• Benzoxaboroles
• Bioisosteric replacement
• Boron
• Boronic acid
• Drug design
• Phosphate

• Phosphorus
• Boron
• Phosphates
• Drug Design
• Boronic Acids

• Epitranscriptomics
• Methyltransferases
• YTHDC
• m5C
• m6A

• Lysophosphatidylcholines
• Lysophospholipids/metabolism
• Medical Marijuana
• Receptors, Lysophosphatidic Acid/metabolism
• Dronabinol/antagonists & inhibitors

• EMBL
• Marie Skłodowska-Curie Actions

The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.

• KAI1/CD82
• Autotaxin
• Lysophosphatidic acid
• Pancreatic cancer
• Liver cancer

Calcified aortic valve disease (CAVD) is the most common valvular cardiovascular disease with increasing incidence and mortality. The primary treatment for CAVD is surgical or transcatheter aortic valve replacement and there remains a lack of effective drug treatment. Recently, lipoprotein (a) (Lp(a)) has been considered to play a crucial role in CAVD pathophysiology. Multiple studies have shown that Lp(a) represents an independent risk factor for CAVD. Moreover, Lp(a) mediates the occurrence and development of CAVD by affecting aortic valve endothelial dysfunction, indirectly promoting foam cell formation through oxidized phospholipids (OxPL), inflammation, oxidative stress, and directly promotes valve calcification. However, there is a lack of clinical trials with Lp(a) reduction as a primary endpoint. This review aims to explore the relationship and mechanism between Lp(a) and CAVD, and focuses on the current drugs that can be used as potential therapeutic targets for CAVD.

• National Natural Science Foundation of China

• Autotaxin
• anticancer drug
• carbazole derivatives
• cytotoxicity
• molecular docking
• phosphodiesterase inhibitor.

• Autotaxin
• Insulin resistance
• Liver fibrosis
• Lysophosphatidic acid
• Lysophosphatidic acid receptors
• Obesity

• Adipocytes/physiology
• Animals
• Humans
• Insulin Resistance/physiology
• Liver Cirrhosis/blood
• Liver Cirrhosis/pathology
• Lysophosphatidylcholines/metabolism
• Lysophospholipids/blood
• Lysophospholipids/metabolism
• Models, Animal
• Obesity/blood
• Obesity/pathology
• Phosphoric Diester Hydrolases/metabolism
• Receptors, Lysophosphatidic Acid/metabolism
• Signal Transduction/physiology

We previously discovered that tetracyclines increase the expression of lipid phosphate phosphatases at the surface of cells. These enzymes degrade circulating lysophosphatidate and therefore doxycycline increases the turnover of plasma lysophosphatidate and decreases its concentration. Extracellular lysophosphatidate signals through six G protein-coupled receptors and it is a potent promoter of tumor growth, metastasis and chemo-resistance. These effects depend partly on the stimulation of inflammation that lysophosphatidate produces.

In this work, we used a syngeneic orthotopic mouse model of breast cancer to determine the impact of doxycycline on circulating lysophosphatidate concentrations and tumor growth. Cytokine/chemokine concentrations in tumor tissue and plasma were measured by multiplexing laser bead technology. Leukocyte infiltration in tumors was analyzed by immunohistochemistry. The expression of IL-6 in breast cancer cell lines was determined by RT-PCR. Cell growth was measured in Matrigel™ 3D culture. The effects of doxycycline on NF-κB-dependent signaling were analyzed by Western blotting.

Doxycycline decreased plasma lysophosphatidate concentrations, delayed tumor growth and decreased the concentrations of several cytokines/chemokines (IL-1β, IL-6, IL-9, CCL2, CCL11, CXCL1, CXCL2, CXCL9, G-CSF, LIF, VEGF) in the tumor. These results were compatible with the effects of doxycycline in decreasing the numbers of F4/80⁺ macrophages and CD31⁺ blood vessel endothelial cells in the tumor. Doxycycline also decreased the lysophosphatidate-induced growth of breast cancer cells in three-dimensional culture. Lysophosphatidate-induced Ki-67 expression was inhibited by doxycycline. NF-κB activity in HEK293 cells transiently expressing a NF-κB-luciferase reporter vectors was also inhibited by doxycycline. Treatment of breast cancer cells with doxycycline also decreased the translocation of NF-κB to the nucleus and the mRNA levels for IL-6 in the presence or absence of lysophosphatidate.

These results contribute a new dimension for understanding the anti-inflammatory effects of tetracyclines, which make them potential candidates for adjuvant therapy of cancers and other inflammatory diseases.

The online version of this article (doi:10.1186/s12943-017-0607-x) contains supplementary material, which is available to authorized users.

• Autotaxin
• Inflammatory cyotokines
• Macrophage infiltration
• Peripheral blood mononuclear cells
• Tetracyclines

• Animals
• Biomarkers
• Colon/metabolism
• Computational Biology/methods
• Diet, High-Fat
• Gene Expression Profiling
• Genetic Association Studies
• Genome-Wide Association Study
• Insulin/blood
• Leptin/blood
• Male
• Mice
• Mice, Inbred C57BL
• Phenotype

• SRC program
• Mid-Career Research Program

Stress arises from an external demand placed on an organism that triggers physiological, cognitive and behavioural responses in order to cope with that request. It is thus an adaptive response useful for the survival of an organism. The objective of this study was to identify and characterize global changes in gene expression in the hippocampus in response to acute stress stimuli, by employing a mouse model of short-term restraint stress. In our experimental design mice were subjected to a one time exposure of restraint stress and the regulation of gene expression in the hippocampus was examined 3, 12 and 24 hours thereafter. Microarray analysis revealed that mice which had undergone acute restraint stress differed from non-stressed controls in global hippocampal transcriptional responses. An up-regulation of transcripts contributing directly or indirectly to neurogenesis and neuronal protection including, Ttr, Rab6, Gh, Prl, Ndufb9 and Ndufa6, was observed. Systems level analyses revealed a significant enrichment for neurogenesis, neuron morphogenesis- and cognitive functions-related biological process terms and pathways. This work further supports the hypothesis that acute stress mediates a positive action on the hippocampus favouring the formation and the preservation of neurons, which will be discussed in the context of current data from the literature.

• acute
• hippocampus
• neurogenesis
• neuroprotection
• restraint stress

• autotaxin
• calcific aortic valve disease
• calcific aortic valve stenosis
• lipoprotein(a)
• oxidized phospholipids

• autotaxin
• adipokines
• lysophosphatidic acid
• obesity
• insulin resistance
• metabolic syndrome

• Adiposity
• Aged
• Aging/blood
• Aging/metabolism
• Animals
• Blood Glucose/metabolism
• Female
• Humans
• Insulin Resistance
• Male
• Middle Aged
• Obesity/blood
• Obesity/therapy
• Phosphoric Diester Hydrolases/blood
• Weight Reduction Programs

• UL1 TR000005 NCATS NIH HHS
• M01 RR00056 NCRR NIH HHS
• T35 DK065521 NIDDK NIH HHS
• P30 DK046204 NIDDK NIH HHS
• M01 RR000056 NCRR NIH HHS
• P30 DK46204 NIDDK NIH HHS
• T32 DK063922 NIDDK NIH HHS
• Howard Hughes Medical Institute
• R01 AG20128 NIA NIH HHS
• T32 DK007052 NIDDK NIH HHS
• UL1-TR000005 NCATS NIH HHS
• R01 DK090166 NIDDK NIH HHS

• Immune response
• Oxygen
• Pulmonary inflammation

• G-protein-coupled receptors
• autotaxin
• breast cancer
• cell migration
• epidermal growth factor receptor
• lysophosphatidate
• thyroid cancer

Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.

Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.

This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.

• Autotaxin inhibition
• Cytokine
• Inflammation
• Lysophosphatidate
• Tumor microenvironment
• Wound healing

• Autotaxin
• Fatty acyltransferase
• Glycerolipid
• Inhibitor
• Lipase
• Lipid kinase
• Lipin
• Metabolism
• Phospholipase

Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.

• Autotaxin
• Lysophosphatidic acid
• Lung
• Acute lung injury
• Pulmonary fibrosis
• Asthma
• Lung cancer

Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA.

• Animals
• Arthritis, Experimental/chemically induced
• Arthritis, Experimental/drug therapy
• Arthritis, Experimental/metabolism
• Arthritis, Experimental/pathology
• Arthritis, Rheumatoid/chemically induced
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/metabolism
• Arthritis, Rheumatoid/pathology
• Collagen/adverse effects
• Enzyme Activation/drug effects
• Female
• Hydrolysis/drug effects
• Lysophosphatidylcholines/metabolism
• Lysophospholipids/metabolism
• Lysophospholipids/pharmacology
• Mice
• Phosphoric Diester Hydrolases/metabolism
• Substrate Specificity

• Adipocytes/cytology
• Animals
• Body Weight
• Diet, High-Fat
• Gene Expression Regulation
• Glucose/metabolism
• Glycogen/metabolism
• Homeostasis
• Insulin/metabolism
• Insulin Secretion
• Isoxazoles/pharmacology
• Lipids/chemistry
• Lysophospholipids/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Muscle, Skeletal/metabolism
• Oxygen/metabolism
• Propionates/pharmacology
• Time Factors

• alkaline phosphatase
• catalytic mechanism
• 5′-nucleotidase
• ecto-nucleotidase
• npp
• ntpdase
• nucleoside triphosphate diphosphohydrolase
• nucleotide pyrophosphatase/phosphodiesterase

• 5'-Nucleotidase/chemistry
• 5'-Nucleotidase/metabolism
• Alkaline Phosphatase/metabolism
• Animals
• Catalysis
• Catalytic Domain
• Glycosylation
• Humans
• Isoenzymes/chemistry
• Isoenzymes/physiology
• Models, Molecular
• Nucleoside-Diphosphate Kinase/metabolism
• Nucleoside-Diphosphate Kinase/physiology
• Nucleotidases/chemistry
• Nucleotidases/physiology
• Nucleotides/metabolism
• Phosphoric Diester Hydrolases/chemistry
• Phosphoric Diester Hydrolases/metabolism
• Phylogeny
• Protein Conformation
• Proteins/chemistry
• Pyrophosphatases/chemistry
• Pyrophosphatases/metabolism
• Receptors, Purinergic/physiology
• Signal Transduction/physiology
• Species Specificity

Ectonucleotide pyrophosphatase/phosphodiestrase 2 (Enpp2) isolated from the supernatant of human melanoma cells is a lysophospholipase D that transforms lysophosphatidylcholine into lysophospatidic acid. Although multiple analyses have investigated the function of Enpp2 in the hypothalamus, its role in the uterus during the estrous cycle is not well understood. In the present study, rat uterine Enpp2 was analyzed by RT-PCR, Western blotting, and immunohistochemistry. Quantitative PCR analysis demonstrated that uterine Enpp2 mRNA was decreased during estrus compared to proestrus and diestrus. To determine whether uterine Enpp2 expression is affected by sex steroid hormones, immature rats were treated with 17β-estradiol (E2), progesterone, or both on postnatal days 14 to 16. Interestingly, the expression of Enpp2 mRNA and protein were down-regulated by E2 in the uterus during estrus but not during proestrus or diestrus, suggesting that Enpp2 may play a role in uterine function during estrus. Enpp2 is primarily localized in the stromal cells of the endometrium during proestrus and estrus. During diestrus, Enpp2 was highly expressed in the epithelial cells of the endometrium. Taken together, these results suggest that uterine Enpp2 may be regulated by E2 and plays a role in reproductive functions during female rat development.

Constitutive activation of the alternative NF-κB pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-κB signaling may result in the development and progression of cancer. Here, we focused on the question how does the constitutive alternative NF-κB signaling exert its effects in these malignant processes.

To explore the consequences of unrestricted alternative NF-κB activation on genome-wide transcription, we compared gene expression profiles of wild-type and NF-κB2/p100-deficient (p100^−/−) primary mouse embryonic fibroblasts (MEFs) and spleens. Microarray experiments revealed only 73 differentially regulated genes in p100^−/− vs. wild-type MEFs. Chromatin immunoprecipitation (ChIP) assays showed in p100^−/− MEFs direct binding of p52 and RelB to the promoter of the Enpp2 gene encoding ENPP2/Autotaxin, a protein with an important role in lymphocyte homing and cell migration. Gene ontology analysis revealed upregulation of genes with anti-apoptotic/proliferative activity (Enpp2/Atx, Serpina3g, Traf1, Rrad), chemotactic/locomotory activity (Enpp2/Atx, Ccl8), and lymphocyte homing activity (Enpp2/Atx, Cd34). Most importantly, biochemical and gene expression analyses of MEFs and spleen, respectively, indicated a marked crosstalk between classical and alternative NF-κB pathways.

Our results show that p100 deficiency alone was insufficient for full induction of genes regulated by the alternative NF-κB pathway. Moreover, alternative NF-κB signaling strongly synergized both in vitro and in vivo with classical NF-κB activation, thereby extending the number of genes under the control of the p100 inhibitor of the alternative NF-κB signaling pathway.

• Animals
• Embryo, Mammalian/cytology
• Fibroblasts/metabolism
• Gene Expression Profiling
• Gene Expression Regulation
• Mice
• NF-kappa B p52 Subunit/deficiency
• NF-kappa B p52 Subunit/metabolism
• Phosphoric Diester Hydrolases/genetics
• Promoter Regions, Genetic/genetics
• Protein Binding
• Signal Transduction
• Spleen/metabolism
• Transcription Factor RelB/metabolism
• Transcription, Genetic
• Tumor Necrosis Factors/metabolism

Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.

• Alzheimer Disease/genetics
• Alzheimer Disease/metabolism
• Amygdala/metabolism
• Amygdala/pathology
• Animals
• Astrocytes/metabolism
• Astrocytes/pathology
• Cell Differentiation/drug effects
• Cell Differentiation/genetics
• Cell Line, Tumor
• Cytoplasm/metabolism
• Down-Regulation
• Entorhinal Cortex/metabolism
• Entorhinal Cortex/physiopathology
• Frontotemporal Lobar Degeneration/genetics
• Frontotemporal Lobar Degeneration/metabolism
• Gene Expression Profiling
• Humans
• Male
• Mice
• Mice, Transgenic
• Mitomycin/pharmacology
• Neurons/metabolism
• Neurons/pathology
• PTB-Associated Splicing Factor
• Pick Disease of the Brain/genetics
• Pick Disease of the Brain/metabolism
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• Tretinoin/pharmacology
• tau Proteins/genetics
• tau Proteins/metabolism

• Animals
• Catalase/metabolism
• Cytoprotection
• Gene Expression
• Hydrogen Peroxide/pharmacology
• Inflammation/metabolism
• Lysophospholipids/metabolism
• Mice
• Microglia/enzymology
• Microglia/metabolism
• Nitric Oxide Synthase Type II/metabolism
• Oxidants/pharmacology
• Oxidation-Reduction
• Oxidative Stress
• Phosphoric Diester Hydrolases/genetics
• Phosphoric Diester Hydrolases/metabolism
• Proteasome Endopeptidase Complex/metabolism
• Protein Carbonylation
• Recombinant Proteins/genetics
• Recombinant Proteins/metabolism
• Superoxide Dismutase/metabolism

Autotaxin (ATX) is an extracellular lysophospholipase D (lysoPLD) released from normal cells and cancer cells. Activity of ATX is detected in various biological fluids. The lysophosphatidic acid (LPA) is the main product of ATX. LPA acting through specific G protein-coupled receptors (LPA₁-LPA₆) affects immunological response, normal development, and malignant tumors' formation and progression. In this review, the impact of autotoxin on biology of melanoma cells and potential treatment is discussed.

Autotaxin (ATX) is a secreted glycoprotein with the lysophospholipase D (lysoPLD) activity to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive lysophospholipid involved in diverse biological actions. ATX is highly expressed in some cancer cells and contributes to their tumorigenesis, invasion, and metastases, while in other cancer cells ATX is silenced or expressed at low level. The mechanism of ATX expression regulation in cancer cells remains largely unknown.

In the present study, we demonstrated that trichostatin A (TSA), a well-known HDAC inhibitor (HDACi), significantly induced ATX expression in SW480 and several other cancer cells with low or undetectable endogenous ATX expression. ATX induction could be observed when HDAC3 and HDAC7 were down-regulated by their siRNAs. It was found that HDAC7 expression levels were low in the cancer cells with high endogenous ATX expression. Exogenous over-expression of HDAC7 inhibited ATX expression in these cells in a HDAC3-dependent manner. These data indicate that HDAC3 and HDAC7 collaboratively suppress ATX expression in cancer cells, and suggest that TSA induce ATX expression by inhibiting HDAC3 and HDAC7. The biological significance of this regulation mechanism was revealed by demonstrating that TSA-induced ATX protected cancer cells against TSA-induced apoptosis by producing LPA through its lysoPLD activity, which could be reversed by BrP-LPA and S32826, the inhibitors of the ATX-LPA axis.

We have demonstrated that ATX expression is repressed by HDAC3 and HDAC7 in cancer cells. During TSA treatment, ATX is induced due to the HDAC3 and HDAC7 inhibition and functionally antagonizes the TSA-induced apoptosis. These results reveal an internal HDACi-resistant mechanism in cancer cells, and suggest that the inhibition of ATX-LPA axis would be helpful to improve the efficacy of HDACi-based therapeutics against cancer.

• Animals
• Disease Progression
• Drug Resistance, Neoplasm
• Female
• Humans
• Intercellular Signaling Peptides and Proteins/metabolism
• Lysophospholipids/metabolism
• Male
• Mice
• Multienzyme Complexes/metabolism
• Neoplasm Metastasis
• Neoplasms/blood supply
• Neoplasms/metabolism
• Neoplasms/pathology
• Neovascularization, Pathologic/metabolism
• Phosphatidate Phosphatase/metabolism
• Phosphodiesterase I/metabolism
• Phospholipase D/metabolism
• Phosphoric Diester Hydrolases
• Pyrophosphatases/metabolism
• Signal Transduction
• Sphingosine/analogs & derivatives
• Sphingosine/metabolism

• Canadian Institutes of Health Research