Search

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD. [ABSTRACT FROM AUTHOR]

ASICs (Acid-Sensing Ion Channels) constitute a family of excitatory cation channels activated by extracellular protons. They are widely expressed in pain pathways both in the peripheral nervous system (sensory neurons) and the central nervous system (spinal and supraspinal neurons). The ASIC3 channel, which is mainly expressed in peripheral sensory neurons, is also sensitive to lipids such as lysophosphatidylcholine (LPC). LPC increases the sensitivity of the channel to protons, generating activation at physiological pH as well as potentiation of its activity at acidic pH. The ability of LPC to activate/potentiate ASIC3, but also other channels expressed by sensory neurons and involved in pain such as TRPV1, TRPM8, TRPC5, or the K+ channels TREK-1 and TRAAK, has highlighted the important role of this lipid in pain. Its effect is not limited to neurons and can affect other channels such as TRPV4 expressed in keratinocytes that also participate in sensory transduction. Elevated levels of LPC have pathophysiological consequences in pain that may involve these channels, including in humans, in fibromyalgia, rheumatic diseases, musculoskeletal disorders, or obesity (ASIC3), as well as in inflammatory and neuropathic pain (TRPC5) or in cholestatic pruritus (TRPV4). [ABSTRACT FROM AUTHOR]

Lipids, defined by low solubility in water and high solubility in nonpolar solvents, can be classified into fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. Lipids not only regulate integrity and fluidity of biological membranes, but also serve as energy storage and bioactive molecules for signaling. Causal mutations in SPTLC1 (serine palmitoyltransferase long chain subunit 1) gene within the lipogenic pathway have been identified in amyotrophic lateral sclerosis (ALS), a paralytic and fatal motor neuron disease. Furthermore, lipid dysmetabolism within the central nervous system and circulation is associated with ALS. Here, we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis. Among the different lipids, accumulation of ceramides, arachidonic acid, and lysophosphatidylcholine is commonly emerging as detrimental to motor neurons. We end with exploring the potential ALS therapeutics by reducing these toxic lipids. [ABSTRACT FROM AUTHOR]

Aim: The role of lipids in periodontitis has not been well studied. Thus, this study aimed to explore periodontitis‐associated lipid profile changes and identify differentially expressed lipid metabolites in gingival tissues. Materials and Methods: Gingival tissues from 38 patients with periodontitis (periodontitis group) and 38 periodontally healthy individuals (control group) were collected. A ultra‐high performance liquid chromatography‐quadrupole time‐of‐flight mass spectrometry‐based non‐targeted metabolomics platform was used to identify and compare the lipid profiles of the two groups. The distribution and expression of related proteins were subsequently analysed via immunohistochemistry to further validate the identified lipids. Results: Lipid profiles significantly differed between the two groups, and 20 differentially expressed lipid species were identified. Lysophosphatidylcholines (lysoPCs), diacylglycerols (DGs), and phosphatidylethanolamines (PEs) were significantly up‐regulated, while triacylglycerols (TGs) were downregulated in the periodontitis group. Moreover, the staining intensity of ABHD5/CGI‐58, secretory phospholipase A2 (sPLA2), and sPLA2‐IIA was significantly stronger in the gingival tissues of patients with periodontitis than in those of healthy controls. Conclusions: LysoPCs, DGs, and PEs were significantly up‐regulated, whereas TGs were down‐regulated in gingival tissues of patients with periodontitis. Correspondingly, the immunohistochemical staining of ABHD5/CGI‐58, sPLA2, and sPLA2‐IIA in gingival tissues was consistent with the downstream production of lipid classes (lysoPCs, TGs, and DGs). [ABSTRACT FROM AUTHOR]

Lysophosphatidylcholine (LPC), a major class of glycerophospholipids ubiquitously present in most tissues, plays a dominant role in many diseases, while it is still unknown about the potential mechanism of LPC affecting the testicular Leydig cells. In the present study, mouse TM3 Leydig cells in vitro were treated with LPC for 48 h. LPC was found to significantly induce apoptosis and oxidative stress of mouse TM3 Leydig cells; while inhibition of oxidative stress by N‐acetyl‐L‐cysteine, an inhibitor of oxidative stress, could rescue the induction of apoptosis, indicating that LPC induced apoptosis of mouse TM3 Leydig cells via oxidative stress. Interestingly, LPC was showed to inhibit autophagy; however, induction of autophagy by rapamycin significantly alleviated the induction of apoptosis by LPC. Taken together, oxidative stress was involved in LPC‐induced apoptosis of mouse TM3 Leydig cells, and autophagy might play a protective role in LPC‐induced apoptosis. [ABSTRACT FROM AUTHOR]

We reported that lysophosphatidic acid (LPA) is present at 0.8 μM in mixed human saliva (MS). In this study, we examined the distribution, origin, and enzymatic generation pathways of LPA in MS. LPA was distributed in the medium and cell pellet fraction; a true level of soluble LPA in MS was about 150 nM. The soluble LPA was assumed to be generated by ecto-type lysophospholipase D on exfoliated cells in MS from LPC that originated mainly from the major salivary gland saliva. Our results with the albumin-back extraction procedures suggest that a significant pool of LPA is kept in the outer layer of the plasma membranes of detached oral mucosal cells. Such pool of LPA may contribute to wound healing in upper digestive organs including oral cavity. We obtained evidence that the choline-producing activity in MS was mainly due to Ca2+-activated lysophospholipase D activity of glycerophosphodiesterase 7. • Mixed human saliva is a lysophosphatidic acid (LPA)-rich biological fluid. • Lysophospholipase D on oral mucosa converts LPC secreted from salivary glands to LPA. • Glycerophosphodiesterase 7 is a potential enzyme that produce LPA in mixed saliva. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a common feature in neurodegenerative diseases such as multiple sclerosis (MS). This study aims to explore the potential of enhancing the beneficial effects of fluoxetine (FLX), a neuroprotective agent known for its ability to increase neural plasticity by utilizing nanoparticles. The study specifically focuses on the synthesis and evaluation of PEGylated chitosan nanoparticles of FLX and its effect on demyelination and the subsequent cognitive impairment (CI) in the hippocampus of rats induced by local injection of lysophosphatidylcholine (LPC). Chitosan/polyethylene glycol nanoparticles were synthesized, and their properties were analyzed. Demyelination was induced in rats via hippocampal injections of lysolecithin. Behavioral assessments included open field maze, elevated plus maze, and novel object recognition memory (NORM) tests. Hippocampal levels of insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) were measured using enzyme-linked immunoassay (ELISA). The extent of remyelination was quantified using Luxol fast blue staining. Nanoparticle size measured 240.2 nm with 53 % encapsulation efficacy. Drug release exhibited a slow pattern, with 76 % released within 4 h. Nanoparticle-treated rats displayed reduced anxiety-like behavior, improved memory, increased BDNF levels, and a reduced extent of demyelination, with no change in IGF- levels. In addition, FLX -loaded chitosan nanoparticles had better effect on cognitive improvement, BDNF levels in the hippocampus that FLX. Altering pharmacokinetics and possibly pharmacodynamics. These findings highlight the potential of innovative drug delivery systems, encouraging further research in this direction. Graphical representation of the synthesis of FLX nanoparticles using the ionic gelation method followed by their characterization (encapsulation efficacy, size analysis, zeta potential, scanning electron microscopy (SEM), and release profile). Subsequent animal studies detail the induction of demyelination and treatment using the formulated nanoparticles of fluoxetine (NFLX) or fluoxetine (FLX) alone. Behavioral assessments, including the open field maze, novel object recognition memory, and elevated plus maze tests were conducted. The study concluded with hippocampus extraction and measurement of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) using the enzyme-linked immunosorbent assay (ELISA). Luxol fast blue staining was used to assess the extent of de-/re-myelination. [Display omitted] • Nanoparticle-treated rats displayed reduced anxiety-like behavior, improved memory, and a reduced extent of demyelination. • FLX -loaded chitosan nanoparticles had no effect on hippocampal IGF- levels. • FLX -loaded chitosan nanoparticles had better effect on cognitive improvement, BDNF levels in the hippocampus that FLX. [ABSTRACT FROM AUTHOR]

Enzyme-modified lecithin that contains lysophosphatidylcholine (LPC) is generally recognized as safe. However, its potential as a functional ingredient has been less investigated than other choline (Ch)-containing compounds, such as glycerophosphocholine (GPC). Reports on the possibility of LPC functioning as a cholinergic precursor in vivo and on its kinetics are limited to docosahexaenoic acid-bound LPC. Herein, three experiments were performed to investigate these processes in scopolamine (SCO)-treated rats. First, an egg-derived LPC reagent was orally administered to rats, and brain acetylcholine (ACh), Ch, plasma Ch, and LPC were measured. Second, soy- and rapeseed-derived enzyme-modified lecithins and GPC were administered for comparison. Third, soy-derived enzyme-modified lecithins with different fat contents were administered for comparison. The LPC reagent mitigated SCO-induced ACh depletion at 500 mg/kg body weight and increased plasma Ch, but not LPC, concentrations. Additionally, soy-derived LPC-containing food additive counteracted brain ACh depletion similarly to GPC. Interestingly, plasma Ch and linoleoyl-LPC levels were higher when soy-derived LPC with a higher fat content was administered, whereas the plasma levels of palmitoyl-LPC decreased and those of total LPC remained constant. In conclusion, egg- and soy-derived LPC species function as cholinergic precursors in vivo, and future studies should explore this potential.

Various groups of antihypertensive drugs targeting different pathways have been developed; however, the pharmacometabolic responses to these drugs have rarely been compared to elucidate the common pathway of blood pressure regulation. Here, we performed a comparative multi-dimensional pharmacometabolic study on the four major lines of antihypertensive drugs, namely angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics (DIURs), through ultra-performance liquid chromatography coupled to quantum time-of-flight mass spectrometry. Two hundred fifty patients with young-onset hypertension, who were equally divided among five study groups: non-medicated, ACEi, ARB, CCB, and DIUR groups, were recruited. In a metabolome-wide association study conducted through analysis of covariance, 37 molecular features significantly associated with pharmacometabolic responses to antihypertensive drugs were identified. One-third of these features were shared by multiple medications. ACEis, ARBs, and DIURs shared more features than CCB, partially reflecting that ACEis, ARBs, and DIURs affect the renin-angiotensin-aldosterone system. Thirteen molecular features were consistently identified by all four models of the analysis of covariance. A tandem mass spectrometry (or MS/MS) experiment was performed to decipher the chemical structure of these 13 molecular features, including ARB-associated lysophosphatidylcholine (P4135), CCB-associated diacylglycerol(15:0/18:2) (P1175), and DIUR-associated oleamide (P1516). In addition, diacylglycerol(15:0/14:2) (P408) was significantly associated with the pharmacometabolic response to all four antihypertensive drugs. The identified metabolites provide insights into the mechanisms of blood pressure regulation and potential predictive markers of pharmacometabolic responses to antihypertensive drugs.

Abstract Being born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p

The malaria parasite Plasmodium falciparum synthesizes significant amounts of phospholipids to meet the demands of replication within red blood cells. De novo phosphatidylcholine (PC) biosynthesis via the Kennedy pathway is essential, requiring choline that is primarily sourced from host serum lysophosphatidylcholine (lysoPC). LysoPC also acts as an environmental sensor to regulate parasite sexual differentiation. Despite these critical roles for host lysoPC, the enzyme(s) involved in its breakdown to free choline for PC synthesis are unknown. Here, we show that a parasite glycerophosphodiesterase (PfGDPD) is indispensable for blood stage parasite proliferation. Exogenous choline rescues growth of PfGDPD-null parasites, directly linking PfGDPD function to choline incorporation. Genetic ablation of PfGDPD reduces choline uptake from lysoPC, resulting in depletion of several PC species in the parasite, whilst purified PfGDPD releases choline from glycerophosphocholine in vitro. Our results identify PfGDPD as a choline-releasing glycerophosphodiesterase that mediates a critical step in PC biosynthesis and parasite survival.

Abstract: Rheumatic diseases are often associated to debilitating chronic pain, which remains difficult to treat and requires new therapeutic strategies. We had previously identified lysophosphatidylcholine (LPC) in the synovial fluids from few patients and shown its effect as a positive modulator of acid-sensing ion channel 3 (ASIC3) able to induce acute cutaneous pain in rodents. However, the possible involvement of LPC in chronic joint pain remained completely unknown. Here, we show, from 2 independent cohorts of patients with painful rheumatic diseases, that the synovial fluid levels of LPC are significantly elevated, especially the LPC16:0 species, compared with postmortem control subjects. Moreover, LPC16:0 levels correlated with pain outcomes in a cohort of osteoarthritis patients. However, LPC16:0 do not appear to be the hallmark of a particular joint disease because similar levels are found in the synovial fluids of a second cohort of patients with various rheumatic diseases. The mechanism of action was next explored by developing a pathology-derived rodent model. Intra-articular injections of LPC16:0 is a triggering factor of chronic joint pain in both male and female mice, ultimately leading to persistent pain and anxiety-like behaviors. All these effects are dependent on ASIC3 channels, which drive sufficient peripheral inputs to generate spinal sensitization processes. This study brings evidences from mouse and human supporting a role for LPC16:0 via ASIC3 channels in chronic pain arising from joints, with potential implications for pain management in osteoarthritis and possibly across other rheumatic diseases. [ABSTRACT FROM AUTHOR]

Introduction: Pro-inflammatory cytokines are responsible for initiating an effective defense against exogenous pathogens, and their regulation has a vital role in maintaining physiological homeostasis. The involvement of pro-inflammatory cytokines in pathological conditions have been explored in great detail, however, studies investigating metabolic pathways associated with these cytokines under normal homeostatic conditions are scarce. Objectives: The aim of the current study was to identify metabolites and metabolic pathways associated with circulating pro-inflammatory cytokines under homeostatic conditions using a metabolomics approach. Methods: The study participants (n = 133) were derived from the Newfoundland Osteoarthritis Study (NFOAS) and the Complex Diseases in the Newfoundland population: Environment and Genetics (CODING) study. Plasma concentrations of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and macrophage migration inhibitory factor (MIF) were assessed by enzyme-linked immunosorbent assay. Targeted metabolomic profiling on fasting plasma samples was performed using Biocrates MxP® Quant 500 kit which measures a total of 630 metabolites. Associations between natural log-transformed metabolite concentrations and metabolite sums/ratios and cytokine levels were assessed using linear regression with adjustment for age, sex, body mass index (BMI), and osteoarthritis status. Results: Seven metabolites and 11 metabolite sums/ratios were found to be significantly associated with TNF-α, IL-1β, and MIF (all p ≤ 5.13 × 10− 5) after controlling multiple testing with Bonferroni method, indicating the association between glutathione (GSH), polyamine, and lysophosphatidylcholine (lysoPC) synthesis pathways and these pro-inflammatory cytokines. Conclusion: GSH, polyamine, and lysoPC synthesis pathways were positively associated with circulating TNF-α, IL-1β, and MIF levels under homeostatic conditions. [ABSTRACT FROM AUTHOR]

Polar lipids were extracted from residual biomass of hemp (Cannabis sativa L.) by-products with EtOH and partitioned into aqueous and chloroform fractions. The chloroform fractions were studied for their lipid composition using solid-phase extraction (SPE) followed by UHPLC/HRMS and NMR analyses. The 1H NMR and gravimetric yield of SPE indicated triacylglycerols covered ≥ 51.3% of the chloroform fraction of hemp seed hulls and hemp cake. UHPLC/HRMS analyses of remaining polar lipids led to the identification of nine diacylglycerols (DAGs), six lysophosphatidylcholines (LPCs), five lysophosphatidylethanolamines (LPEs), eight phosphatidylethanolamines (PEs), and thirteen phosphatidylcholines (PCs) for the first time from hemp seed hulls. The regiospecificity of fatty acyl substitutes in glycerol backbone of individual phospholipids were assigned by analyzing the diagnostic fragment ions and their intensities. The heat-map analysis suggested that DAG 18:2/18:2, 1-LPC 18:2, 1-LPE 18:2, PE 18:2/18:2, and PC 18:2/18:2 were the predominant molecules within their classes, supported by the fact that linoleic acid was the major fatty acid covering > 41.1% of the total fatty acids determined by GC-FID analysis. The 31P NMR analysis confirmed the identification of phospholipids and suggested PC covers ≥ 37.9% of the total phospholipid present in hemp by-products. HPLC purification led to the isolation of 1,2-dilinoleoylphosphatidylcholine and 1-palmitoyl-2-linoleoylphosphatidylcholine. These two major PCs further confirmed the UHPLC/HRMS finding. [ABSTRACT FROM AUTHOR]

Even though macrophages have the potential to harm tissues through excessive release of inflammatory mediators, they play protective roles to maintain tissue integrity. In this study, we hypothesized that lysophosphatidylcholine (LPC), via G2A and A2B receptors, puts brakes on macrophages by the induction of adenosine release which could contribute to termination of inflammation. Mechanistically, LPC-induced PGE2 production followed by the activation of cAMP/protein kinase A (PKA) pathway which results in the activation of LKB1/AMPK signaling pathway leading to increasing Mg2+ influx concomitantly with an increase in mitochondrial membrane potential (MMP, Δψm) and ATP production. Then, ATP is converted to adenosine intracellularly followed by efflux via ENT1. In a parallel pathway, LPC-induced elevation of cytosolic calcium was essential for adenosine release, and Ca2+/calmodulin signaling cooperated with PKA to regulate ENT1 permeation to adenosine. Pharmacological blockade of TRPM7 and antisense treatment suppressed LPC-induced adenosine release and magnesium influx in bone marrow-derived macrophages (BMDMs). Moreover, LPC suppressed LPS-induced phosphorylation of connexin-43, which may counteract TLR4-mediated inflammatory response. Intriguingly, we found LPC increased netrin-1 production from BMDMs. Netrin-1 induces anti-inflammatory signaling via A2B receptor. In the presence of adenosine deaminase which removes adenosine in the medium, the chemotaxis of macrophages toward LPC was significantly increased. Hypoxia and metabolic acidosis are usually developed in a variety of inflammatory situations such as sepsis. We found LPC augmented hypoxia- or acidosis-induced adenosine release from BMDMs. These results provide evidence of LPC-induced brake-like action on macrophages by adenosine release via cellular magnesium signaling. [ABSTRACT FROM AUTHOR]

The rapid clearance of apoptotic cells (ACs), known as efferocytosis, prompts the inhibition of inflammatory responses and autoimmunity and maintains homeostatic cell turnover by controlling the release of intracellular contents. The fast clearance of ACs requires professional and nonprofessional phagocytic cells that can accurately and promptly recognize ACs and migrate towards them. Cells undergoing apoptosis alarm their presence by releasing special soluble chemotactic factors, such as lactoferrin, that act as "Find me," "Keep out," or "Stay away" signals to recruit phagocytic cells, such as macrophages or prevent granulocyte migration. Efferocytosis effectively serves to prevent damage‐associated molecular pattern release and secondary necrosis and inhibit inflammation/autoimmunity at the very first step. Since less attention has been given to the cross‐talk and balance of "Find me" and "Keep out" signals released from ACs in efferocytosis, we set out to investigate the current knowledge of the roles of "Find me" and "Keep out" signals in the efferocytosis process. [ABSTRACT FROM AUTHOR]

The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain. [ABSTRACT FROM AUTHOR]

The interaction of reactive oxygen species with cell membrane lipids is usually considered in the context of lipid peroxidation in the nonpolar component of the membrane. In this work, for the first time, data were obtained indicating that damage to human cell membranes can occur in the polar part of lysophospholipids at the interface with the aqueous environment due to free radical fragmentation (FRF) processes. FRF products, namely 1-hexadecanoyloxyacetone (PAc) and 1-octadecanoyloxyacetone (SAc), were identified in human serum, and a GC-MS method was developed to quantify PAc and SAc. The content of FRF products in serum samples of 52 healthy donors was found to be in the range of 1.98-4.75 μmol/L. A linear regression equation, C PAc&SAc (μmol/L) = 0.51 + 0.064 × years, was derived to describe the relationship between age and content of FRF products. In 70 patients with acute surgical pathology in comparison with the control group of healthy donors, two distinct clusters with different concentration levels of FRF products were revealed. The first cluster: groups of 43 patients with various localized inflammatory-destructive lesions of hollow organ walls and bacterial translocation (septic inflammation) of abdominal cavity organs. These patients showed a 1.5-1.9-fold (p = 0.012) decrease in the total concentration of PAc and SAc in serum. In the second cluster: groups of 27 patients with ischemia-reperfusion tissue damage (aseptic inflammation), - a statistically significant increase in the concentration of FRF products was observed: in 2.2-4.0 times (p = 0.0001). The obtained data allow us to further understand the role of free-radical processes in the damage of lipid molecules. FRF products can potentially be used as markers of the degree of free-radical damage of hydroxyl containing phospholipids., Competing Interests: Declaration of competing interest We are sending the manuscript (original research article) by Alexey Fedoruk, Oleg Shadyro. Irina Edimecheva, Dmitry Fedoruk, Valery Khrutskin, Leanid Kirkovsky, Viktor Sorokin, Halina Talkachova entitled « Free radical fragmentation and oxidation in the polar part of lysophospholipids: results of the study of blood serum of healthy donors and patients with acute surgical pathology » to be evaluated for publication in «Redox Biology». The authors declare that there are no conflicts of interest. The authors alone are responsible for the content and writing of the paper. All authors have read the manuscript and concur with the submission, the work has not been published elsewhere, either completely, in part, or in another form, the manuscript has not been submitted to another journal and will not be published elsewhere., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Glycogen storage disease type Ia (GSDIa) is a rare, inherited glucose-6-phosphatase-α (G6Pase-α) deficiency-induced carbohydrate metabolism disorder. Although hyperlipidaemia is a hallmark of GSDI, the extent of lipid metabolism disruption remains incompletely understood. Lipidomic analysis was performed to characterise the serum lipidome in patients with GSDIa, by including age- and sex-matched healthy controls and age-matched hypercholesterolemic controls. Metabolic control and dietary information biochemical markers were obtained from patients with GSDIa. Patients with GSDIa showed higher total serum lysophosphatidylcholine (Fold Change, FC 2.2, p < 0.0001), acyl-acyl-phosphatidylcholine (FC 2.1, p < 0.0001), and ceramide (FC 2.4, p < 0.0001) levels and bile acid (FC 0.7, p < 0.001), acylcarnitines (FC 0.7, p < 0.001), and cholesterol esters (FC 1.0, p < 0.001) than those of healthy controls, and higher di- (FC 1.1, p < 0.0001; FC 0.9, p < 0.01) and triacylglycerol (FC 6.3, p < 0.0001; FC 3.9, p < 0.01) levels than those of healthy controls and hypercholesterolemic subjects. Both total cholesterol (TC) and TG values correlated with Cer(d16:1/22:0), Cer(d18:1/20:0), Cer(d18:1/20:0(OH)), Cer(d18:1/22:0), Cer(d18:1/23:0), Cer(d18:1/24:1), Cer(d18:2/22:0), Cer(d18:2/24:1). TC also correlated with Cer(d18:1/24:0), Cer(d18:2/20:0), HexCer(d16:1/22:0), HexCer(d18:1/18:0), and Hex2Cer(d18:1/20:0). TGlevels correlated with Cer(d18:0/24:1). Alanine transaminase values correlated with Cer(d18:0/22:0), insulin with Cer(d18:1/22:1) and Cer(d18:1/24:1), and HDL with hexosylceramide (HexCer)(d18:2/23:0). These results expand on the currently known involvement of lipid metabolism in GSDIa. Circulating Cer may allow for refined dietary assessment compared with traditional biomarkers. Because specific lipid species are relatively easy to assess, they represent potential novel biomarkers of GSDIa., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

High salt (HS) intake induces hypertension and cognitive impairment. Preventive strategies include against dietary supplements. Soybean lecithin is a widely used phospholipid supplement. Lysolecithin is important in cell signaling, digestion, and absorption. This study aimed to investigate the effects of lysophosphatidylcholine containing >70% of the total phospholipids (LPC70), on hypertension and cognitive impairment induced in mice by HS intake. Mice were provided with HS solution (2% NaCl in drinking water) with or without LPC70 for 12 weeks. Blood pressure, cognitive function, and inflammatory response of intestine were determined. Hypertension and impaired object recognition memory induced by HS intake were implicated with increased inducible nitric oxide synthase in the small intestine and tau hyperphosphorylation in the prefrontal cortex. LPC70 treatment prevented cognitive impairment by suppressing inducible nitric oxide synthase and tau hyperphosphorylation. LPC70 may be valuable as a functional food component in preventing HS-induced cognitive impairment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kazuhiro Kagotani, Yuki Fujimoto, Akihito Hayashi and Ryoji Sono are employees of the Tsuji Oil Mills Corporation, an oil company. Takehiko Tsuji is the CEO of the Tsuji Oil Mills Corporation. Kuniaki Saito reports financial support and equipment, drugs, or supplies were provided by Tsuji Oil Mills Corporation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Multiple sclerosis, neuromyelitis optica, Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy are representative demyelinating diseases of the central and peripheral nervous system. Remyelination by myelin forming cells is important for functional recovery from the neurological deficits caused in the demyelinating diseases. Lysophosphatidylcholine-induced demyelination in mice is commonly used to identify and study the molecular pathways of demyelination and remyelination. However, detection of focally demyelinated lesions is difficult and usually requires sectioning of demyelinated lesions in tissues for microscopic analysis. In this review, we describe the development and application of a novel vital staining method for labeling demyelinated lesions using intraperitoneal injection of neutral red (NR) dye. NR labeling reduces the time and effort required to search for demyelinated lesions in tissues, and facilitates electron microscopic analysis of myelin structures. NR labeling also has the potential to contribute to the elucidation of pathologies in the central and peripheral nervous system and assist with identification of drug candidates that promote remyelination., Competing Interests: VThe authors declare no conflicts of interest., (2024 The Japan Society of Histochemistry and Cytochemistry.)

Phospholipids (PL) are major components of cellular membranes and changes in PL metabolism have been associated with the pathogenesis of numerous diseases. Lysophosphatidylcholine (LPC) in particular, is a comparably abundant component of oxidatively damaged tissues. LPC originates from the cleavage of phosphatidylcholine (PC) by phospholipase A 2 or the reaction of lipids with reactive oxygen species (ROS) such as HOCl. Another explanation of increased LPC concentration is the decreased re-acylation of LPC into PC. While there are also several other lysophospholipids, LPC is the most abundant lysophospholipid in mammals and will therefore be the focus of this review. LPC is involved in many physiological processes. It induces the migration of lymphocytes, fostering the production of pro-inflammatory compounds by inducing oxidative stress. LPC also "signals" via G protein-coupled and Toll-like receptors and has been implicated in the development of different diseases. However, LPCs are not purely "bad": this is reflected by the fact that the concentration and fatty acyl composition of LPC varies under different conditions, in plasma of healthy and diseased individuals, in tissues and different tumors. Targeting LPC and lipid metabolism and restoring homeostasis might be a potential therapeutic method for inflammation-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Synovial fluid (SF) from human knee joints with osteoarthritis (OA) has elevated levels of lysophosphatidylcholine (LPC) species, but their functional role is not well understood. This in vitro study was designed to test the hypothesis that various LPCs found elevated in OA SF and their metabolites, lysophosphatidic acids (LPAs), modulate the abundance of proteins and phospholipids (PLs) in human fibroblast-like synoviocytes (FLSs), with even minute chemical variations in lysophospholipids determining the extent of regulation. Cultured FLSs (n = 5–7) were treated with one of the LPC species, LPA species, IL-1β, or a vehicle. Tandem mass tag peptide labeling coupled with LC-MS/MS/MS was performed to quantify proteins. The expression of mRNA from regulated proteins was analyzed using RT-PCR. PL synthesis was determined via ESI-MS/MS, and the release of radiolabeled PLs was determined by means of liquid scintillation counting. In total, 3960 proteins were quantified using multiplexed MS, of which 119, 8, and 3 were significantly and reproducibly regulated by IL-1β, LPC 16:0, and LPC 18:0, respectively. LPC 16:0 significantly inhibited the release of PLs and the synthesis of phosphatidylcholine, LPC, and sphingomyelin. Neither LPC metabolite—LPA 16:0 nor LPA 18:0—had any reproducible effect on the levels of each protein. In conclusion, small chemical variations in LPC species can result in the significantly altered expression and secretion of proteins and PLs from FLSs. IL-1β influenced all proteins that were reproducibly regulated by LPC 16:0. LPC species are likely to modulate FLS protein expression only in more advanced OA stages with low IL-1β levels. None of the eight proteins being significantly regulated by LPC 16:0 have been previously reported in OA. However, our in vitro findings show that the CD81 antigen, calumenin, and B4E2C1 are promising candidates for further study, focusing in particular on their potential ability to modulate inflammatory and catabolic mechanisms.

This study was performed to investigate the effects of persimmon (Diospyros kaki) on high-fat diet (HFD)-induced hepatic lipotoxicity. The compounds of persimmon water extract (PWE) were identified as gallic acid, glucogallin, 1-O-Galloyl-(2-O-acetyl)-glu, and trihydroxy-octadecadienoic acid. The PWE was ingested by C57BL/6 mice with an HFD for 8 weeks. The PWE improved glucose tolerance and suppressed weight gain by inhibiting increases in the weight of liver and adipose tissues. The results of serum biomarker analysis showed that PWE suppressed biomarkers such as liver injury and dyslipidemia. In ex vivo tests, reduction of oxidative stress and improvement of mitochondrial dysfunction were confirmed in the liver of PWE groups. In a molecular study, it was confirmed that PWE decreased lipid accumulation, insulin resistance, inflammation, and apoptosis in the liver. Finally, in a metabolite analysis of liver tissue using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), it was confirmed that PWE has an effect on lipid metabolism. In particular, PWE reduced phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs). Notably, it is presumed that the reduction of lysoPCs and PCs in the PWE group is related to the improvement of liver dysfunction due to lipotoxicity. [ABSTRACT FROM AUTHOR]

Objective: We aimed to explore associations of branched-chain amino acids (BCAA) in early pregnancy with gestational diabetes mellitus (GDM), and whether high BCAAs and lipidomics markers had interactive effects on the risk of GDM. Methods: We conducted a 1:1 case-control study (n = 486) nested in a prospective cohort of pregnant women in Tianjin, China. Blood samples were collected at their first antenatal care visit (median 10 gestational weeks). Serum BCAAs, saturated fatty acids (SFA) and lysophosphatidylcholines (LPC) were measured by liquid chromatography-tandem mass spectrometry analysis. Conditional logistic regression was performed to examine associations of BCAAs with the risk of GDM. Interactions between high BCAAs and high SFA16:0 for GDM were examined using additive interaction measures. Results: High serum valine, leucine, isoleucine, and total BCAAs were associated with markedly increased risk of GDM (OR of top vs bottom tertiles: 1.91 [95% CI, 1.22-3.01]; 1.87 [1.20-2.91]; 2.23 [1.41-3.52]; 1.93 [1.23-3.02], respectively). The presence of high SFA16:0 defined as ≥ 17.1 nmol/mL (ie, median) markedly increased the ORs of high leucine alone and high isoleucine alone up to 4.56 (2.37-8.75) and 4.41 (2.30-8.43) for the risk of GDM, with significant additive interaction. After adjustment for LPCs, the ORs were greatly elevated (6.33, 2.25-17.80 and 6.53, 2.39-17.86) and the additive interactions became more significant. Conclusion: BCAAs in early pregnancy were positively associated with the risk of GDM, and high levels of leucine and isoleucine enhanced the risk association of high SFA16:0 with GDM, independent of LPCs. [ABSTRACT FROM AUTHOR]

The protein Mfsd2a (Major Facilitator Superfamily Domain Containing 2a), a specific Na+-dependent transporter of lysophosphatidylcholine (lysoPC) esterified by omega-3 polyunsaturated fatty acids (PUFA), is selectively expressed in the endothelium of brain capillaries. This review summarizes current concepts on the molecular mechanisms of its functioning in endothelial cells and the role of transported lipids in the inhibition of caveolin-dependent transcytosis and maintaining a low permeability of the blood–brain barrier (BBB). A special focus is on the Mfsd2a-mediated lysoPC transfer as it is a major route of entry into the brain and retina for docosahexaenoic acid and other omega-3 PUFA essential for the normal development and functioning of the CNS and visual system. The protective role of Mfsd2a in various CNS neuropathologies is also discussed, as well as the prospects for developing Mfsd2a-based therapeutic strategies to increase the bioavailability of essential PUFA and to deliver the drugs that do not penetrate the BBB to brain tissue. [ABSTRACT FROM AUTHOR]

Translocation of azurophil granules is pivotal for bactericidal activity of neutrophils, the first-line defense cells against pathogens. Previously, we reported that lysophosphatidylcholine (LPC), an endogenous lipid, enhances bactericidal activity of human neutrophils via increasing translocation of azurophil granules. However, the precise mechanism of LPC-induced azurophil granule translocation was not fully understood. Treatment of neutrophil with LPC significantly increased CD63 (an azurophil granule marker) surface expression. Interestingly, cytochalasin B, an inhibitor of action polymerization, blocked LPC-induced CD63 surface expression. LPC increased F-actin polymerization. LPC-induced CD63 surface expression was inhibited by both a Rho specific inhibitor, Tat-C3 exoenzyme, and a Rho kinase (ROCK) inhibitor, Y27632 which also inhibited LPC-induced F-actin polymerization. LPC induced Rho-GTP activation. NSC23766, a Rac inhibitor, however, did not affect LPC-induced CD63 surface expression. Theses results suggest a novel regulatory mechanism for azurophil granule translocation where LPC induces translocation of azurophil granules via Rho/ROCK/F-actin polymerization pathway. [ABSTRACT FROM AUTHOR]

Sepsis is predominantly initiated by bacterial infection and can cause systemic inflammation, which frequently leads to rapid death of the patient. However, this acute systemic inflammatory response requires further investigation from the perspectives of clinical judgment criteria and early treatment strategies for the relief of symptoms. Lysophosphatidylcholine (LPC) 18:0 may relieve septic symptoms, but the relevant mechanism is not clearly understood. Therefore, we aimed to assess the effectiveness of LPC as a therapeutic treatment for acute inflammation in the lung induced by lipopolysaccharide in mice. Systemic inflammation of mice was induced by lipopolysaccharide (LPS) inoculation to investigate the role of LPC in the migration and the immune response of neutrophils during acute lung injury. By employing two-photon intravital imaging of the LPS-stimulated LysM-GFP mice and other in vitro and in vivo assays, we examined whether LPC alleviates the inflammatory effect of sepsis. We also tested the effect of LPC to human neutrophils from healthy control and sepsis patients. Our data showed that LPC treatment reduced the infiltration of innate immune cells into the lung. Specifically, LPC altered neutrophil migratory patterns and enhanced phagocytic efficacy in the damaged lung. Moreover, LPC treatment reduced the release of neutrophil extracellular trap (NET), which can damage tissue in the inflamed organ and exacerbate disease. It also reduced human neutrophil migration under inflammatory environment. Our results suggest that LPC can alleviate sepsis-induced lung inflammation by regulating the function of neutrophils. These findings provide evidence for the beneficial application of LPC treatment as a potential therapeutic strategy for sepsis.

Lysophosphatidylcholine (LPC) plays a vital role in promoting jejuna morphology in broilers. However, the potential mechanism behind LPC improving the chicken jejuna morphology is unclear. Therefore, the present study was designed to reveal the important genes associated with LPC regulation in birds' jejuna. Thus, GSE94622, the gene expression microarray, was obtained from Gene Expression Omnibus (GEO). GSE94622 consists of 15 broiler jejuna samples from two LPC-treated (LPC500 and LPC1000) and the control groups. Totally 98 to 217 DEGs were identified by comparing LPC500 vs. control, LPC1000 vs. control, and LPC1000 vs. LPC500. Gene ontology (GO) analysis suggested that those DEGs were mainly involved in the one-carbon metabolic process, carbon dioxide transport, endodermal cell differentiation, the positive regulation of dipeptide transmembrane transport, cellular pH reduction, and synaptic transmission. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated the DEGs were enriched in NOD-like receptor (NLR), RIG-I-like receptor (RILR), Toll-like receptor (TLR), and necroptosis signaling pathway. Moreover, many genes, such as RSAD2, OASL, EPSTI1, CMPK2, IFIH1, IFIT5, USP18, MX1, and STAT1 might be involved in promoting the jejuna morphology of broilers. In conclusion, this study enhances our understanding of LPC regulation in jejuna morphology.

Objective To explore the alteration profile of lysophosphatidylcholine (LPC) content in donor liver with the elapse of total ischemic time and investigate its application value in the evaluation of donor liver quality. Methods A total of 100 patients who underwent liver transplantation in our hospital from June 2018 to August 2020 were enrolled in this study. Donor liver samples were collected respectively at the moment of donor liver acquisition (group A) and after reperfusion (group B). Pathomorphological scoring was performed and the tissue content of LPC was detected. The incidence of early allograft dysfunction (EAD) was used as a grouping variable. The efficacy of LPC in the evaluation of the quality of donor liver was analyzed. Results The tissue concentration of LPC in the liver samples of both group A and B was significantly higher in EAD group than non-EAD group (P < 0.05), and the concentration was higher in group B than group A. The LPC concentration in group B showed a good value in prediction for EAD (AUC=0.909, 95%CI: 0.849~ 0.969) when the cut-off value was 15 258 fg/mg. The best regression equation was Y=-7554+22.64×t-0.169 2×X0+0.000345×t× X0(Y: LPC concentration after reperfusion; t: total ischemic time; X0: LPC concentration at the moment of donor liver acquisition). The adjusted determination coefficients R2 in the modeling set and validation set were 0.944 7 and 0.915 4, respectively, which could well explain the changes of LPC and had a good prediction accuracy for LPC concentration after perfusion. Conclusion Our established prediction model well shows the changes of LPC concentration in donor liver tissue, indicates the severity of donor liver damage, and has clinical value in prediction of the occurrence of EAD.

Abstract Membrane lipids serve as substrates for the generation of numerous signaling lipids when plants are exposed to environmental stresses, and jasmonic acid, an oxidized product of 18‐carbon unsaturated fatty acids (e.g., linolenic acid), has been recognized as the essential signal in wound‐induced gene expression. Yet, the contribution of individual membrane lipids in linolenic acid generation is ill‐defined. In this work, we performed spatial lipidomic experiments to track lipid changes that occur locally at the sight of leaf injury to better understand the potential origin of linolenic and linoleic acids from individual membrane lipids. The central veins of tomato leaflets were crushed using surgical forceps, leaves were cryosectioned and analyzed by two orthogonal matrix‐assisted laser desorption/ionization mass spectrometry imaging platforms for insight into lipid spatial distribution. Significant changes in lipid composition are only observed 30 min after wounding, while after 60 min lipidome homeostasis has been re‐established. Phosphatidylcholines exhibit a variable pattern of spatial behavior in individual plants. Among lysolipids, lysophosphatidylcholines strongly co‐localize with the injured zone of wounded leaflets, while, for example, lysophosphatidylglycerol (LPG) (16:1) accumulated preferentially toward the apex in the injured zone of wounded leaflets. In contrast, two other LPGs (LPG [18:3] and LPG [18:2]) are depleted in the injured zone. Our high‐resolution co‐localization imaging analyses suggest that linolenic acids are predominantly released from PCs with 16_18 fatty acid composition along the entire leaf, while it seems that in the apex zone PG (16:1_18:3) significantly contributes to the linolenic acid pool. These results also indicate distinct localization and/or substrate preferences of phospholipase isoforms in leaf tissue.

The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism.

Albumin is the most abundant protein in blood plasma and acts as a carrier for many circulating molecules. Hypoalbuminaemia, mostly caused by either renal or liver disease or malnutrition, can perturb vascular homeostasis and is involved in the development of multiple diseases. Here we review four functions of albumin and the consequences of hypoalbuminaemia on vascular homeostasis. (i) Albumin is the main determinant of plasma colloid osmotic pressure. Hypoalbuminaemia was therefore thought to be the main mechanism for oedema in nephrotic syndrome (NS), however, experimental studies showed that intrarenal mechanisms rather than hypoalbuminaemia determine formation and, in particular, maintenance of oedema. (ii) Albumin functions as an interface between lysophosphatidylcholine (LPC) and circulating factors (lipoproteins and erythrocytes) and the endothelium. Consequently, hypoalbuminaemia results in higher LPC levels in lipoproteins and erythrocyte membrane, thereby increasing atherosclerotic properties of low-density lipoprotein and blood viscosity, respectively. Furthermore, albumin dose-dependently restores LPC-induced inhibition of vasodilation. (iii) Hypoalbuminaemia impacts on vascular nitric oxide (NO) signalling by directly increasing NO production in endothelial cells, leading to reduced NO sensitivity of vascular smooth muscle cells. (iv) Lastly, albumin binds free fatty acids (FFAs). FFAs can induce vascular smooth muscle cell apoptosis, uncouple endothelial NO synthase and decrease endothelium-dependent vasodilation. Unbound FFAs can increase the formation of reactive oxygen species by mitochondrial uncoupling in multiple cell types and induce hypertriglyceridemia in NS. In conclusion, albumin acts as an interface in the circulation and hypoalbuminaemia impairs multiple aspects of vascular function that may underlie the association of hypoalbuminaemia with adverse outcomes. However, hypoalbuminaemia is not a key to oedema in NS. These insights have therapeutic implications. [ABSTRACT FROM AUTHOR]

Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this study, we analyzed bezafibrate (BEZ) treated, streptozotocin (STZ) injected mice, which showed an improved glucose metabolism compared to untreated STZ animals. In order to identify key molecules and pathways which participate in the beneficial effects of BEZ, we studied plasma, skeletal muscle, white adipose tissue (WAT) and liver samples using non-targeted metabolomics (NMR spectroscopy), targeted metabolomics (mass spectrometry), microarrays and mitochondrial enzyme activity measurements, with a particular focus on the liver. The analysis of muscle and WAT demonstrated that STZ treatment elevated inflammatory pathways and reduced insulin signaling and lipid pathways, whereas BEZ decreased inflammatory pathways and increased insulin signaling and lipid pathways, which can partly explain the beneficial effects of BEZ on glucose metabolism. Furthermore, lysophosphatidylcholine levels were lower in the liver and skeletal muscle of STZ mice, which were reverted in BEZ-treated animals. BEZ also improved circulating and hepatic glucose levels as well as lipid profiles. In the liver, BEZ treatment reduced elevated fumarate levels in STZ mice, which was probably due to a decreased expression of urea cycle genes. Since fumarate has been shown to participate in glucotoxic pathways, our data suggests that BEZ treatment attenuates the urea cycle in the liver, decreases fumarate levels and, in turn, ameliorates glucotoxicity and reduces insulin resistance in STZ mice. [ABSTRACT FROM AUTHOR]

Lysophosphatidylcholine (LPC), the active metabolite of palmitate, triggers hepatocyte death by activating endoplasmic reticulum stress and JNK signalling‐mediated lipoapoptosis. However, LPC‐induced cytotoxicity in hepatocytes is not well understood. Here, we found for the first time that LPC‐induced cell rounding occurred prior to apoptosis. LPC‐induced rounding of cells reduced both cell–extracellular matrix (ECM) adhesion and cell–cell junctions, which promoted detachment‐induced apoptosis (defined as anoikis) in hepatocytes. Further study revealed that LPC altered cellular morphology and cell adhesion by inhibiting integrin and cadherin signalling‐mediated microfilament polymerization. We also found that ECM supplementation and microfilament cytoskeletal stabilization inhibited LPC‐induced hepatocyte death by attenuating anoikis. Our data indicate a novel cytotoxic process and signalling pathway induced by LPC. [ABSTRACT FROM AUTHOR]

• Lipid metabolism imbalance in HIV-infected patients is probed by HPLC–MS/MS. • Lysophosphatidylcholines (LPCs) and acylcarnitines (ACs) are identified as biomarkers. • A robust and sensitive method of LPC and AC analysis in blood serum is developed. • Multi-LPC and AC indices enable discrimination of different HIV infections & controls. Human immunodeficiency virus (HIV) infection and highly active antiretroviral therapy use are associated with the disruption of lipid and glucose metabolism. Herein, a sensitive and robust high-performance liquid chromatography–tandem mass spectrometry method for the quantitation of lysophosphatidylcholines (LPCs) and acylcarnitines (ACs) in human blood serum was developed and validated to investigate them as markers of metabolic disorders in HIV-infected patients. Under optimal extraction and detection conditions, the lower limits of quantification reached 5 ng/mL (LPCs) and 0.1 ng/mL (ACs), and precision and accuracy for both intra- and inter-day analyses were generally below 15%. Serum samples were stable for at least six months when stored at − 80 °C and for at least 12 h when stored at 4 °C or 25 °C. We investigated inter-group differences and associations between the biomarkers and observed a particular volatility trend of LPCs and ACs for HIV-infected patients with metabolic disorders. Thus, the developed method can be used for the rapid and sensitive quantitation of LPCs and ACs in vivo to further appraise the process of HIV infection, evaluate intervening measures, conduct mechanistic investigations, and further study the utility of LPCs and ACs as biomarkers of HIV infection coupled with metabolic disorders. [ABSTRACT FROM AUTHOR]

Mouse chow supplemented with lysophosphatidylcholine with oleic acid at sn-1 and a hydroxyl group at sn-2 (LysoPC 18:1) increased LysoPC 18:1 in tissue of the jejunum of LDL receptor (LDLR)-null mice by 8.9 ± 1.7-fold compared with chow alone. Western diet (WD) contained dramatically less phosphatidylcholine 18:1 or LysoPC 18:1 compared with chow, but feeding WD increased LysoPC 18:1 in the jejunum by 7.5 ± 1.4-fold compared with chow. Feeding LysoPC 18:1 or feeding WD increased oxidized phospholipids in the jejunum by 5.2 ± 3.0-fold or 8.6 ± 2.2-fold, respectively, in LDLR-null mice (P < 0.0004), and 2.6 ± 1.5-fold or 2.4 ± 0.92-fold, respectively, in WT C57BL/6J mice (P < 0.0001). Adding 0.06% by weight of a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) decreased LysoPC 18:1 in the jejunum of LDLR-null mice on both diets (P < 0.0001), and prevented the increase in oxidized phospholipids in the jejunum in LDLR-null and WT mice on both diets (P < 0.008). Tg6F decreased inflammatory cells in the villi of the jejunum, decreased dyslipidemia, and decreased systemic inflammation in LDLR-null and WT mice on both diets. We conclude that Tg6F reduces diet-induced inflammation by reducing the content of unsaturated LysoPC and oxidized phospholipids in the jejunum of mice.

Chlorpromazine hydrochloride (CH) and N -acetyl- p -amino-phenoltriptolide (APAP) are typical acentral dopamine receptor antagonists and antipyretic analgesics in clinical applications, respectively. However, it has been reported that these 2 drugs could cause liver damage. Lysophosphatidylcholines (LPCs) have multiple physiological functions and are metabolized primarily in the liver, where it undergoes significant changes when the liver is damaged. In the study, 15 LPCs in the rat serum with CH- and APAP-induced liver injury were quantified based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry, and multivariate statistical analyses including principal component analysis (PCA) and orthogonal partial least squares discriminate analysis (OPLS-DA) were combined to understand CH- and APAP-induced liver injury from the perspective of LPC metabolic profiling. The quantitative results showed that there were significant changes in 10 LPCs and 5 LPCs after CH- and APAP-administration, separately. The results of PCA and OPLS-DA indicated that CH- and APAP-induced liver injury could be well distinguished by the LPC metabolic profiling, and 7 LPCs and 1 LPC biomarkers that could characterize CH- and APAP-induced liver damage in turn had been screened. This study will not only provide a new perspective for the clinical diagnosis of CH- and APAP-induced liver injury, but also offer a reference for further study of their hepatotoxicity mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Skin‐brightening agents prevent melanogenesis and reduce melanin production. However, a lower melanin content leads to weaker protection against sunlight. In this study, we evaluated the effect of lysophosphatidylcholine (LPC) and its commercial‐grade product, Lysofix Dry™ (LD), on heat shock protein 70 (HSP70) expression in epidermal cells and their anti‐skin photoaging effect against ultraviolet B (UVB) and blue light. Methods: The HSP70 induction was detected using ELISA. To confirm the inhibition of melanin synthesis by LPC or LD, the melanin content assay and gene expression were analyzed. Cell viability was assessed to verify whether LPC or LD prevents photo‐induced skin damage. The split‐face test was performed to confirm skin‐brightening effect of LD. Cream formulation with 2% of LD and placebo were used for 8 weeks, and skin brightness (L) was measured with chromameter (CR‐400, Konica Minolta). Results: LPC‐ and LD‐induced HSP70 expression in epidermal cells. LPC and LD effectively suppressed melanogenesis provoked by α‐MSH in B16 cells. They also inhibited the mRNA transcription of MITF and tyrosinase under blue light irradiation. LD increased the viability of B16 and HaCaT cells after UVB and blue light irradiation in vitro. The cream containing 2% LD increased ΔL by 1.7 after 8 weeks of use, whereas the placebo led to an increase of 0.7. Conclusion: LPC and LD were effective in suppressing melanogenesis and enhancing cell viability under UVB and blue light via HSP70 expression. Thus, they can be considered as potent skin‐brightening agents with protective effects against skin photoaging. [ABSTRACT FROM AUTHOR]

The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published. Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event. A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatography–mass spectrometry. A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase. Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events. [ABSTRACT FROM AUTHOR]

Being born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p < 0.01) and restored in CLM fed animals (p < 0.05). LysoPC(18:2) levels at PN42 correlated inversely with adult blood glucose levels. These data indicate that early-life LysoPC(18:2) blood levels may predict adult blood glucose levels and are affected by a postnatal diet with an adapted lipid droplet structure in IUGR offspring. [ABSTRACT FROM AUTHOR]

Phospholipids (PL) are converted into lipid biomarkers by the action of phospholipases and reactive oxygen species (ROS), which are activated or released under certain physiological and pathophysiological conditions. Therefore, the in vivo concentration of such lipid biomarkers [e.g., lysophospholipids (LPLs)] is altered in humans and animals under different conditions such as inflammation, stress, medication, and nutrition. LPLs are particularly interesting because they are known to possess pro- and anti-inflammatory properties and may be generated by two different pathways: either by the influence of phospholipase A2 or by different reactive oxygen species that are generated in significant amounts under inflammatory conditions. Both lead to the cleavage of unsaturated acyl residues. This review provides a short summary of the mechanisms by which lipid biomarkers are generated under in vitro and in vivo conditions. The focus will be on lysophosphatidylcholine (LPC) because usually, this is the LPL species which occurs in the highest concentration and is, thus, easily detectable by chromatographic and spectroscopic methods. Finally, the effects of lipid biomarkers as signaling molecules and their roles in different human and animal pathologies such as infertility, cancer, atherosclerosis, and aging will be shortly discussed. [ABSTRACT FROM AUTHOR]

Introduction: Vascular endothelial cell disorders are closely related to cardiovascular disease (CVD) and pulmonary diseases. Abnormal lipid metabolism in the endothelium leads to changes in cell signalling, and the expression of genes related to immunity and inflammation. It is therefore important to investigate the pathophysiology of vascular endothelial disorders in terms of lipid metabolism, using a disease model of endothelium. Methods: Human induced pluripotent stem cell-derived endothelial cells (iECs) were cultured on a matrigel to form an iEC network. Lipids in the iEC network were investigated by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) analysis. Ion fragments obtained by mass spectrometry were analysed using an infusion method, involving precursor ion scanning with fragment ion. Results: The MALDI TOF IMS analysis revealed co-localized intensity of peaks at m/z 592.1 and 593.1 in the iEC network. Tandem mass spectrometry (MS/MS) analysis by MALDI-imaging, in conjunction with precursor ion scanning using an infusion method with lipid extracts, identified that these precursor ions were lysophosphatidylcholine (LPC) (22:5) and its isotype. Conclusion: The MALDI-imaging analysis showed that LPC (22:5) was abundant in an iEC network. As an in vitro test model for disease and potential therapy, present analysis methods using MALDI-imaging combined with, for example, mesenchymal stem cells (MSC) to a disease derived iEC network may be useful in revealing the changes in the amount and distribution of lipids under various stimuli.

Acne is one of the most common dermatological conditions, but the details of its pathology are unclear, and current management regimens often have adverse effects. Cutibacterium acnes is known as a major acne-associated bacterium that derives energy from lipase-mediated sebum lipid degradation. C. acnes is commensal, but lipase activity has been observed to differ among C. acnes types. For example, higher populations of the type IA strains are present in acne lesions with higher lipase activity. In the present study, we examined a conserved lipase in types IB and II that was truncated in type IA C. acnes strains. Closed, blocked, and open structures of C. acnes ATCC11828 lipases were elucidated by X-ray crystallography at 1.6–2.4 Å. The closed crystal structure, which is the most common form in aqueous solution, revealed that a hydrophobic lid domain shields the active site. By comparing closed, blocked, and open structures, we found that the lid domain-opening mechanisms of C. acnes lipases (CAlipases) involve the lid-opening residues, Phe-179 and Phe-211. To the best of our knowledge, this is the first structure-function study of CAlipases, which may help to shed light on the mechanisms involved in acne development and may aid in future drug design.

Aims: Allergic airway disease manifestation is induced by lysophosphatidylcholine (LPC) through CD1d-restricted Natural killer T (NKT) cells. Choline chloride (ChCl) and LPC both have the “choline” moiety in their structure and this may interplay the effect in allergic airway disease pathway. Main methods: To test the hypothesis, mice were sensitized with cockroach extract (CE); challenged with CE or exposed to LPC and were given ChCl 1hr later. Key findings: A significant increase in Airway hyperresponsiveness (AHR), total and differential cell count, Th2 cytokines, 8-isoprostanes level in bronchoalveolar lavage fluid (BALF) and inflammation score based on lung histology were observed on challenge with CE or exposure to LPC (p ​

Phospholipids (PL) are converted into lipid biomarkers by the action of phospholipases and reactive oxygen species (ROS), which are activated or released under certain physiological and pathophysiological conditions. Therefore, the in vivo concentration of such lipid biomarkers [e.g., lysophospholipids (LPLs)] is altered in humans and animals under different conditions such as inflammation, stress, medication, and nutrition. LPLs are particularly interesting because they are known to possess pro- and anti-inflammatory properties and may be generated by two different pathways: either by the influence of phospholipase A2 or by different reactive oxygen species that are generated in significant amounts under inflammatory conditions. Both lead to the cleavage of unsaturated acyl residues. This review provides a short summary of the mechanisms by which lipid biomarkers are generated under in vitro and in vivo conditions. The focus will be on lysophosphatidylcholine (LPC) because usually, this is the LPL species which occurs in the highest concentration and is, thus, easily detectable by chromatographic and spectroscopic methods. Finally, the effects of lipid biomarkers as signaling molecules and their roles in different human and animal pathologies such as infertility, cancer, atherosclerosis, and aging will be shortly discussed.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD.

Summary: Obstructive sleep apnoea (OSA) is prevalent in obese women with gestational diabetes mellitus (GDM). The present pilot study explored associations between OSA severity and metabolites in women with GDM. A total of 81 obese women with diet‐controlled GDM had OSA assessment (median gestational age [GA] 29 weeks). The metabolic profile was assayed from fasting serum samples via liquid chromatography–mass spectrometry (LC‐MS) using an untargeted approach. Metabolites were extracted and subjected to an Agilent 1,290 UPLC coupled to an Agilent 6,545 quadrupole time‐of‐flight (Q‐TOF) MS. Data were acquired using electrospray ionisation in positive and negative ion modes. The raw LC‐MS data were processed using the OpenMS toolkit to detect and quantify features, and these features were annotated using the Human Metabolite Database. The feature data were compared with OSA status, apnea–hypopnea index (AHI), body mass index (BMI) and GA using "limma" in R. Correlation analyses of the continuous covariates were performed using Kendall's Tau test. The p values were adjusted for multiple testing using the Benjamini–Hochberg false discovery rate correction. A total of 42 women (51.8%) had OSA, with a median AHI of 9.1 events/hr. There were no significant differences in metabolomics profiles between those with and without OSA. However, differential analyses modelling in GA and BMI found 12 features that significantly associated with the AHI. These features could be annotated to oestradiols, lysophospholipids, and fatty acids, with higher levels related to higher AHI. Metabolites including oestradiols and phospholipids may be involved in pathogenesis of OSA in pregnant women with GDM. A targeted approach may help elucidate our understanding of their role in OSA in this population. [ABSTRACT FROM AUTHOR]

The altered levels of phospholipids (PLs) and lysophospholipids (LPLs) in prostate cancer (CaP) and benign tissues in our previous findings prompted us to explore PLs and LPLs as potential biomarkers for CaP. Urinary lipidomics has attracted increasing attention in clinical diagnostics and prognostics for CaP. In this study, 31 prostate tissues obtained from radical prostatectomy were assessed using high‐resolution matrix‐assisted laser desorption/ionization imaging mass spectrometry (HR‐MALDI‐IMS). Urine samples were collected after digital rectal examination (DRE), and urinary lipids were extracted using the acidified Bligh‐Dyer method. The discovery set comprised 75 patients with CaP and 44 with benign prostatic hyperplasia (BPH) at Kyoto University Hospital; the validation set comprised 74 patients with CaP and 59 with BPH at Osaka University Hospital. Urinary lipidomic screening was performed using MALDI time‐of‐flight MS (MALDI‐TOF/MS). The levels of urinary lysophosphatidylcholine (LPC) and phosphatidylcholines (PCs) were compared between the CaP and BPH groups. The (PC [34:2] + PC [34:1])/LPC (16:0) ratio was significantly higher (P <.001) in CaP tissues than in benign epithelial tissues. The urinary PCs/LPC ratio was significantly higher (P <.001) in the CaP group than in the BPH group in the discovery and validation sets. [ABSTRACT FROM AUTHOR]