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Sarcopenia is an age-related disorder characterised by a progressive decrease in skeletal muscle mass. As the genetic biomarkers for sarcopenia are not yet well characterised, this study aimed to investigate the genetic variations related to sarcopenia in a relatively aged cohort, using genome-wide association study (GWAS) meta-analyses of lean body mass (LBM) in 6961 subjects. Two Korean cohorts were analysed, and subgroup GWAS was conducted for appendicular skeletal muscle mass (ASM) and skeletal muscle index. The effects of significant single nucleotide polymorphisms (SNPs) on gene expression were also investigated using multiple expression quantitative trait loci datasets, differentially expressed gene analysis, and gene ontology analyses. Novel genetic biomarkers were identified for LBM (rs1187118; rs3768582) and ASM (rs6772958). Their related genes, including RPS10, NUDT3, NCF2, SMG7, and ARPC5, were differently expressed in skeletal muscle tissue, while GPD1L was not. Furthermore, the 'mRNA destabilisation' biological process was enriched for sarcopenia. Our study identified RPS10, NUDT3, and GPD1L as significant genetic biomarkers for sarcopenia. These genetic loci were related to lipid and energy metabolism, suggesting that genes involved in metabolic dysregulation may lead to the pathogenesis of age-related sarcopenia. [ABSTRACT FROM AUTHOR]

Food allergy (FA) is a widespread issue, affecting as many as 10% of the population. Over the past two to three decades, the prevalence of FA has been on the rise, particularly in industrialized and westernized countries. FA is a complex, multifactorial disease mediated by type 2 immune responses and involving environmental and genetic factors. However, the precise mechanisms remain inadequately understood. Metabolomics has the potential to identify disease endotypes, which could beneficially promote personalized prevention and treatment. A metabolome approach would facilitate the identification of surrogate metabolite markers reflecting the disease activity and prognosis. Here, we present a literature overview of recent metabolomic studies conducted on children with FA. [ABSTRACT FROM AUTHOR]

Background and objective: Lipid metabolism dysregulation has been implicated in the pathogenesis of IPF; however, the roles of most lipid metabolites in lung fibrosis remain unexplored. Therefore, we aimed to identify changes in lipid metabolites in the lung tissues of IPF patients and determine their roles in pulmonary fibrosis. Methods: Free fatty acids in the lung tissues of IPF patients and controls were quantified using a metabolomic approach. The roles of free fatty acids in fibroblasts or epithelial cells treated with TGF‐β1 were evaluated using fibrotic markers. The antifibrotic role of stearic acid was also assessed in a bleomycin‐induced lung fibrosis mouse model. Protein levels in cell lysates or tissues were measured by western blotting. Results: The levels of stearic acid were lower in IPF lung tissues than in control lung tissues. Stearic acid significantly reduced TGF‐β1‐induced α‐SMA and collagen type 1 expression in MRC‐5 cells. Furthermore, stearic acid decreased the levels of p‐Smad2/3 and ROS in MRC‐5 cells treated with TGF‐β1 and disrupted TGF‐β1‐induced EMT in Beas‐2B cells. Stearic acid reduced the levels of bleomycin‐induced hydroxyproline in a mouse model. Conclusion: Changes in the free fatty acid profile, including low levels of stearic acid, were observed in IPF patients. Stearic acid may exert antifibrotic activity by regulating profibrotic signalling. Stearic acid levels in IPF lung tissues were reduced compared with those in control lung tissues. Stearic acid alleviated pulmonary fibrosis in vitro by inhibiting TGF‐β1‐induced p‐Smad2/3. Stearic acid also showed antifibrotic effects in mice with bleomycin‐induced lung fibrosis. Taken together, stearic acid may be a therapeutic target for IPF. See relatedEditorial [ABSTRACT FROM AUTHOR]

Background: Mechanisms underlying persistent food allergy (FA) are not well elucidated. The intestinal mucosa is the primary exposure route of food allergens. However, no study has examined intestinal metabolites associated with FA persistence. The goal of this study was to investigate intestinal metabolites and associated microbiomes in early life that aid in determining the development and persistence of FA. Methods: We identified metabolomic alterations in the stool of infants according to FA by mass spectrometry‐based untargeted metabolome profiling. The targeted metabolomic analysis of bile acid metabolites and stool microbiome was performed. Bile acid metabolite composition in infancy was evaluated by characterizing the subjects at the age of 3 into FA remission and persistent FA. Results: In untargeted metabolomics, primary bile acid biosynthesis was significantly different between subjects with FA and healthy controls. In targeted metabolomics for bile acids, intestinal bile acid metabolites synthesized by the alternative pathway were reduced in infants with FA than those in healthy controls. Subjects with persistent FA were also distinguished from healthy controls and those with FA remission by bile acid metabolites of the alternative pathway. These metabolites were negatively correlated with specific IgE levels in egg white. The abundance of intestinal Clostridia was decreased in the FA group and was correlated with ursodeoxycholic acid. Conclusion: Intestinal bile acid metabolites of the alternative pathway could be predictive biomarkers for persistent FA in early childhood. These findings require replication in future studies. [ABSTRACT FROM AUTHOR]

Background Neutrophils play a role in xenograft rejection. When neutrophils are stimulated, they eject the DNA-histone complex into the extracellular space, called neutrophil extracellular traps (NET). We investigated whether NET formation actively occurs in the xenograft and contributes to coagulation and endothelial activation. Methods Human whole blood was incubated with porcine aortic endothelial cells (pEC) from wild-type or α1,3-galactosyltransferase gene-knockout (GTKO) pigs. In the supernatant plasma from human blood, the level of the DNA-histone complex was measured by ELISA, and thrombin generation was measured using a calibrated automated thrombogram. Histone-induced tissue factor and adhesion molecule expression were measured by flow cytometry. Results pEC from both wild-type and GTKO pigs significantly induced DNA-histone complex formation in human whole blood. The DNA-histone complex produced shortened the thrombin generation time and clotting time. Histone alone dose-dependently induced tissue factor and adhesion molecule expression in pEC. Aurintricarboxylic acid pretreatment partially inhibited pEC-induced DNA-histone complex formation. Conclusions DNA-histone complex actively generated upon xenotransplantation is a novel target to inhibit coagulation and endothelial activation. To prevent tissue factor and adhesion molecule expression, a strategy to block soluble histone may be required in xenotransplantation. [ABSTRACT FROM AUTHOR]

Introduction: When leukocytes are stimulated by reactive oxygen species (ROS), they release nuclear contents into the extracellular milieu, called by extracellular traps (ET). The nuclear contents are mainly composed of the histone–DNA complex and neutrophil elastase. This study investigated whether leukemic cells could release ET and the released histone could induce endothelial activation, eventually resulting in leukemic progression. Methods: The circulating ET were measured in 80 patients with hematologic diseases and 40 healthy controls. ET formation and ROS levels were investigated during leukemic cell proliferation in vitro. Histone-induced endothelial adhesion molecules expression and cell survival were measured by flow cytometry. Results: Acute leukemia patients had high levels of ET, which correlated with peripheral blast count. Leukemic cells produced high ROS levels and released extracellular histone, which was significantly blocked by antioxidants. Histone significantly induced 3 endothelial adhesion molecules expression, and promoted leukemic cell adhesion to endothelial cells, which was inhibited by histone inhibitors (heparin, polysialic acid, and activated protein C), neutralizing antibodies against these adhesion molecules, and a Toll like receptor(TLR)9 antagonist. When leukemic cells were co-cultured with endothelial cells, adherent leukemic cells showed better survival than the non-adherent ones, demonstrating that histone-treated endothelial cells protected leukemic cells from both spontaneous and chemotherapy-induced death. Conclusion: Our data demonstrate for the first time that extracellular histone can be released from leukemic cells through a ROS-dependent mechanism. The released histone promotes leukemic cell adhesion by inducting the surface expression of endothelial adhesion molecules and eventually protects leukemic cells from cell death. [ABSTRACT FROM AUTHOR]

The high circulating levels of histones found in various thrombotic diseases may compromise the anticoagulant barrier of endothelial cells. We determined how histones affect endothelial procoagulant tissue factor (TF) and anticoagulant thrombomodulin (TM). Surface antigens, soluble forms, and mRNA levels of TF and TM were measured by flow cytometry, ELISA, and real-time RT-PCR, respectively. TF and TM activity were measured using procoagulant activity, thrombin generation, or chromogenic assays. Involvement of the toll-like receptor (TLR) was assessed using the neutralizing antibodies. Histones dose-dependently induced surface antigens, activity and mRNA levels of endothelial TF. Histone-treated endothelial cells significantly shortened the lag time and enhanced the endogenous thrombin potential of normal plasma, which was normalized by a TF neutralizing antibody. Histones induced phosphatidylserine and protein-disulfide isomerase expression in endothelial cells. Histones also reduced the surface antigen, activity, and mRNA levels of endothelial TM. Polysialic acid and heparin reversed the histone-induced TF up-regulation and TM down-regulation. Activated protein C did not affect the TF up-regulation, but interrupted TM down-regulation. TLR2, and TLR4 inhibitors partially blocked the TF up-regulation. Histones induced the endothelial procoagulant phenotype through TF up-regulation and TM down-regulation. The effects of histones were partly mediated by TLR2, TLR4. Strategies to inhibit the harmful effects of histones in endothelial cells may be required in order to prevent a thrombotic environment. [ABSTRACT FROM AUTHOR]

Background: Obesity is a common comorbid condition in adult asthmatics and known as a feature of asthma severity. However, the molecular mechanism under obesity‐induced inflammation has not yet been fully understood. Objective: Considering the essential role of hydrophobic surfactant protein B (SP‐B) in lung function, SP‐B was targeted to examine its involvement in the development of obesity‐induced airway inflammation in asthmatics. Methods: The aim was to examine an alteration in circulating SP‐B according to obesity in adult asthmatics, 129 asthmatics were enrolled and classified into 3 groups (obese, overweight and normal‐weight groups) according to body mass index (BMI). Circulating SP‐B levels were determined by enzyme‐linked immunosorbent assay. Four single nucleotide polymorphisms of SFTPB gene were genotyped. Serum ceramide levels were measured by liquid chromatography‐tandem mass spectrometry. Results: Significantly lower serum SP‐B levels were noted in the obese group than in the overweight or normal‐weight group (p =.002). The serum SP‐B level was significantly correlated with serum levels of C18:0 ceramide and transforming growth factor beta 1 as well as BMI (r = −0.200; r = −0.215; r = −0.332, p <.050 for all). An inverse correlation was noted between serum SP‐B and fractional exhaled nitric oxide levels in female asthmatics (r = −0.287, p =.009). Genetic predisposition of the SFTPB gene at 9306 A>G to the obese and overweight groups was noted. Conclusion: Obesity altered ceramide metabolism leading to pulmonary surfactant dysfunction and impaired resolution of airway inflammation, finally contributing to the phenotypes of obese asthmatics. [ABSTRACT FROM AUTHOR]

Several phosphate-containing metabolites, including nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), adenosine 5′-diphosphate ribose (ADP-r), adenosine 5′-triphosphate (ATP), and guanosine 5′-triphosphate (GTP), have been characterized with electron capture dissociation (ECD) and sustained off-resonance irradiation collision-activated dissociation (SORI-CAD) tandem mass spectrometry (MS/MS) in positive-ion mode. Calcium complexation was used to successfully produce abundant doubly charged cationic precursor ions with or without hydration. This approach enabled application of ECD to acidic metabolites for the first time. Fragmentation pathways observed in ECD and SORI-CAD of calcium-adducted phosphate-containing metabolites were complementary. Unique fragmentation was observed in ECD compared to SORI-CAD MS/MS, including ribose cross-ring cleavage for NAD and NADP, and generation of hydrated product ions, including cross-ring fragments, for hydrated ATP and GTP. A combination of ECD and CAD appears promising for maximizing structural information about metabolites. [Copyright &y& Elsevier]

In vitro and animal experiments demonstrated that lumican exerts anabolic effects on bone and muscle by stimulating osteoblastogenesis, suppressing osteoclastogenesis and increasing myogenesis. However, the relationship between circulating lumican and musculoskeletal phenotypes in humans remains unclear. We aimed to analyze the relationship between serum lumican levels and osteosarcopenia in older adults. Blood samples were collected from 134 participants (age: 65 years and older) who underwent comprehensive assessment of bone and muscle phenotypes. Osteoporosis and sarcopenia were diagnosed based on World Health Organization and Asian consensus guidelines, respectively. Osteosarcopenia was defined as the simultaneous presence of osteoporosis and sarcopenia. After adjusting for sex, age, and body mass index, older adults with osteosarcopenia had 20.2 % lower serum lumican levels than those without (P = 0.010). The odds ratio (OR) for osteosarcopenia per standard deviation decrease in serum lumican level was 4.17 (P = 0.003). Consistently, higher serum lumican levels were correlated with higher bone mass at all measured sites (P = 0.004 to 0.045) and higher grip strength (P = 0.023). Furthermore, participants in the lowest tertile (T1) had 7.56-fold higher OR for osteosarcopenia (P = 0.024) than those in the highest lumican tertile (T3). In conclusion, these findings clinically validate previous experimental data showing the musculoskeletal protective effects of lumican and suggest that blood lumican levels could be used as a potential biomarker to assess the risk of not only osteosarcopenia but also osteoporosis or sarcopenia in older adults. • Older adults with osteosarcopenia had 20.2 % lower serum lumican levels than controls. • Lower serum lumican was associated with higher risk for osteosarcopenia. • Serum lumican had positive associations with bone mass and grip strength. [ABSTRACT FROM AUTHOR]

Background In diabetic retinopathy (DR), neutrophil extracellular traps (NET) and kallikrein-kinin system are considered as contributing factors. However, the detail activation mechanisms has not been fully understood. Since the NET could provide negative-charged surface for factor XII activation and the activated factor XII (XIIa) can initiate kallikrein-kinin system, this study investigated whether patients with DR show activation of NET, factor XII and kallikrein-kinin system. Methods The markers related to NET (DNA-histone complex) and kallikrein-kinin system (high-molecular-weight kininogen, prekallikrein, bradykinin) and factor XIIa were measured in 253 patients with diabetes. To access ex vivo effect of glucose, DNA-histone complex and factor XIIa were measured in whole blood stimulated by glucose. Results The circulating level of DNA-histone complex and factor XIIa were significantly higher in patients with DR than those without DR. In logistic regression analysis, DNA-histone complex, factor XIIa, and high-molecular-weight kininogen were the risk factors of DR. In recursive partitioning analysis, among patients with diabetes duration less than 10 years, patients with high level of DNA-histone complex (>426 AU) showed high risk of DR. In ex vivo experiment, glucose significantly elevated both DNA-histone complex and factor XIIa. Conclusion Our findings suggest that activation of factor XII and kallikrein-kinin system combined with NET formation actively occur in patients with DR and circulating levels of DNA-histone complex, factor XIIa and HMWK can be potential biomarkers to estimate the risk of DR. Strategies against factor XII activation may be beneficial to inhibit DR. [ABSTRACT FROM AUTHOR]

Linoleic acid (LA) is the major polyunsaturated fatty acid (PUFA) in most Western foods. Although there is no direct evidence, it has been reported that the LA metabolite decreased in patients with AD due to impairment of the delta-6 desaturase activity involved in the conversion of LA to gamma linolenic acid.3 However, previous studies on the role of omega-6 PUFA supplementation in AD, commonly using evening primrose oil, have produced conflicting results.4 Among the functional fatty acids, LA is one of the most crucial metabolites produced from microbial sources, including I Bifidobacterium i and I Lactobacillus i . [Extracted from the article]

The goal of this study was to quantitatively assess the changes in the cerebral neurochemical profile and to identify those factors that contribute to the alteration of endogenous biomolecules when rats are subjected to stress-induced sleep disturbance. We exposed Sprague-Dawley rats (controls: n = 9; stress-induced sleep perturbation rats: n = 11) to a psychological stressor (cage exchange method) to achieve stress-induced sleep perturbation. In vivo magnetic resonance imaging assessments were carried out using a high-resolution 9.4 T system. For in vivo neurochemical analysis, a single voxel was localized in the right dorsal hippocampal region, and in vivo spectra were quantified for 17 cerebral neurochemical signals. Rats were sacrificed upon completion of the magnetic resonance spectroscopy protocol, and whole-brain tissue was harvested from twenty subjects. The dopamine and serotonin signals were obtained by performing in vitro liquid chromatography-tandem mass spectrometry on the harvested tissue. In the right dorsal hippocampal region, the gamma-aminobutyric-acid (GABA) and glutamine (Gln) concentrations were significantly higher in the sleep-perturbed rats than in the sham controls. The ratios of Gln/Glu (glutamate), Gln/tCr (total-creatine), and GABA/Glu were also significantly higher in the sleep-perturbed group, while serotonin concentrations were significantly lower in the sleep-perturbed rats. Pearson correlation results among individual rat data indicate that concentrations of dopamine (DA) and serotonin (5-HT) were significantly higher in SSP rats. A larger correlation coefficient was also observed for the SSP rats. Analysis of the correlation between the in vivo and in vitro signals indicated that the concentrations of Gln, 5-HT, and DA exhibited a significant negative correlation in the SSP rat data but not in that of control rats. The authors propose that the altered and correlated GABA, Gln, 5-HT, and DA concentrations/ratios could be considered key markers of neurological function in animal models of stress-induced sleep perturbation. [ABSTRACT FROM AUTHOR]

Heavy metals are commonly released into the environment through industrial processes such as mining and refining. The rapid industrialization that occurred in South Korea during the 1960s and 1970s contributed significantly to the economy of the country; however, the associated mining and refining led to considerable environmental pollution, and although mining is now in decline in South Korea, the detrimental effects on residents inhabiting the surrounding areas remain. The bioaccumulation of toxic heavy metals leads to metabolic alterations in human homeostasis, with disruptions in this balance leading to various health issues. This study used metabolomics to explore metabolomic alterations in the plasma samples of residents living in mining and refining areas. The results showed significant increases in metabolites involved in glycolysis and the surrounding metabolic pathways, such as glucose-6-phosphate, phosphoenolpyruvate, lactate, and inosine monophosphate, in those inhabiting polluted areas. An investigation of the associations between metabolites and blood clinical parameters through meet-in-the-middle analysis indicated that female residents were more affected by heavy metal exposure, resulting in more metabolomic alterations. For women, inhabiting the abandoned mine area, metabolites in the glycolysis and pentose phosphate pathways, such as ribose-5-phosphate and 3-phosphoglycerate, have shown a negative correlation with albumin and calcium. Finally, Mendelian randomization(MR) was used to determine the causal effects of these heavy metal exposure-related metabolites on heavy metal exposure-related clinical parameters. Metabolite biomarkers could provide insights into altered metabolic pathways related to exposure to toxic heavy metals and improve our understanding of the molecular mechanisms underlying the health effects of toxic heavy metal exposure. [ABSTRACT FROM AUTHOR]

microRNA-155 (miR-155) is one of the well-known oncogenic miRNA implicated in various types of tumors. Thiamine, commonly known as vitamin B1, is one of critical cofactors for energy metabolic enzymes including pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase, and transketolase. Here we report a novel role of miR-155 in cancer metabolism through the up-regulation of thiamine in breast cancer cells. A bioinformatic analysis of miRNA array and metabolite-profiling data from NCI-60 cancer cell panel revealed thiamine as a metabolite positively correlated with the miR-155 expression level. We confirmed it in MCF7, MDA-MB-436 and two human primary breast cancer cells by showing reduced thiamine levels upon a knock-down of miR-155. To understand how the miR-155 controls thiamine level, a set of key molecules for thiamine homeostasis were further analyzed after the knockdown of miR-155. The results showed the expression of two thiamine transporter genes (SLC19A2, SLC25A19) as well as thiamine pyrophosphokinase-1 (TPK1) were decreased in both RNA and protein level in miR-155 dependent manner. Finally, we confirm the finding by showing a positive correlation between miR-155 and thiamine level in 71 triple negative breast tumors. Taken altogether, our study demonstrates a role of miR-155 in thiamine homeostasis and suggests a function of this oncogenic miRNA on breast cancer metabolism. [ABSTRACT FROM AUTHOR]

In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders. [ABSTRACT FROM AUTHOR]

Obesity is implicated in cardiovascular disease and heart failure. When fatty acids are transported to and not adequately oxidized in cardiac cells, they accumulate, causing lipotoxicity in the heart. Since hepatic progesterone receptor membrane component 1 (Pgrmc1) suppressed de novo lipogenesis in a previous study, it was questioned whether cardiac Pgrmc1 protects against lipotoxicity. Hence, we focused on the role of cardiac Pgrmc1 in basal (Resting), glucose-dominant (Refed) and lipid-dominant high-fat diet (HFD) conditions. Pgrmc1 KO mice showed high FFA levels and low glucose levels compared to wild-type (WT) mice. Pgrmc1 KO mice presented low number of mitochondrial DNA copies in heart, and it was concomitantly observed with low expression of TCA cycle genes and oxidative phosphorylation genes. Pgrmc1 absence in heart presented low fatty acid oxidation activity in all conditions, but the production of acetyl-CoA and ATP was in pronounced suppression only in HFD condition. Furthermore, HFD Pgrmc1 KO mice resulted in high cardiac fatty acyl-CoA levels and TG level. Accordingly, HFD Pgrmc1 KO mice were prone to cardiac lipotoxicity, featuring high levels in markers of inflammation, endoplasmic reticulum stress, oxidative stress, fibrosis, and heart failure. In vitro study, it was also confirmed that Pgrmc1 enhances rates of mitochondrial respiration and fatty acid oxidation. This study is clinically important because mitochondrial defects in Pgrmc1 KO mice hearts represent the late phase of cardiac failure. [ABSTRACT FROM AUTHOR]

Introduction: Chemotherapy is a major etiology of cachexia. Ginseng products are known to have various anti-cachectic and health-promoting effects, such as inhibiting inflammation and promoting energy production. In particular, BST204, purified ginseng dry extract, contains multiple ginsenosides that can reduce chemotherapy-related fatigue and toxicity. Objectives: To investigate the effects of BST204 on the alleviation of chemotherapy-induced cachexia using a multimodal approach. Methods: In a CT26 mouse syngeneic colon cancer model, cachexia was predominantly induced by chemotherapy with 5-fluorouracil (5-FU) than by tumor growth. BST204 at a dose of 100 or 200 mg/kg was administered to 5-FU-treated mice. Results: BST204 significantly mitigated the decrease in tumor-excluded body weight (change in 5-FU group and BST204 groups: − 13% vs. − 6% on day 7; − 30% vs. − 20% on day 11), muscle volume (− 19% vs. − 11%), and fat volume (− 91% vs. − 56%). The anti-cachectic effect of BST204 was histologically demonstrated by an improved balance between muscle regeneration and degeneration and a decrease in muscle cross-sectional area reduction. Conclusion: Chemotherapy-induced cachexia was biochemically and metabolically characterized by activated inflammation, enhanced oxidative stress, increased protein degradation, decreased protein stabilization, reduced glucose-mediated energy production, and deactivated glucose-mediated biosynthesis. These adverse effects were significantly improved by BST204 treatment. Overall, our multimodal study demonstrated that BST204 could effectively alleviate chemotherapy-induced cachexia. [ABSTRACT FROM AUTHOR]

Dietary fiber functions as a prebiotic to determine the gut microbe composition. The gut microbiota influences the metabolic functions and immune responses in human health. The gut microbiota and metabolites produced by various dietary components not only modulate immunity but also impact various organs. Although recent findings have suggested that microbial dysbiosis is associated with several respiratory diseases, including asthma, cystic fibrosis, and allergy, the role of microbiota and metabolites produced by dietary nutrients with respect to pulmonary disease remains unclear. Therefore, we explored whether the gut microbiota and metabolites produced by dietary fiber components could influence a cigarette smoking (CS)-exposed emphysema model. In this study, it was demonstrated that a high-fiber diet including non-fermentable cellulose and fermentable pectin attenuated the pathological changes associated with emphysema progression and the inflammatory response in CS-exposed emphysema mice. Moreover, we observed that different types of dietary fiber could modulate the diversity of gut microbiota and differentially impacted anabolism including the generation of short-chain fatty acids, bile acids, and sphingolipids. Overall, the results of this study indicate that high-fiber diets play a beneficial role in the gut microbiota-metabolite modulation and substantially affect CS-exposed emphysema mice. Furthermore, this study suggests the therapeutic potential of gut microbiota and metabolites from a high-fiber diet in emphysema via local and systemic inflammation inhibition, which may be useful in the development of a new COPD treatment plan. [ABSTRACT FROM AUTHOR]

Background: We examined the changes in glucose metabolites of papillary thyroid cancer (PTC) and identified phosphoglycerate dehydrogenase (PHGDH) as a potential target. The role of PHGDH in the proliferation and tumorigenesis of thyroid cancer cells and its clinical significance were analyzed. Methods: Glucose metabolites of various thyroid tissues were analyzed via targeted metabolomics analysis. In vitro experiments using shPHGDHs, inhibitor (NCT503), or PHGDH overexpression in thyroid cell lines (BCPAP, 8505C, and Nthy-Ori) were performed. In vivo experiments were performed by using shPHGDH. Human tissue samples and The Cancer Genome Atlas (TCGA) data were used to validate the experimental findings. Results:PHGDH knockdown in BCPAP and 8505c cell lines significantly inhibited cell viability, colony formation, and tumor spheroid formation compared with the control. In addition, treatment with NCT503 showed similar results. PHGDH inhibition by both knockdown and treatment with NCT503 significantly inhibited the expression of embryonic cancer stemness markers (Oct4, Sox2, KLF4, and Nanog). PHGDH overexpression in Nthy-Ori cells significantly increased cell viability and colony formation. The stemness markers were significantly increased after PHGDH overexpression. PHGDH knockdown significantly inhibited tumor growth in an in vivo mouse xenograft study using 8505c cells. The protein expression of Oct4 in tumors was significantly reduced after PHGDH knockdown. The associations between PHGDH expression and stemness markers were confirmed in the TCGA data and human thyroid tissue samples. Positive PHGDH protein expression was associated with metastases of PTC. Conclusions:PHGDH expression is induced in thyroid cancer and is associated with stemness and aggressiveness of PTC. [ABSTRACT FROM AUTHOR]

Background: Obesity associated with various complications has increased worldwide. Body weight gain alters lipid metabolites (especially sphingolipids) contributing to obesity‐induced inflammation. However, the significance of the metabolites in the development of obese asthma is not yet clear. Methods: The serum levels of sphingolipids were measured using liquid chromatography‐tandem mass spectrometry in obese controls (n = 7) and patients with asthma: the obese group (BMI > 25 kg/m2, n = 13) vs the nonobese (n = 28) group. To examine the relationship between metabolic changes in sphingolipids and macrophage polarization, public microarray data were analyzed. In addition, the alteration in sphingolipid metabolism was investigated in wild‐type BALB/c mice fed a high‐fat diet. Results: The obese asthma had higher levels of serum C18:0 and C20:0 ceramides than the nonobese asthma group (P =.028 and P =.040, respectively). The value of the serum C18:0 ceramide (184.3 ng/mL) for discriminating the obese asthma from the nonobese asthma group showed 53.9% sensitivity and 85.7% specificity (AUC = 0.721, P =.024). The microarray data showed significantly increased ceramide synthesis and metabolic shift to ceramide accumulation during M1 macrophage polarization in humans. Increased airway hyperresponsiveness, M1 macrophage polarization, and C18:0 ceramide levels were noted in obese mice, but not in nonobese mice. Increased expression of ceramide synthase (CerS) 1 and CerS6 (not CerS2) was noted in lung tissues of obese mice. Conclusion: Alteration in sphingolipid metabolism favoring ceramide accumulation (especially long‐chain ceramides) may contribute to developing obese asthma. [ABSTRACT FROM AUTHOR]

Background: Asthma is associated with inflammatory dysregulation, but the underlying metabolic signatures are unclear. This study aimed to classify asthma inflammatory phenotypes based on cellular and metabolic features. Methods: To determine cellular and metabolic profiles, we assessed inflammatory cell markers using flow cytometry, sphingolipid (SL) metabolites using LC‐MS/MS, and serum cytokines using ELISA. Targeted gene polymorphisms were determined to identify genetic predispositions related to the asthma inflammatory phenotype. Results: In total, 137 patients with asthma and 20 healthy controls (HCs) were enrolled. Distinct cellular and metabolic profiles were found between them; patients with asthma showed increased expressions of inflammatory cell markers and higher levels of SL metabolites compared to HCs (P <.05 for all). Cellular markers (CD66+ neutrophils, platelet‐adherent eosinophils) and SL metabolic markers (C16:0 and C24:0 ceramides) for uncontrolled asthma were also identified; higher levels were observed in uncontrolled asthma compared to controlled asthma (P <.05 for all). Asthmatics patients with higher levels of CD66+ neutrophils had lower FEV1(%), higher ACQ (but lower AQLO) scores, and higher sphingosine and C16:0 ceramide levels compared to those with low levels of CD66+ neutrophils. Asthmatics patients with higher levels of platelet‐adherent eosinophils had higher S1P levels compared to those with lower levels of platelet‐adherent eosinophils. Patients carrying TT genotype of ORMDL3 had more CD66+ neutrophils; those with AG/ GG genotypes of SGMS1 exhibited higher platelet‐adherent eosinophils. Conclusion: Patients with uncontrolled asthma possess distinct inflammatory phenotypes including increased CD66+ neutrophils and platelet‐adherent eosinophils, with an imbalanced ceramide/S1P rheostat, potentially involving ORMDL3 and SGMS1 gene polymorphisms. Ceramide/S1P synthesis could be targeted to control airway inflammation. [ABSTRACT FROM AUTHOR]

The RNA binding proteins (RBPs) have multiple roles in human cancer. However, their molecular target and function have not been clearly identified. Our genomic analysis derived from patients reveals that NONO is a potential oncogenic gene in lung cancer. NONO is highly expressed in lung cancer tissues compared with normal tissues, and its expression has been correlated with the prognosis of lung cancer patients. We found that NONO significantly influences cancer cell proliferation in lung cancer. Gene expression profiles with NONO-depleted cells revealed that the sirtuin signaling pathway is highly correlated with NONO. Thus, NONO-silenced cells caused reduction of the TCA cycle and glycolysis metabolism. We identified that NONO regulated NAMPT, which is a well-known gene involved in sirtuin signaling, and NONO has a significant correlation with NAMPT in lung cancer patients. We propose that NONO modulates energy metabolism by direct interaction with NAMPT and suggest that a functional relationship between NONO and NAMPT contributes to lung cancer cell survival. Targeting the axis can be a promising approach for patient treatment in lung cancer. • RNA-binding protein, NONO expression is increased in lung cancer. • NONO contributes to cancer cell growth by regulating energy metabolism via NAMPT. • NONO-NAMPT axis is crucial for cancer cell survival. [ABSTRACT FROM AUTHOR]

• Pluripotent stem cell (PSC)-derived expandable human hepatocyte-like liver organoids were generated. • PSC-derived human hepatic organoids are capable of long-term expansion with competent liver functionality. • PSC-derived human hepatic organoids provide a robust hepatic model for toxicity prediction and drug screening. The development of hepatic models capable of long-term expansion with competent liver functionality is technically challenging in a personalized setting. Stem cell-based organoid technologies can provide an alternative source of patient-derived primary hepatocytes. However, self-renewing and functionally competent human pluripotent stem cell (PSC)-derived hepatic organoids have not been developed. We developed a novel method to efficiently and reproducibly generate functionally mature human hepatic organoids derived from PSCs, including human embryonic stem cells and induced PSCs. The maturity of the organoids was validated by a detailed transcriptome analysis and functional performance assays. The organoids were applied to screening platforms for the prediction of toxicity and the evaluation of drugs that target hepatic steatosis through real-time monitoring of cellular bioenergetics and high-content analyses. Our organoids were morphologically indistinguishable from adult liver tissue-derived epithelial organoids and exhibited self-renewal. With further maturation, their molecular features approximated those of liver tissue, although these features were lacking in 2D differentiated hepatocytes. Our organoids preserved mature liver properties, including serum protein production, drug metabolism and detoxifying functions, active mitochondrial bioenergetics, and regenerative and inflammatory responses. The organoids exhibited significant toxic responses to clinically relevant concentrations of drugs that had been withdrawn from the market due to hepatotoxicity and recapitulated human disease phenotypes such as hepatic steatosis. Our organoids exhibit self-renewal (expandable and further able to differentiate) while maintaining their mature hepatic characteristics over long-term culture. These organoids may provide a versatile and valuable platform for physiologically and pathologically relevant hepatic models in the context of personalized medicine. A functionally mature, human cell-based liver model exhibiting human responses in toxicity prediction and drug evaluation is urgently needed for pre-clinical drug development. Here, we develop a novel human pluripotent stem cell-derived hepatocyte-like liver organoid that is critically advanced in terms of its generation method, functional performance, and application technologies. Our organoids can contribute to the better understanding of liver development and regeneration, and provide insights for metabolic studies and disease modeling, as well as toxicity assessments and drug screening for personalized medicine. [ABSTRACT FROM AUTHOR]

The link between Val232Met variant of phospholipase D3 (PLD3) and late-onset Alzheimer's disease (AD) is still obscure. While it may not affect directly the amyloid precursor protein function, PLD3 could be regulating multiple cellular compartments. Here, we investigated the function of wild-type human PLD3 (PLD3WT) and the Val232Met variant (PLD3VM) in the presence of β-amyloid (Aβ) in a Drosophila melanogaster model of AD. We expressed PLD3WT in CNS of the Aβ-model flies and monitored its effect on the ER stress, cell apoptosis and recovery the Aβ-induced cognitive impairment. The expression reduced ER stress and neuronal apoptosis, which resulted in normalized antioxidative phospholipids levels and brain protection. A specific O-glycosylation at pT271 in PLD3 is essential for its normal trafficking and cellular localization. The V232 M substitution impairs this O-glycosylation, leading to enlarged lysosomes and plausibly aberrant protein recycling. PLD3VM was less neuroprotective, and while, PLD3WT expression enhances the lysosomal functions, V232 M attenuated PLD3's trafficking to the lysosomes. Thus, the V232 M mutation may affect AD pathogenesis. Further understanding of the mechanistic role of PLD3 in AD could lead to developing novel therapeutic agents. • A specific O-glycosylation at pT271 in PLD3 is essential for its normal trafficking and cellular localization. • PLD3WT expression is neuroprotective, while pV232M attenuated PLD3's glycosylation, trafficking and lead to enlarged lysosomal structures. • The mechanistic role of PLD3 in AD could lead to developing novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Myonectin is a muscle-secreted factor that helps maintain homeostasis in the body by regulating several functions, including lipid metabolism. Previous studies suggested that myonectin may play a role in muscle health in an autocrine manner, but its impact on human skeletal muscle is still unclear. We aimed to investigate the relationship of serum myonectin levels with sarcopenia and related muscle parameters. We conducted a cross-sectional study of 142 older adults whose muscle mass, grip strength, gait speed, chair stands, and short physical performance battery (SPPB) were evaluated in the geriatric clinic of a tertiary medical center. Sarcopenia was defined based on Asian-specific cutoff values, and circulating myonectin levels were measured using an enzyme immunoassay. Before and after adjusting for age, sex, and body mass index, the serum myonectin level was not significantly different when the patients were stratified by status of sarcopenia, muscle mass, muscle strength, and physical performance. Furthermore, whether given as a continuous variable or divided into quartile groups, the serum myonectin level had no association with the skeletal muscle mass, grip strength, gait speed, chair stand test, or SPPB score. Our findings did not confirm the potential role of myonectin in muscle metabolism observed in experimental research. Thus, serum myonectin levels cannot predict the risk of sarcopenia in older Asian adults. • Serum myonectin was not different according to sarcopenia or related parameters. • The null association was consistent in age, sex, and BMI adjusted models. • Serum myonectin cannot predict the risk of sarcopenia in older Asian adults. [ABSTRACT FROM AUTHOR]

Nonimmune hydrops fetalis is the most severe clinical manifestation of lysosomal storage diseases (LSDs). Around 14 different LSDs have been accounted for as 1–15% of the cause of nonimmune hydrops fetalis. We report a Korean infant affected by an extremely rare but severe form of sialic acid storage disease. The patient presented with nonimmune hydrops fetalis, dysmorphic facial features, hepatosplenomegaly, and dysostosis multiplex and died at 39 days of age due to persistent pulmonary hypertension. LSD was suspected based on the presence of diffuse vacuolation of syncytiotrophoblast, villous stromal cells, and intermediate trophoblast in placental biopsy. Increased excretion of urinary free sialic acid was detected by liquid chromatography-tandem mass spectrometry. The patient was compound heterozygous of the c.908G>A (p.Trp303Ter) and the splicing mutation c.1259+5G>T (IVS9+5 G>T) in the SLC17A5 gene. [ABSTRACT FROM AUTHOR]

Background: The fatty acid profile of the fecal metabolome and its association with colorectal cancer (CRC) has not been fully evaluated.Aims: We aimed to compare the fecal fatty acid profiles of CRC patients and healthy controls.Methods: We enrolled 26 newly diagnosed CRC patients and 28 healthy individuals between July 2014 and August 2014 from our institute. Long- and short-chain fatty acids were extracted from fecal samples and analyzed using gas chromatography-mass spectrometry.Results: Regarding fecal long-chain fatty acids, the levels of total ω-6 polyunsaturated fatty acids and, particularly, of linoleic acid (C18:2ω-6) were significantly higher in male CRC patients than in healthy men (2.750 ± 2.583 vs. 1.254 ± 0.966 µg/mg feces, P = 0.040; 2.670 ± 2.507 vs. 1.226 ± 0.940 µg/mg feces, P = 0.034, respectively). In addition, the levels of total monounsaturated fatty acid and, particularly, of oleic acid (C18:1ω-9) were significantly higher in male CRC patients than in healthy men (1.802 ± 1.331 vs. 0.977 ± 0.625 µg/mg feces, P = 0.027; 1.749 ± 1.320 vs. 0.932 ± 0.626 µg/mg feces, P = 0.011, respectively). However, those differences were not shown in female gender. The level of fecal short-chain fatty acids was not different between CRC patients and healthy controls.Conclusions: There were changes in the profiles of fecal fatty acid metabolomes in CRC patients compared to healthy controls, implying that fecal fatty acids could be used as a novel screening tool for CRC. [ABSTRACT FROM AUTHOR]

Summary: Context: Serotonin acts as a neurotransmitter in the central and enteric nervous systems, modulating psychological, metabolic and gastrointestinal functions. Serotonin is also found in the serum or plasma, indicating its potential role as a hormone. Objective: We aimed to assess the 24‐hour diurnal profile of serum serotonin in relation to meal ingestion in healthy adult men. Methods: Ten healthy (5 lean and 5 obese) male subjects were enrolled in this study. Blood samples were drawn every 30‐60 minutes throughout a 24‐hour period to determine the serotonin levels. Three meals were provided on a fixed schedule. To confirm the effect of meal intake on serum serotonin levels, 4 subjects underwent fasting until 1500 h and were then provided a meal without notice. Results: Serum serotonin levels had distinct diurnal variations, with the highest levels early in the morning and the lowest levels in the midafternoon and during sleep. Notably, these diurnal oscillations were markedly reduced in obese subjects. Fluctuations in serum serotonin levels were associated with meal intake, and the levels peaked 30 minutes before meals and exhibited a trough during the postprandial period. Fasting blunted the meal‐related oscillations in serum serotonin levels. Moreover, unexpected meal intake did not lead to a premeal increase in serum serotonin levels. Conclusions: Serum serotonin levels displayed meal‐related diurnal oscillations, which were disrupted by fasting and obesity. These findings suggest the possibility that circulating serotonin modulates metabolic function in humans. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background and objective: Matrix degradation is a key feature of chronic obstructive pulmonary disease (COPD). Desmosine and isodesmosine (desmosines) are excreted in urine following matrix degradation. The main purpose of this study was to investigate the association between computed tomography (CT) emphysema indices and urinary desmosines in patients with COPD. Methods: A total of 152 subjects were selected from the Korean Obstructive Lung Disease cohort. Their urine samples were assayed for desmosines using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) methods. The cohort was divided into emphysema‐dominant (n = 80) and non‐emphysema dominant‐ (n = 72) groups according to the CT emphysema index. Results: The level of urinary desmosines was significantly higher in the emphysema‐dominant group. Significant differences were also observed between the two groups for body mass index and lung function. Multivariate analysis indicated that a high level of urinary desmosines was a significant independent predictor of emphysema (relative risk: 2.6; 95% CI: 1.11–6.09; P = 0.028). The percentage of frequent exacerbators was significantly higher in the high urinary desmosine group in the first year of follow‐up (P = 0.041). The mean number of exacerbations was higher in the high urinary desmosine group, although this difference was not statistically significant (P = 0.067). The changes in emphysema index did not differ between the two urinary desmosine groups over 3 years of follow‐up. Conclusion: This study indicates that the level of urinary desmosines measured by LC‐MS/MS methods is associated with the CT emphysema index. Urinary desmosine can be a useful predictor in identifying frequent exacerbators. [ABSTRACT FROM AUTHOR]

Very long chain fatty acids are required for sphingolipid synthesis, lipid homeostasis, myelin formation, epidermal permeability, and retinal function. Seven different enzymes are known to be involved in the elongation cycle of fatty acids, with different chain-length specificities. Elovl1 is one of those enzymes whose function has been linked mainly to the synthesis of sphingolipids and the epidermal barrier. However, the role of Elovl1 in organogenesis is not clear. In zebrafish, 2 Elovl1 genes, elovl1a and elovl1b, are highly expressed in the swim bladder, and elovl1b is also expressed in the kidney. We found that both elovl1 knockdown embryos contain increased levels of long chain fatty acids from carbon number 14 to 20 as compared to control embryos. Oil-Red-O staining shows that yolk lipid consumption is greatly reduced, whereas lipid droplets accumulate within the swim bladder. Notably, knockdown of either elovl1a or elovl1b affects the expression of genes involved in swim bladder development and impairs inflation of the swim bladder. Consistent with its expression in the pronephros, knockdown of elovl1b alone affects the expression of genes required for kidney development and reduces renal clearance. Our findings strongly suggest that both elovl1 genes are a key determinant of swim bladder and kidney development in zebrafish, which may be comparatively applicable to lung and kidney development in humans. [ABSTRACT FROM AUTHOR]

Stem cell (SC) therapy has become a potential treatment modality for pulmonary artery hypertension (PAH), but the efficacy of human SC and priming effects have not yet been established. The mobilization and homing of hematopoietic stem cells (HSCs) are modulated by priming factors that include a bioactive lipid, sphingosine-1-phosphate (S1P), which stimulates CXCR4 receptor kinase signaling. Here, we show that priming human mesenchymal stem cells (MSCs) with S1P enhances their therapeutic efficacy in PAH. Human MSCs, similar to HSCs, showed stronger chemoattraction to S1P in transwell assays. Concomitantly, MSCs treated with 0.2 μM S1P showed increased phosphorylation of both MAPKp42/44 and AKT protein compared with nonprimed MSCs. Furthermore, S1P-primed MSCs potentiated colony forming unit-fibroblast, anti-inflammatory, and angiogenic activities of MSCs in culture. In a PAH animal model induced by subcutaneously injected monocrotaline, administration of human cord blood-derived MSCs (hCB-MSCs) or S1P-primed cells significantly attenuated the elevated right ventricular systolic pressure. Notably, S1P-primed CB-MSCs, but not unprimed hCB-MSCs, also elicited a significant reduction in the right ventricular weight ratio and pulmonary vascular wall thickness. S1P-primed MSCs enhanced the expression of several genes responsible for stem cell trafficking and angiogenesis, increasing the density of blood vessels in the damaged lungs. Thus, this study demonstrates that human MSCs have potential utility for the treatment of PAH, and that S1P priming increases the effects of SC therapy by enhancing cardiac and vascular remodeling. By optimizing this protocol in future studies, SC therapy might form a basis for clinical trials to treat human PAH. [ABSTRACT FROM AUTHOR]

Abstract: Non-immune hydrops fetalis is the most severe presenting feature of lysosomal storage disorders. However, it is difficult to identify the underlying condition because the different lysosomal storage diseases share many clinical features. A neonate with hydrops fetalis is described here. A lysosomal storage disorder was first suspected when the placental biopsy showed the presence of macrophages containing numerous cytoplasmic vacuoles. Subsequent comprehensive diagnostic processes and biochemical and molecular genetics characterization revealed a rare genetic cause, namely sialidosis type 2. Liquid chromatography–mass spectrometry revealed increased amounts of bound sialic acid in the urine. Pathogenic NEU1 mutations were detected. This is the first case with sialidosis type 2 ever known in the Korean population, exhibiting its most severe manifestation. [Copyright &y& Elsevier]

This study was conducted to identify the composition and diversity of the microbiome in tissues of pancreatic cancer and to determine its role. First, extracellular vesicles (EVs) were obtained from the paired tumor and normal tissues, and 16s rRNA gene sequencing was performed. We identified the microbiomes, compared the diversity between groups, and found that Tepidimonas was more abundant in tumors. Second, larger tumors resulted in lower levels of Leuconostoc and Sutterella, and increased lymph node metastasis resulted in higher levels of Comamonas and Turicibacter in tumor tissues. Moreover, in the case of tumor recurrence, the levels of Streptococcus and Akkermansia were decreased in tumor tissues. Finally, with the supernatant of Tepidimonasfonticaldi, proliferation and migration of cells increased, and epithelial-mesenchymal transition and the Tricarboxylic Acid (TCA) cycle-related metabolites were enhanced. The composition and diversity of EV-derived microbiomes are important for providing novel insights into theragnostic approaches in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Macroautophagy (autophagy) is believed to maintain energy homeostasis by degrading unnecessary cellular components and molecules. Its implication in regulating cancer metabolism recently started to be uncovered. However, the precise roles of autophagy in cancer metabolism are still unclear. Here, we show that autophagy plays a critical role in glutamine metabolism, which is required for tumor survival. Pancreatic ductal adenocarcinoma (PDAC) cells require both autophagy and typical glutamine transporters to maintain intracellular glutamine levels. Glutamine deprivation, but not that of glucose, led to the activation of macropinocytosis-associated autophagy through TFEB induction and translocation into the nucleus. In contrast, glutamine uptake increased as a compensatory response to decreased intracellular glutamine levels upon autophagy inhibition. Moreover, autophagy inhibition and glutamine deprivation did not induce cell death, while glutamine deprivation dramatically activated apoptotic cell death upon autophagy inhibition. Interestingly, the addition of α-ketoglutarate significantly rescued the apoptotic cell death caused by the combination of the inhibition of autophagy with glutamine deprivation. Our data suggest that macropinocytosis-associated autophagy is a critical process providing glutamine for anaplerosis of the TCA cycle in PDAC. Thus, targeting both autophagy and glutamine metabolism to completely block glutamine supply may provide new therapeutic approaches to treat refractory tumors. [ABSTRACT FROM AUTHOR]

Sphingolipid (SL) metabolites have been suggested to be important inflammatory mediators in airway inflammation and asthma. However, little is known about SL metabolites in aspirin-exacerbated respiratory disease (AERD). We aimed to explore the potential AERD biomarkers by conducting lipidomics targeting SL metabolites. The levels of SL metabolites in serum and urine samples from 45 AERD patients and 45 aspirin-tolerant asthma (ATA) patients were quantified through mass spectrometry. During the lysine-aspirin bronchoprovocation test (ASA-BPT), the levels of serum sphingomyelin (SM) were significantly decreased in AERD (P < 0.05) but not in ATA. The serum SM levels were positively correlated with airway responsiveness to methacholine. At the basal status before the ASA-BPT, the levels of serum sphingosine-1-phosphate (S1P) and urine sphingosine were significantly higher in the AERD patients compared with that of ATA patients (P < 0.001) and were positively correlated with a greater decrease in FEV1 (%) values following the ASA-BPT test (P < 0.001 for each), and with serum periostin level (P < 0.05 for each). This study is the first to evaluate serum S1P and urine sphingosine as potential biomarkers of AERD as well as to examine the metabolic disturbance of SL in AERD patients. [ABSTRACT FROM AUTHOR]