intervention altered the serum metabolite contents and pathways represented by decreasing xanthine and sphinganine levels. Changes in gene expressions correlated with metabolite variations led by the suppression of the expression of the inflammatory factors, colorectal cancer promoter, and NF-κB pathway as well as the enhancement of tight junctions. This study demonstrated that the ameliorating effect of chronic UC was partially ascribed to the alteration of the serum metabolites and changes in gene expression.

Maintenance of delicate homeostasis is very important in various diseases because it ensures appropriate immune surveillance against pathogens and prevents excessive inflammation. In a disturbed homeostatic condition, hyperactivation of immune cells takes place and interplay between these cells triggers a plethora of signaling pathways, releasing various pro-inflammatory cytokines such as Tumor necrosis factor alpha (TNFα), Interferon-gamma (IFNƴ), Interleukin-6 (IL-6), and Interleukin-1 beta (IL-1β), which marks cytokine storm formation. To be precise, dysregulated balance can impede or increase susceptibility to various pathogens. Pathogens have the ability to hijack the host immune system by interfering with the host's chromatin architecture for their survival and replication in the host cell. Cytokines, particularly IL-6, Interleukin-17 (IL-17), and Interleukin-23 (IL-23), play a key role in orchestrating innate immune responses and shaping adaptive immunity. Understanding the interplay between immune response and the role of epigenetic modification to maintain immune homeostasis and the structural aspects of IL-6, IL-17, and IL-23 can be illuminating for a novel therapeutic regimen to treat various infectious diseases. In this review, the light is shed on how the orchestration of epigenetic regulation facilitates immune homeostasis.

Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, its protective mechanism on the central nervous system (CNS) is not clear.

The present study initially evaluated the possible mechanism of PNS to improve cognitive dysfunction due to chronic sleep deprivation (CSD).

In the present study, we used a modified multi-platform aquatic environment sleep deprivation method to induce a cognitively impaired rat model, and explored the mechanism of action of PNS by integrating serum metabolomics and network pharmacology, which was further verified by molecular docking and experiments.

The results showed that PNS significantly shortened the escape latency, increased the target quadrant time and the number of traversing platforms, and attenuated the inflammatory damage in the hippocampal Cornu Ammonis 1 (CA1) region in CSD rats. The non-targeted metabolomics results indicated that 35 biomarkers significantly altered following PNS therapy intervention, with metabolic pathways enriched for the effects of One carbon pool by folate, Riboflavin metabolism, Glycerophospholipid metabolism, Sphingolipid metabolism, Glycerolipid metabolism, Arachidonic acid metabolism, and Tryptophan metabolism. In addition, network pharmacology identified 234 potential targets for PNS intervention in CSD with cognitive impairment. Metabolite-response-enzyme-gene network was constructed by MetaScape and matched with the network pharmacology results to identify a total of five shared targets (LPL, GPAM, HSD11B1, HSD11B2, and SULT2A1) and two metabolic pathways (Sphingolipid metabolism and Steroid hormone biosynthesis). The results of molecular docking revealed that the five active ingredients had good binding ability with the five core targets. qPCR analysis confirmed the ability of PNS to modulate the above five targets.

The combination of metabolomics and network analysis provides a scientific basis for promoting the clinical application of PNS in cognitive impairment.

Allergic rhinitis affects millions globally, causing significant discomfort and reducing the quality of life. This study investigates the metabolic alterations in murine mast cells (MC/9) under allergic rhinitis conditions induced by lipopolysaccharide (LPS) stimulation, employing UHPLC-QTOF-MS-based untargeted and targeted metabolomics. The analysis identified 44 significantly regulated metabolites, including histamine, leukotrienes, prostaglandins, thromboxanes, and ceramides. Key metabolic pathways such as arachidonic acid, histidine, and sphingolipid metabolisms were notably modulated. The study further examined the therapeutic effects of triprolidine and zileuton, demonstrating their capacity to reverse LPS-induced metabolic shifts. Triprolidine primarily modulated histidine and sphingolipid metabolism, while zileuton targeted arachidonic acid and sphingolipid metabolism. These findings underscore the utility of metabolomics analysis in elucidating the complex biochemical pathways involved in allergic rhinitis and highlight the potential of metabolomics for evaluating therapeutic interventions. This study enhances our understanding of mast cell metabolism in allergic responses and provides a robust model for assessing the efficacy of anti-allergic agents, paving the way for more effective treatments.

The utility of environmental RNA (eRNA) in capturing biological responses to stresses has been discussed previously; however, the limited number of genes detected remains a significant hindrance to its widespread implementation. Here, we investigated the potential of eRNA to assess the health status of Japanese medaka fish exposed to linear alkylbenzene sulfonate. Analyzing eRNA and organismal RNA (oRNA) in aquarium water within 12 h, we achieved high mapping rates and 10 times more differentially expressed genes than previously reported. This advancement has facilitated the previously unattainable capability of gene ontology (GO) analysis. The GO analysis revealed that eRNA can detect nuclear genes associated with cellular components and reflect cumulative gene expression signatures over time, while oRNA provided short-term gene expression signatures in biological process. Moreover, eRNA exhibited high sensitivity in responding to genes associated with sphingolipid and ceramide biosynthesis, which are involved in inflammatory responses possibly originating from impaired cells. This finding aligns with the observations made in oRNA. In conclusion, eRNA-sequencing (eRNA-seq) using aquarium water emerges as a valuable high sensitivity tool for analyzing physiological stress. The findings of this study lay the foundation for further development of eRNA-seq technologies.

A stable and reproducible experimental bacterial pneumonia model postintracerebral hemorrhage (ICH) is necessary to help investigating the pathogenesis and novel treatments of Stroke-associated pneumonia (SAP).

To establish a Gram-negative bacterial pneumonia-complicating ICH rat model and an acute lung injury (ALI)-complicating ICH rat model.

We established two standardized models of post-ICH pneumonia by nasal inoculation with Klebsiella pneumoniae (Kp) or intratracheal inoculation with lipopolysaccharide (LPS). Survival and neurological scores were monitored. Magnetic resonance imaging was performed to evaluate hematoma volume. Abdominal aortic blood was collected for leukocyte counting, serum was isolated to determine concentrations of S100β and proinflammatory cytokines using ELISAs. Histopathological changes of brain, lung and gut were assessed using hematoxylin-eosin staining. Lung was isolated for immunofluorescence staining for myeloperoxidase (MPO). Bronchoalveolar lavage fluid was collected for leukocyte counting, and supernatant was prepared to measure MPO activity. Ileum was isolated for immunofluorescence staining for tight junction proteins ZO-1 and γδ TCRs/IL-17A and for Alcian blue-nuclear fast red staining of acidic mucins. Feces were collected, 16S rRNA sequencing, untargeted metabolomics and Spearman's correlation analyses were performed to explore changes of gut microbiota, metabolites and their interactions.

In Kp-induced bacterial pneumonia-complicating ICH rats, we demonstrated that Kp challenge caused more severe neurological deficits, brain damage, neuroinflammation, and aggravated pneumonia and lung injury. Disruptions of the intestinal structure and gut barrier and the reductions of the protective intestinal IL-17A-producing γδT cells were also observed. Kp challenge exacerbated the gut microbiota dysbiosis and fecal metabolic profile disorders, which were characterized by abnormal sphingolipid metabolism especially elevated ceramide levels; increased levels of neurotoxic quinolinic acid and an upregulation of tryptophan (Trp)-serotonin-melatonin pathway. Spearman's correlation analyses further revealed that the reduction or depletion of some beneficial bacteria, such as Allobaculum and Faecalitalea, and the blooming of some opportunistic pathogens, such as Turicibacter, Dietzia, Corynebacterium and Clostridium_sensu_stricto_1 in Kp-induced SAP rats were associated with the disordered sphingolipid and Trp metabolism. Using an LPS-induced ALI complicating ICH model, we also characterized SAP-induced brain, lung and gut histopathology injuries; peripheral immune disorders and intense pulmonary inflammatory responses.

These two models may be highly useful for investigating the pathogenesis and screening and optimizing potential treatments for SAP. Moreover, the differential genera and sphingolipid or Trp metabolites identified above seem to be promising therapeutic targets.

Store-operated calcium (Ca2+) entry (SOCE) represents a major route of Ca2+ permeation across the plasma membrane (PM) in nonexcitable cells, which plays an indispensable role in maintaining intracellular Ca2+ homeostasis. This process is orchestrated through the dynamic coupling between the endoplasmic reticulum (ER)-localized Ca2+ sensor stromal interaction molecule 1 (STIM1) and the PM-resident ORAI1 channel. Upon depletion of ER Ca2+ stores, STIM1 undergoes conformational rearrangements and oligomerization, leading to the translocation of activated STIM1 toward the PM. This movement is facilitated by the physical interactions between positively charged cytosolic domains within STIM1 and negatively charged phospholipids embedded in the PM, ultimately enabling its binding to and activation of the PM-embedded ORAI1 channel. In this mini-review, we provide an overview of STIM1-mediated Ca2+ signaling at ER-PM contact sites, highlighting the regulatory roles of phospholipids in the inner leaflet and sphingolipids in the outer leaflet of the PM. We also discuss the development of molecular tools that enable real-time visualization and manipulation of membrane contact sites (MCSs) at ER-PM junctions. Finally, we highlight recent progress in developing targeted therapies for human diseases linked to STIM1 mutations and dysregulated Ca2+ signaling at ER-PM MCSs.

Pancreatic ductal adenocarcinoma (PDAC) requires innovative therapeutic strategies to counteract its progression and metastatic potential. Since the majority of patients are diagnosed with advanced metastatic disease, treatment strategies targeting not only the primary tumor but also metastatic lesions are needed. Tumor-Associated Macrophages (TAMs) have emerged as central players, significantly influencing PDAC progression and metastasis. Our objective was to validate an innovative therapeutic strategy involving the reprogramming of TAMs using lipid nanosystems to prevent the formation of a pro-metastatic microenvironment in the liver.

In vitro results demonstrate that M2-polarized macrophages lose their M2-phenotype following treatment with lipid nanoemulsions composed of vitamin E and sphingomyelin (VitE:SM), transitioning to an M0/M1 state. Specifically, VitE:SM nanoemulsion treatment decreased the expression of macrophage M2 markers such as Arg1 and Egr2, while M1 markers such as Cd86, Il-1b and Il-12b increased. Additionally, the TGF-βR1 inhibitor Galunisertib (LY2157299) was loaded into VitE:SM nanoemulsions and delivered to C57BL/6 mice orthotopically injected with KPC PDAC tumor cells. Treated mice showed diminished primary tumor growth and reduced TAM infiltration in the liver. Moreover, we observed a decrease in liver metastasis with the nanoemulsion treatment in an intrasplenic model of PDAC liver metastasis. Finally, we validated the translatability of our VitE:SM nanosystem therapy in a human cell-based 3D co-culture model in vivo, underscoring the pivotal role of macrophages in the nanosystem's therapeutic effect in the context of human PDAC metastasis.

The demonstrated effectiveness and safety of our nanosystem therapy highlights a promising therapeutic approach for PDAC, showcasing its potential in reprogramming TAMs and mitigating the occurrence of liver metastasis.

Sphingosine kinases (SPHKs) are essential enzymes that catalyze the phosphorylation of sphingosine to produce sphingosine-1-phosphate (S1P), which plays pivotal roles in inflammation and immune regulation. In this study, genome-wide association analysis (GWAS) identified the Ydsphk1 gene as closely associated with the resistance of yellow drum (Nibea albiflora) to Vibrio harveyi. Structural prediction showed that YDSPHK1 contains a typical diacylglycerol kinase catalytic (DAGKc) domain (154-291 aa). By constructing and transfecting Ydsphk1 expression plasmids into yellow drum kidney cells, we found that YDSPHK1 is localized in the cytoplasm. Subsequent RNA-Seq analysis of an overexpression plasmid identified 25 differentially expressed genes (DEGs), including 13 upregulated and 12 downregulated. Notably, nsun5 and hsp90aa1 were significantly upregulated, while Nfkbia and hmox1 were downregulated. Promoter analysis indicated that the core regulatory regions of Ydsphk1 are located between -1931~-1679 bp and -419~+92 bp, with two predicted TFAP2A binding sites in the -419~+92 bp region. Further studies demonstrated that varying concentrations of TFAP2A significantly reduced Ydsphk1 promoter activity. These findings underscore the pivotal role of Ydsphk1 in regulating immune responses in yellow drum, particularly through its impact on key immune-related genes and pathways such as NF-κB signaling and ferroptosis. The identification of Ydsphk1 as a mediator of immune regulation provides valuable insights into the molecular mechanisms of immune defense and highlights its potential as a target for enhancing pathogen resistance in aquaculture practices. This study lays a strong foundation for future research aimed at developing innovative strategies for disease management in aquaculture species.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with many aspects of disturbed metabolic health. MASLD encompasses a wide spectrum of liver diseases, ranging from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), up to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Limited noninvasive diagnostic tools are currently available to distinguish the various stages of MASLD and as such liver biopsy remains the gold standard for MASLD diagnostics. We aimed to explore whether the plasma lipidome and its variations can serve as a biomarker for MASLD stages.

We investigated the plasma lipidome of 7 MASLD-free subjects and 32 individuals with MASLD, of whom 11 had MASH based on biopsy scoring.

Compared with the MASLD-free subjects, individuals with MASLD had higher plasma concentrations of sphingolipids, glycerolipids, and glycerophospholipids. Only plasma concentrations of ceramide-1-phosphate C1P(d45:1) and phosphatidylcholine PC(O-36:3), PC(O-38:3), and PC(36:2) differed significantly between presence of MASH in individuals with MASLD. Of these lipids, the first three have a very low relative plasma abundance, thus only PC(36:2) might serve as a biomarker with higher plasma concentrations in MASLD individuals without MASH compared to those with MASH.

Plasma lipids hold promise as biomarkers of MASLD stages, whereas plasma PC(36:2) concentrations would be able to distinguish individuals with MASH from those with MASLD without MASH.

Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism.

Triclocarban (TCC) is a widely used antimicrobial agent and known endocrine-disrupting chemical found in various products. While its potential toxicities on endocrine-related organs have been highlighted in previous studies, the effects of TCC on non-endocrine organs, particularly the spleen, remain largely unknown. Here, we employed a novel approach combining long-term TCC exposure in a mouse model with spatial metabolomics and lipidomics to investigate the effects of TCC on the spleen. Our results showed that TCC exposure significantly altered the splenic organ weight and coefficient and induced obvious pathological alterations. Omic analysis revealed that TCC exposure disrupted the splenic homeostasis, as indicated by the upregulation of glutathione metabolism, ceramide-to-sphingomyelin signaling and biosynthesis of glycerophospholipids. Notably, the data of mass spectrometry imaging (MSI) revealed that TCC accumulated in the red pulp of the mouse spleen, while its metabolites concentrated in the white pulp. Further MSI analyses identified region-specific metabolic disruptions, including upregulated ceramide signaling in the red pulp, indicating localized inflammation, and upregulated glutathione metabolism throughout the spleen, suggesting widespread oxidative damage. Our findings provide crucial insights into the spatial distribution and biochemical impact of TCC on mice spleens, highlighting the potential risks of long-term TCC exposure to immune function.

Electro-acupuncture (EA) has demonstrated potential in improving mild-to-moderate dementia in clinics, but the underlying scientific target remains unclear.

EA was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water maze cognitive functional tests. Brain magnetic resonance imaging-positron emission tomography (PET) scans using [18F]TZ4877 targeting sphingosine-1-phosphate receptor 1 (S1PR1) and [18F]AV45 targeting amyloid beta fibrils were conducted. The correlation between regional brain PET quantifications and cognitive functions was analyzed.

EA significantly improved cognitive and memory functions of AD (p  = 0.04) and reduced the uptake of [18F]TZ4877 in the cortex (p  = 0.02) and hippocampus (p  = 0.03). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1. Furthermore, immunohistochemistry showed a significant reduction of interleukin 1β and tumor necrosis factor α after EA treatment.

EA may reverse AD by suppressing neuroinflammation, and the PET imaging of S1PR1 seemed potent in evaluating the treatment for AD patients HIGHLIGHTS: Electro-acupuncture (EA) was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water maze cognitive functional tests and positron emission tomography (PET) imaging quantifications. PET tracer [18F]AV45 was used to detect amyloid beta deposition. An increased uptake of [18F]AV45 was found in AD compared to WT mice, with significance observed only in the cortex and not in the hippocampus. EA treatment exhibited a trend toward reduced [18F]AV45 uptake in AD mouse brains post-treatment. However, statistical difference was not attained in most brain regions. EA "Baihui (DU20) and Sishencong (EX-HN1)" significantly improved cognitive and memory functions of AD (p = 0.04). Brain magnetic resonance imaging p(MRI)-positron emission tomography (PET) quantifications revealed that significantly reduced the uptake of [18F]TZ4877 in the cortex (p = 0.02) and hippocampus (p = 0.03) after EA treatment. The correlation between PET quantifications and cognitive functions was analyzed and the most notable correlations were found between escape latency (reaction cognitive and memory behavior) and volume distribution (VT) quantifications of [18F]TZ4877. VT quantifications of [18F]TZ4877 in key brain regions for cognitive and memory ability, such as the cortex and hippocampus, positively correlated with platform latency (cortex p < 0.01, r = 0.7102; hippocampus p < 0.01, r = 0.6891). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1 in the AD brain. And the EA treatment significantly reduced the signals in the cortex and hippocampus. Immunohistochemistry showed a significant reduction of interleukin 1β and tumor necrosis factor α after EA treatment. EA reversed AD by suppressing neuroinflammation in the cortex and hippocampus. The S1PR1 targeting PET tracer [18F]TZ4877 showed promise in evaluating the pathological progression of AD in clinical settings.

Sphingolipids, particularly sphingosine-1-phosphate (S1P), are bioactive lipids involved in regulating cellular processes such as proliferation, apoptosis, inflammation, and tumor progression. Alkaline ceramidase 2 (ACER2) plays a critical role in sphingolipid metabolism by catalyzing the hydrolysis of ceramide to sphingosine, which is subsequently converted to S1P. Dysregulation of ACER2 has been implicated in various gastrointestinal cancers, including colorectal cancer, gastric cancer, and hepatocellular carcinoma. ACER2-mediated sphingolipid signaling, particularly through the SphK/S1P pathway, influences cancer development by modulating immune responses, inflammation, and the balance between cell survival and death. This review examines the physiological functions of ACER2, and its role in sphingolipid metabolism, and its contribution to the pathogenesis of gastrointestinal cancers. Understanding the mechanisms by which ACER2 regulates tumor progression and immune modulation may open new avenues for targeted therapies in gastrointestinal malignancies.

Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75min - 24h timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad up-regulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.

 Ceramides are lipid species that play several physiological roles in the body, including stress response, inflammation, and apoptosis, and their involvement in lipid metabolism and energy production makes them crucial in the pathophysiology of heart failure (HF).

 Several species of ceramides and ceramide signatures have recently been investigated as possible biomarkers of cardiovascular disease (CVD), and risk scores have demonstrated prognostic value in stratifying patients by risk and possibly predicting adverse cardiac events. With growing interest in targeting metabolic dysfunction, understanding the role of ceramides in CVD also opens the possibility of novel therapeutics that target ceramide metabolism to improve cardiac function and cardiac outcomes in patients.  Understanding the role of ceramides in CVD opens the possibility of novel diagnostics and theragnostic targeting ceramide metabolism to improve cardiac function and cardiac outcomes in patients with heart failure.

Inflammatory bowel disease (IBD) is a serious disease that affects the metabolism and inflammatory responses of human beings. From the perspective of traditional Chinese medicine, damp-heat syndrome is one of the main syndromes of IBD. Rhizoma Paridis, also known as the root of Paris polyphylla, a well-known herbal medicine used in China, is used to treat IBD with damp-heat syndrome (IBD-DH). However, uncertainty still exists regarding the underlying mechanisms and the impact of Rhizoma Paridis on IBD-DH.

The rats in the model (DAT) and medication administration (Rhizoma Paridis total saponins (RPTS) and Pennogenin (PN)) groups were given a high temperature and high humidity environment, high fat and high sugar diet combined with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish the model of experimental colitis of damp-heat type, and the normal control group (RNC) rats were given a normal diet at normal temperature and humidity. Damp-heat control group (DNC) was set with the same condition as DAT without TNBS. Hematoxylin-Eosin (HE) staining was used to observe the histopathological morphology of the rat colorectum. The expression of the metabolism-related genes (Phospholipase A2 (sPLA2, cPLA2), and phosphatidylethanolamine N-methyltransferase (PEMT)) was assessed by using real-time quantitative PCR analysis (RT-qPCR). And the levels of the metabolism-related proteins (sPLA2, cPLA2), S100A8/9, Arg-1, and cytokines were detected by enzyme-linked immunosorbent assay (ELISA) kit. To investigate lipids and amino acids which closely associated with the IBD and IBD-DH, lipid pseudotargeted metabolomics with UHPLC-TQ/MS analysis method, as well as targeted quantitative amino acid analysis were performed.

Our data showed that RPTS (50 mg/kg) and PN (20 mg/kg) significantly ameliorated the severity of TNBS-induced colitis and downregulated the levels of circulating proinflammatory cytokines. Compared with RNC group, lipid pseudotargeted metabolomics demonstrated that glycerophospholipids, sphingolipids, carnitine, and glycerolipids were the four most perturbed lipid classes, and amino acids targeted metabolomics demonstrated that serine, N-acetylneuraminic acid, histidine, proline, taurine, and kynurenine changed significantly in DAT group . Correlation analyses showed tight associations between most of differential metabolites and proinflammatory cytokines. RPTS and PN both regulated glycerophospholipid metabolism and sphingolipid metabolism. However, both of them did not have a significant effect on amino acid modulation. RPTS and PN potentially regulated sPLA2, cPLA2, and PEMT.

These results showed that RPTS (50 mg/kg) and PN (20 mg/kg) effectively alleviated rats' colitis of damp-heat type, affected cytokines, and altered lipid metabolism without significant modulation on amino acid metabolism.