Search Results (29)

Gibberella root rot (GRR), caused by Fusarium graminearum, is one of the major threats to maize production. However, the mechanism underlying maize’s response to GRR is not fully understood. Multi-omics study incorporating metabolomics reveals insights into maize–pathogen interactions. Using metabolomics and mass spectrometry imaging (MSI), maize inbred lines with GRR resistance (W438) and susceptibility (335M) were deployed to characterize specific metabolites associated with GRR. Analysis of significantly altered metabolites suggested that glycerophospholipid metabolism was highly associated with GRR resistance or susceptibility. Furthermore, the distinct accumulation of lysophosphatidylethanolamine (lysoPE) and lysophosphatidylcholine (lysoPC) from glycerophospholipid metabolism, along with the significant up-regulation of phospholipase (PLA) gene in the susceptible line, suggested that high levels of lysoPC and lysoPE contributed to GRR susceptibility. Meanwhile, genes encoding lysophospholipase (LPLA), the detoxification enzymes of lysoPC, were significantly activated in both genotypes. However, the significantly higher expression of LPLAs in the resistant line corresponded to a significant increase in the content of non-toxic sn-glycero-3-phosphocholine, whereas this increase was not observed in the susceptible line. MSI analysis revealed the involvement of other potential phospholipids in GRR susceptibility. Taken together, maintaining an appropriate concentration of lysophospholipids is crucial for their role in the signaling pathway that triggers GRR resistance without causing damage to maize roots. Full article

Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1–6). The ATX–LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX–LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment. Full article

Lysophosphatidic acid (LPA) is a lipid mediator that binds to G-protein-coupled receptors, eliciting a wide variety of responses in mammalian cells. Lyso-phospholipids generated via phospholipase A₂ (PLA₂) can be converted to LPA by a lysophospholipase D (lyso-PLD). Secreted lyso-PLDs have been studied in more detail than membrane-localized lyso-PLDs. This study utilized in vitro enzyme assays with fluorescent substrates to examine LPA generation in membranes from multiple mammalian cell lines (PC12, rat pheochromocytoma; A7r5, rat vascular smooth muscle; Rat-1, rat fibroblast; PC-3, human prostate carcinoma; and SKOV-3 and OVCAR-3, human ovarian carcinoma). The results show that membranes contain a lyso-PLD activity that generates LPA from a fluorescent alkyl-lyso-phosphatidylcholine, as well as from naturally occurring acyl-linked lysophospholipids. Membrane lyso-PLD and PLD activities were distinguished by multiple criteria, including lack of effect of PLD2 over-expression on lyso-PLD activity and differential sensitivities to vanadate (PLD inhibitor) and iodate (lyso-PLD inhibitor). Based on several lines of evidence, including siRNA knockdown, membrane lyso-PLD is distinct from autotaxin, a secreted lyso-PLD. PC-3 cells express GDE4 and GDE7, recently described lyso-PLDs that localize to membranes. These findings demonstrate that membrane-associated lyso-D activity, expressed by multiple mammalian cell lines, can contribute to LPA production. Full article

Over the past few decades, many current uses for cannabinoids have been described, ranging from controlling epilepsy to neuropathic pain and anxiety treatment. Medicines containing cannabinoids have been approved by both the FDA and the EMA for the control of specific diseases for which there are few alternatives. However, the molecular-level mechanism of action of cannabinoids is still poorly understood. Recently, cannabinoids have been shown to interact with autotaxin (ATX), a secreted lysophospholipase D enzyme responsible for catalyzing lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a pleiotropic growth factor that interacts with LPA receptors. In addition, a high-resolution structure of ATX in complex with THC has recently been published, accompanied by biochemical studies investigating this interaction. Due to their LPA-like structure, endocannabinoids have been shown to interact with ATX in a less potent manner. This finding opens new areas of research regarding cannabinoids and endocannabinoids, as it could establish the effect of these compounds at the molecular level, particularly in relation to inflammation, which cannot be explained by the interaction with CB1 and CB2 receptors alone. Further research is needed to elucidate the mechanism behind the interaction between cannabinoids and endocannabinoids in humans and to fully explore the therapeutic potential of such approaches. Full article

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A₂ that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A₂ IIA (sPLA₂-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA₂-IIA levels together with eicosanoids in the sera of COVID patients. sPLA₂ could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A₂, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA₂-IIA in COVID-19-associated coagulopathy (CAC). Full article

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. Full article

Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX–LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Additionally, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. Therefore, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX^−/−) to observe stroke outcomes in a mouse stroke model to analyze the role of endothelial ATX. The AR2 probe and Evans Blue staining were used to perform the ATX activity and vascular permeability assays, respectively. Laser speckle imaging was used to observe the cerebral blood flow following stroke. In this study, we observed that stroke outcomes were alleviated with the endothelial deletion of ATX. Permeability and infarct volume were reduced in ERT2 ATX^−/− mice compared to ischemia–reperfusion (I/R)-only mice. In addition, the cerebral blood flow was retained in ERT2 ATX^−/− compared to I/R mice. The outcomes in the stroke model are alleviated due to the limited LPA concentration, reduced ATX concentration, and ATX activity in ERT2 ATX^−/− mice. This study suggests that endothelial-specific ATX leads to increased LPA in the brain vasculature following ischemic–reperfusion and ultimately disrupts vascular permeability, resulting in adverse stroke outcomes. Full article

Neointimal hyperplasia is characterized by a loss of the contractile phenotype of vascular smooth muscle cells (VSMCs). Our group has recently shown that VSMC proliferation and migration are mediated by lysophosphatidic acid (LPA) during restenosis, but the role of autotaxin (ATX; lysophospholipase D), which produces LPA, remains unclear. Endothelial denudation of the mouse carotid artery was performed to induce neointimal hyperplasia, and the extent of damage caused by the ATX-LPA axis was assessed in VSMCs. We observed the upregulation of ATX activity (p < 0.0002) in the injured carotid artery using an AR2 probe fluorescence assay. Further, the tissue carotid LPA levels were elevated 2.7-fold in carotid vessels, augmenting neointimal hyperplasia. We used an electrical cell–substrate impedance sensor (ECIS) to measure VSMC proliferation and migration. Treatment with an ATX inhibitor (PF8380) or LPA receptor inhibitor (Ki16425) attenuated VSMC proliferation (extracellular signal-regulated kinases) activity and migration in response to recombinant ATX. Indeed, PF8380 treatment rescued the aggravated post-wire injury neointima formation of carotid arteries. The upregulation of ATX following vessel injury leads to LPA production in VSMCs, favoring restenosis. Our observations suggest that inhibition of the ATX-LPA axis could be therapeutically targeted in restenosis to minimize VSMC phenotypic modulation and inflammation after vascular injury. Full article

Lysophosphatidylcholine (LPC) is a bioactive lipid that modulates macrophage polarization during immune responses, inflammation, and tissue remodeling. Patatin-like phospholipase domain containing protein 7 (PNPLA7) is a lysophospholipase with a preference for LPC. However, the role of PNPLA7 in macrophage polarization as an LPC hydrolase has not been explored. In the current study, we found that PNPLA7 is highly expressed in naïve macrophages and downregulated upon lipopolysaccharide (LPS)-induced polarization towards the classically activated (M1) phenotype. Consistently, overexpression of PNPLA7 suppressed the expression of proinflammatory M1 marker genes, including interleukin 1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and tumor necrosis factor α (TNF-α), whereas knockdown of PNPLA7 augmented the inflammatory gene expression in LPS-challenged macrophages. PNPLA7 overexpression and knockdown increased and decreased Sirtuin1 (SIRT1) mRNA and protein levels, respectively, and affected the acetylation of the nuclear factor-kappa B (NF-κB) p65 subunit, a key transcription factor in M1 polarization. In addition, the levels of phosphorylated p38 mitogen-activated protein kinase (MAPK) were suppressed and enhanced by PNPLA7 overexpression and knockdown, respectively. Taken together, these findings suggest that PNPLA7 suppresses M1 polarization of LPS-challenged macrophages by modulating SIRT1/NF-κB- and p38 MAPK-dependent pathways. Full article

Autotaxin (ATX), the protein product of Ectonucleotide Pyrophosphatase Phosphodiesterase 2 (ENPP2), is a secreted lysophospholipase D (lysoPLD) responsible for the extracellular production of lysophosphatidic acid (LPA). ATX-LPA pathway signaling participates in several normal biological functions, but it has also been connected to cancer progression, metastasis and inflammatory processes. Significant research has established a role in breast cancer and it has been suggested as a therapeutic target and/or a clinically relevant biomarker. Recently, ENPP2 methylation was described, revealing a potential for clinical exploitation in liquid biopsy. The current review aims to gather the latest findings about aberrant signaling through ATX-LPA in breast cancer and discusses the role of ENPP2 expression and epigenetic modification, giving insights with translational value. Full article

Black soldier fly larvae have gained popularity as an organic waste bio-conversional tool and fodder protein replacement in recent decades. It can consume all kinds of animal feces, kitchen waste and agricultural waste with great efficiency and transform them into high-value insect protein, fatty acids, and amino acids, which makes the larva a good substitute for costly fish meal and bean pulp in animal diets. However, excess chitin in the larva skin limits its application as an animal feed additive, consequently, employing fermentation with zymocytes to remove the chitin is necessary. In this study, we raised black soldier fly larvae (BSFL) with different carbon sources, such as chicken feces, straws and glucose, and examined the growth condition; we applied Bacillus subtilis and Aspergillus niger to co-ferment BSFL paste to analyze its nutrition changes. Data revealed that among the four kinds of cultures, the body weight of the corn powder group increased most rapidly; the wood chip group was the most underweight; however, it increased faster than others before day 4, and contained the least fat. Label-free quantitative proteomic analysis revealed that the expression of multiple enzymes from B. subtilis and A. niger involved in polysaccharide hydrolysis, amino acid biosynthesis and fatty acid metabolism, such as peptidase of S8 family, maltogenic α-amylase, oligo-1,6-glucosidase and lysophospholipase like protein changed significantly compared to the control group. Production detection showed that free amino acids, acid-soluble proteins, and short-chain fatty acids increased after fermentation; 13 out of 17 amino acids were increased and total free amino acids were increased from 0.08 g/100 g to 0.3 g/100 g; organic acids increased by 4.81 to 17 fold through fermentation, respectively; the actual protein content declined from 3.03 g/100 g to 1.81 g/100 g, the peptide content increased from 1.3 g/100 g to 2.46 g/100 g, the chitin degradation rate was 40.3%, and fat decreased 30% (p < 0.05). These findings might provide important information for future applications of black soldier fly larvae in different carbon waste recycling measures and material for animal feed/organic fertilizer after fermentation. Full article

Autotaxin (ATX) is an enzymatic with lysophospholipase D (lysoPLD) activity. We investigated the role of ATX in high glucose (HG)-induced human retinal pigment epithelial (ARPE-19) cells to explore the pathogenesis of diabetic retinopathy (DR). We performed a quantitative real-time polymerase chain reaction, Western blotting, immunocytochemistry, enzyme-linked immunosorbent assay, cell permeability assay, and transepithelial electrical resistance measurement in HG-induced ARPE-19 cells and compared their results with those of normal glucose and osmotic pressure controls. ATX expression and its lysoPLD activity, barrier function, and expression of vascular endothelial growth factor receptors VEGFR-1 and VEGFR-2 were downregulated, while fibrotic responses, cytoskeletal reorganization, and transforming growth factor-β expression were upregulated, in the HG group. Our results suggest that HG induces intracellular ATX downregulation, barrier dysfunction, and fibrosis, which are involved in early DR and can be targeted for DR treatment. Full article

Lysophosphatidic acid (LPA) is a natural bioactive phospholipid with pleiotropic activities affecting multiple tissues, including bone. LPA exerts its biological functions by binding to G-protein coupled LPA receptors (LPA_1-6) to stimulate cell migration, proliferation, and survival. It is largely produced by autotaxin (ATX), a secreted enzyme with lysophospholipase D activity that converts lysophosphatidylcholine (LPC) into active LPA. Beyond its enzymatic activity, ATX serves as a docking molecule facilitating the efficient delivery of LPA to its specific cell surface receptors. Thus, LPA effects are the result of local production by ATX in a given tissue or cell type. As a consequence, the ATX/LPA axis should be considered as an entity to better understand their roles in physiology and pathophysiology and to propose novel therapeutic strategies. Herein, we provide not only an extensive overview of the relevance of the ATX/LPA axis in bone cell commitment and differentiation, skeletal development, and bone disorders, but also discuss new working hypotheses emerging from the interplay of ATX/LPA with well-established signaling pathways regulating bone mass. Full article

Although metastases are the principal cause of cancer-related deaths, the molecular aspects of the role of stromal cells in the establishment of the metastatic niche remain poorly understood. One of the most prevalent sites for cancer metastasis is the lungs. According to recent research, lung stromal cells such as bronchial epithelial cells and resident macrophages secrete autotaxin (ATX), an enzyme with lysophospholipase D activity that promotes cancer progression. In fact, several studies have shown that many cell types in the lung stroma could provide a rich source of ATX in diseases. In the present study, we sought to determine whether ATX derived from alveolar type II epithelial (ATII) pneumocytes could modulate the progression of lung metastasis, which has not been evaluated previously. To accomplish this, we used the B16-F10 syngeneic melanoma model, which readily metastasizes to the lungs when injected intravenously. Because B16-F10 cells express high levels of ATX, we used the CRISPR-Cas9 technology to knock out the ATX gene in B16-F10 cells, eliminating the contribution of tumor-derived ATX in lung metastasis. Next, we used the inducible Cre/loxP system (Sftpc-CreER^T2/Enpp2^fl/fl) to generate conditional knockout (KO) mice in which ATX is specifically deleted in ATII cells (i.e., Sftpc-KO). Injection of ATX-KO B16-F10 cells into Sftpc-KO or Sftpc-WT control littermates allowed us to investigate the specific contribution of ATII-derived ATX in lung metastasis. We found that targeted KO of ATX in ATII cells significantly reduced the metastatic burden of ATX-KO B16-F10 cells by 30% (unpaired t-test, p = 0.028) compared to Sftpc-WT control mice, suggesting that ATX derived from ATII cells could affect the metastatic progression. We detected upregulated levels of cytokines such as IFNγ (unpaired t-test, p < 0.0001) and TNFα (unpaired t-test, p = 0.0003), which could favor the increase in infiltrating CD8⁺ T cells observed in the tumor regions of Sftpc-KO mice. Taken together, our results highlight the contribution of host ATII cells as a stromal source of ATX in the progression of melanoma lung metastasis. Full article