Lipid Signaling Molecules Research Articles

The 15-hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates abnormal hepatic glucose metabolism through PGE2–EP4 receptor–AKT signaling in a type 2 diabetes mellitus mouse model

Type 2 diabetes mellitus (T2DM) is associated with high rates of morbidity and mortality worldwide. Prostaglandin E2 (PGE2) is a lipid signaling molecule that can ameliorate the symptoms of some metabolic diseases, including T2DM, and improve tissue repair and regeneration. Although SW033291 can increase PGE2 levels through its action as a small molecule inhibitor of the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase, its effects on T2DM remain unclear. In the present study, we evaluated whether SW033291 treatment exerts a protective effect against T2DM and explored the underlying mechanisms. A T2DM mouse model was established using a high-fat diet combined with streptozotocin treatment. Palmitic acid-treated LO2 cells were used as an insulin-resistant cell model. SW033291 treatment reduced body weight and fasting blood glucose levels as well as serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels in vivo. In addition to ameliorating glucose and insulin tolerance, SW033291 treatment reversed the T2DM-induced decrease in glycogen synthesis and increase in gluconeogenesis in the liver. Furthermore, SW033291 administration increased hepatic glycogen synthase kinase 3 beta (GSK3β) phosphorylation levels to promote glycogen synthesis. SW033291 treatment also inhibited gluconeogenesis by upregulating AKT serine/threonine kinase (AKT) and forkhead box O1 (FOXO1) phosphorylation and reducing glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 expression in the livers of T2DM model mice. Additionally, SW033291 treatment improved abnormal hepatic glucose metabolism through the PGE2–EP4 receptor–AKT–GSK3β/FOXO1 signaling pathway in vitro. These results suggest a novel role of SW033291 in improving T2DM and support its potential as a novel therapeutic agent.

Phosphatidic acid-regulated SOS2 controls sodium and potassium homeostasis in Arabidopsis under salt stress.

The maintenance of sodium/potassium (Na+ /K+ ) homeostasis in plant cells is essential for salt tolerance. Plants export excess Na+ out of cells mainly through the Salt Overly Sensitive (SOS) pathway, activated by a calcium signal; however, it is unknown whether other signals regulate the SOS pathway and how K+ uptake is regulated under salt stress. Phosphatidic acid (PA) is emerging as a lipid signaling molecule that modulates cellular processes in development and the response to stimuli. Here, we show that PA binds to the residue Lys57 in SOS2, a core member of the SOS pathway, under salt stress, promoting the activity and plasma membrane localization of SOS2, which activates the Na+ /H+ antiporter SOS1 to promote the Na+ efflux. In addition, we reveal that PA promotes the phosphorylation of SOS3-like calcium-binding protein 8 (SCaBP8) by SOS2 under salt stress, which attenuates the SCaBP8-mediated inhibition of Arabidopsis K+ transporter 1 (AKT1), an inward-rectifying K+ channel. These findings suggest that PA regulates the SOS pathway and AKT1 activity under salt stress, promoting Na+ efflux and K+ influx to maintain Na+ /K+ homeostasis.

Host-Erythrocytic Sphingosine-1-Phosphate Regulates Plasmodium Histone Deacetylase Activity and Exhibits Epigenetic Control over Cell Death and Differentiation.

The evolution of resistance to practically all antimalarial drugs poses a challenge to the current malaria elimination and eradication efforts. Given that the epigenome of Plasmodium falciparum governs several crucial parasite functions, pharmaceutical interventions with transmission-blocking potential that target epigenetic molecular markers and regulatory mechanisms are likely to encounter drug resistance. In the malaria parasite, histone deacetylases (HDACs) are essential epigenetic modulators that regulate cellular transcriptional rearrangements, notably the molecular mechanisms underlying parasite proliferation and differentiation. We establish "lipid sequestration" as a mechanism by which sphingolipids, specifically Sphingosine-1-Phosphate (S1P) (a metabolic product of Sphingosine Kinase 1 [SphK-1]), regulate epigenetic reprogramming in the parasite by interacting with, and modulating, the histone-deacetylation activity of PfHDAC-1, thereby regulating Plasmodium pathogenesis. Furthermore, we demonstrate that altering host S1P levels with PF-543, a potent and selective Sphk-1 inhibitor, dysregulates PfHDAC-1 activity, resulting in a significant increase in the global histone acetylation signals and, consequently, transcriptional modulation of genes associated with gametocytogenesis, virulence, and proliferation. Our findings point to a hitherto unrecognized functional role for host S1P-mediated sphingolipid signaling in modulating PfHDAC-1's enzymatic activity and, as a result, the parasite's dynamic genome-wide transcriptional patterns. The epigenetic regulation of parasite proliferation and sexual differentiation offers a novel approach for developing host-targeted therapeutics to combat malaria resistance to conventional regimens. IMPORTANCE Sphingolipid is an 18-carbon amino-alcohol-containing lipid with a sphingosine backbone, which when phosphorylated by sphingosine kinase 1 (SphK-1), generates sphingosine-1-phosphate (S1P), an essential lipid signaling molecule. Dysregulation of S1P function has been observed in a variety of pathologies, including severe malaria. The malaria parasite Plasmodium acquires a host S1P pool for its growth and survival. Here, we describe the molecular attuning of histone deacetylase-1 (PfHDAC-1), a crucial epigenetic modulator that contributes to the establishment of epigenetic chromatin states and parasite survival, in response to S1P binding. Our findings highlight the host lipid-mediated epigenetic regulation of malaria parasite key genes.

Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy.

Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. Herein, we found that carboxylesterase 1 (CES1) was expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, LC-MS/MS and lipidomic analyses revealed that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Consistently, clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the "CES1-PPARα/γ-SCD" axis sensitized HCC cells to cisplatin treatment. As a demonstration, the growth of HCC xenograft tumors in NU/J mice was potently limited by co-administration of cisplatin and CES1 inhibition. Our results suggest that CES1 is a promising therapeutic target for HCC treatment.

SAF-A/hnRNP U binds polyphosphoinositides via a lysine rich polybasic motif located in the SAP domain.

Polyphosphoinositides (PPIn) play essential functions as lipid signalling molecules and many of their functions have been elucidated in the cytoplasm. However, PPIn are also intranuclear where they contribute to chromatin remodelling, transcription and mRNA splicing. Using quantitative interactomics, we have previously identified PPIn-interacting proteins with roles in RNA processing/splicing including the heterogeneous nuclear ribonucleoprotein U (hnRNPU/SAF-A). In this study, hnRNPU was validated as a direct PPIn-interacting protein via 2 regions located in the N and C termini. Furthermore, deletion of the polybasic motif region located at aa 9-24 in its DNA binding SAP domain prevented PPIn interaction. In conclusion, these results are consistent with hnRNPU harbouring a polybasic region with dual functions in DNA and PPIn interaction.

The Role of Cytosolic Lipid Droplets in Hepatitis C Virus Replication, Assembly, and Release.

The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer-the progressive liver damage results from the host's immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host's lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host-virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small-molecule inhibitors of cLD-regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication.

Prospects for the pharmacological application of N-acyle-thanolamines of polyunsaturated fatty acids in the therapy of respiratory diseases on the example of bronchial asthma

Introduction. At present, the mechanisms of the processes of resolving chronic inflammation in asthma are not fully understood. A search for new pharmacological preparations and substances for the treatment and control of the course of asthma is required. Promising in this direction are N-acylethanolamines (NAE) of polyunsaturated fatty acids - bioactive lipid molecules that exhibit many signaling functions. NAEs are capable of influencing the synthesis of pro-inflammatory cytokines and are also appear to be a substrate for the synthesis of pro-permissive lipid signaling molecules. This review collects data on NAE, provides an overview, biosynthesis, and describes their anti-inflammatory effects.Aim. Summarizing the data of domestic and foreign researchers on the possibility of NAE in the treatment of respiratory diseases on the example of bronchial asthma.Materials and methods. The review uses data from articles published in PubMed, Google Scholar, eLIBRARY.Results. The study and compilation of literature on this issue made it possible to conclude that synthetic NAEs are promising pharmacological objects for asthma therapy, however, further testing of the anti-in­flammatory effects of NAEs and the establishment of the molecular mechanism of their action on inflammation processes are needed.

Rational Design and Synthesis of D-galactosyl Lysophospholipids as Selective Substrates and non-ATP-competitive Inhibitors of Phosphatidylinositol Phosphate Kinases.

Phosphatidylinositol phosphate kinases (PIPKs) produce lipid signaling molecules and have been attracting increasing attention as drug targets for cancer, neurodegenerative diseases, and viral infection. Given the potential cross-inhibition of kinases and other ATP-utilizing enzymes by ATP-competitive inhibitors, targeting the unique lipid substrate binding site represents a superior strategy for PIPK inhibition. Here, by taking advantage of the nearly identical stereochemistry between myo-inositol and D-galactose, we designed and synthesized a panel of D-galactosyl lysophospholipids, one of which was found to be a selective substrate of phosphatidylinositol 4-phosphate 5-kinase. Derivatization of this compound led to the discovery of a human PIKfyve inhibitor with an apparent IC50 of 6.2 μM, which significantly potentiated the inhibitory effect of Apilimod, an ATP-competitive PIKfyve inhibitor under clinical trials against SARS-CoV-2 infection and amyotrophic lateral sclerosis. Our results provide the proof of concept that D-galactose-based phosphoinositide mimetics can be developed into artificial substrates and new inhibitors of PIPKs.

Abstract C051: Ceramide signaling regulates PDA aggression through exosome reprogramming of the stroma

Abstract Ceramide is a bioactive lipid signaling molecule that regulates multiple cellular processes influencing pancreatic tumor progression and drug response. The pleiotropic role of ceramide signaling in cancer includes modulation of exosome biogenesis and secretion. Smpd3 encodes an enzyme that generates ceramide through hydrolysis of sphingomyelin. Employing the KPC mouse model of pancreatic cancer, we demonstrated that Smpd3 regulates exosome biogenesis in pancreatic ductal adenocarcinoma (PDA) cells and is pro-tumorigenic during PDA progression. Ablation of Smdp3 in KPC mice significantly extends survival by 19% when compared to KPC; Smpd3wt/wt controls. KPC; Smpd3f/f mice display significantly less PanIN and tumor burden compared to KPC; Smpd3wt/wt controls. Lipidomics analysis of epithelial cell lines generated from end-stage pancreatic tumors of KPC; Smpd3f/f and KPC; Smpd3wt/wt mice demonstrated an alteration in hundreds of lipid species including ceramides, triacylglycerides, sphingomyelins, and phosphatidylcholines. Analysis of RNA-seq data of these epithelial cell lines showed a switching of primary tumors from the predominant more aggressive basal-like subtype seen in KPC; Smpd3wt/wt mice to classical in KPC; Smpd3f/f mice. Pathways analysis of our RNA-seq dataset showed an enrichment for genes involved in cellular mechanics and regulation of the tumor microenvironment. To query if Smpd3-generated exosomes have a direct effect on pancreatic tumor progression, we injected KPC; Smpd3wt/wt and KPC; Smpd3f/f mice with exosomes isolated from KPC; Smpd3f/f and KPC; Smpd3wt/wt PDA cell lines. Injection of exosomes derived from KPC; Smpd3f/f mice significantly extended survival of both Smpd3wt/wt and KPC; Smpd3f/f mice when compared to injection of exosomes isolated from KPC; Smpd3wt/wt mice, suggesting an anti-tumorigenic effect of exosomes isolated from Smpd3-deficient PDA cell lines. We observed a decrease in extracellular matrix collagen abundance and fewer activated stellate cells and fibroblasts in KPC; Smpd3f/f compared to control KPC; Smpd3wt/wt pancreata. Abrogation of Smpd3 expression also affected immune cell infiltration, as demonstrated by a significant increase in iNOS+ F4/80+ double positive macrophages in KPC; Smpd3f/f pancreata when compared to KPC; Smpd3wt/wt pancreata. Loss of Smpd3 resulted in a significant reduction in CD31+ endothelial cells in pancreatic tumors of KPC; Smpd3f/f mice when compared to KPC; Smpd3wt/wt mice, which may influence the ability of chemotherapeutics to enter pancreatic tumors. Our patient data demonstrate that high SMPD3 expression in surgically resected, treatment naive PDA significantly correlated with longer patient survival when patients received adjuvant chemotherapy, more than 95% of which was gemcitabine. Collectively, our data show that ceramide-dependent exosomes promote tumorigenesis, specifically activation of stellate cells and fibroblasts – which may in turn induce a stiff, fibrotic, proinflammatory tumor microenvironment that also impedes vasculature formation. Citation Format: Audrey M. Hendley, Atsushi Urano, Xianlu L. Peng, Sudipta Ashe, Natanya R. Kerper, Tuan A. Phu, Martin Ng, Simone Giacometti, David I. Berrios, Gun H. Jang, Jen J. Yeh, Steven Gallinger, David K. Chang, Andrew V. Biankin, Valerie M. Weaver, Grace E. Kim, David W. Dawson, Robert L. Raffai, Matthias Hebrok. Ceramide signaling regulates PDA aggression through exosome reprogramming of the stroma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C051.

Hyperthermia-Induced Seizures Enhance Brain Concentrations of the Endocannabinoid-Related Linoleoyl Glycerols in a Scn1a+/- Mouse Model of Dravet Syndrome.

Introduction: The endocannabinoid system contributes to the homeostatic response to seizure activity in epilepsy, a disease of brain hyperexcitability. Indeed, studies using conventional epilepsy models have shown that seizures increase endocannabinoids in the brain. However, it is unknown whether endocannabinoids and structurally related fatty acid amides and monoacylglycerols are similarly released in response to acute seizures in animal models of drug-resistant epilepsy. Therefore, in this study, we investigated whether a hyperthermia-induced seizure increased concentrations of endocannabinoids and related signaling lipids in the Scn1a+/- mouse model of Dravet syndrome. Materials and Methods: We compared hippocampal concentrations of the major endocannabinoids and related monoglycerols and N-acylethanolamines in wild-type mice, naïve Scn1a+/- mice, and Scn1a+/- mice primed with a single, hyperthermia-induced, generalized tonic-clonic seizure. Samples were collected 5 and 60 min following the seizure and then analyzed with LC-MS/MS. Results: We found that a hyperthermia-induced seizure in Scn1a+/- mice did not affect hippocampal concentrations of the major endocannabinoids, 2-AG and anandamide, or the N-acylethanolamines studied, although the sampling of tissue 5 min postseizure may have been too late to capture any effect on these lipids. Heterozygous deletion of Scn1a alone did not affect these lipid signaling molecules. Notably, however, we found that a hyperthermia-induced seizure significantly increased hippocampal concentrations of the monoacylglycerols, 2-linoleoyl glycerol (2-LG) and 1-linoleoyl glycerol (1-LG), in Scn1a+/- mice. Conclusions: Our results show the unprecedented elevation of the lesser-studied endocannabinoid-related monoacylglycerols, 2-LG and 1-LG, following a hyperthermia-induced seizure in a mouse model of Dravet syndrome. Future research is needed to comprehensively explore the function of these lipid signaling molecules during seizure activity and whether their actions can be exploited to develop new therapeutics.

Two cooperative binding sites sensitize PI(4,5)P2 recognition by the tubby domain.

Phosphoinositides (PIs) are lipid signaling molecules that operate by recruiting proteins to cellular membranes via PI recognition domains. The dominant PI of the plasma membrane is phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. One of only two PI(4,5)P2 recognition domains characterized in detail is the tubby domain. It is essential for targeting proteins into cilia involving reversible membrane association. However, the PI(4,5)P2 binding properties of tubby domains have remained enigmatic. Here, we used coarse-grained molecular dynamics simulations to explore PI(4,5)P2 binding by the prototypic tubby domain. The comparatively low PI(4,5)P2 affinity of the previously described canonical binding site is underpinned in a cooperative manner by a previously unknown, adjacent second binding site. Mutations in the previously unknown site impaired PI(4,5)P2-dependent plasma membrane localization in living cells and PI(4,5)P2 interaction in silico, emphasizing its importance for PI(4,5)P2 affinity. The two-ligand binding mode may serve to sharpen the membrane association-dissociation cycle of tubby-like proteins that underlies delivery of ciliary cargo.

Targeting the Sphingolipid Rheostat in Gliomas.

Gliomas are highly aggressive cancer types that are in urgent need of novel drugs and targeted therapies. Treatment protocols have not improved in over a decade, and glioma patient survival remains among the worst of all cancer types. As a result, cancer metabolism research has served as an innovative approach to identifying novel glioma targets and improving our understanding of brain tumors. Recent research has uncovered a unique metabolic vulnerability in the sphingolipid pathways of gliomas that possess the IDH1 mutation. Sphingolipids are a family of lipid signaling molecules that play a variety of second messenger functions in cellular regulation. The two primary metabolites, sphingosine-1-phosphate (S1P) and ceramide, maintain a rheostat balance and play opposing roles in cell survival and proliferation. Altering the rheostat such that the pro-apoptotic signaling of the ceramides outweighs the pro-survival S1P signaling in glioma cells diminishes the hallmarks of cancer and enhances tumor cell death. Throughout this review, we discuss the sphingolipid pathway and identify the enzymes that can be most effectively targeted to alter the sphingolipid rheostat and enhance apoptosis in gliomas. We discuss each pathway’s steps based on their site of occurrence in the organelles and postulate novel targets that can effectively exploit this vulnerability.

Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice.

Humans with post-traumatic stress disorder (PTSD) exhibit sleep disturbances that include insomnia, nightmares, and enhanced daytime sleepiness. Sleep disturbances are considered a hallmark feature of PTSD; however, little is known about the cellular and molecular mechanisms regulating trauma-induced sleep disorders. Using a rodent model of PTSD called "Single Prolonged Stress" (SPS) we examined the requirement of the brain-type fatty acid binding protein Fabp7, an astrocyte expressed lipid-signaling molecule, in mediating trauma-induced sleep disturbances. We measured baseline sleep/wake parameters and then exposed Fabp7 knock-out (KO) and wild-type (WT) C57BL/6N genetic background control animals to SPS. Sleep and wake measurements were obtained immediately following the initial trauma exposure of SPS, and again 7 days later. We found that active-phase (dark period) wakefulness was similar in KO and WT at baseline and immediately following SPS; however, it was significantly increased after 7 days. These effects were opposite in the inactive-phase (light period), where KOs exhibited increased wake in baseline and following SPS, but returned to WT levels after 7 days. To examine the effects of Fabp7 on unconditioned anxiety following trauma, we exposed KO and WT mice to the light-dark box test before and after SPS. Prior to SPS, KO and WT mice spent similar amounts of time in the lit compartment. Following SPS, KO mice spent significantly more time in the lit compartment compared to WT mice. These results demonstrate that mutations in an astrocyte-expressed gene (Fabp7) influence changes in stress-dependent sleep disturbances and associated anxiety behavior.

Effects of Arachidonic Acid and Its Metabolites on Functional Beta-Cell Mass.

Arachidonic acid (AA) is a polyunsaturated 20-carbon fatty acid present in phospholipids in the plasma membrane. The three primary pathways by which AA is metabolized are mediated by cyclooxygenase (COX) enzymes, lipoxygenase (LOX) enzymes, and cytochrome P450 (CYP) enzymes. These three pathways produce eicosanoids, lipid signaling molecules that play roles in biological processes such as inflammation, pain, and immune function. Eicosanoids have been demonstrated to play a role in inflammatory, renal, and cardiovascular diseases as well type 1 and type 2 diabetes. Alterations in AA release or AA concentrations have been shown to affect insulin secretion from the pancreatic beta cell, leading to interest in the role of AA and its metabolites in the regulation of beta-cell function and maintenance of beta-cell mass. In this review, we discuss the metabolism of AA by COX, LOX, and CYP, the roles of these enzymes and their metabolites in beta-cell mass and function, and the possibility of targeting these pathways as novel therapies for treating diabetes.

Discovery of Phospholipase D Inhibitors with Improved Drug-like Properties and Central Nervous System Penetrance.

Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression as well as a target for neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for in vivo studies. To capture the in vivo measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15-20-fold.

The sustained PGE2 release matrix improves neovascularization and skeletal muscle regeneration in a hindlimb ischemia model

BackgroundThe promising therapeutic strategy for the treatment of peripheral artery disease (PAD) is to restore blood supply and promote regeneration of skeletal muscle regeneration. Increasing evidence revealed that prostaglandin E2 (PGE2), a lipid signaling molecule, has significant therapeutic potential for tissue repair and regeneration. Though PGE2 has been well reported in tissue regeneration, the application of PGE2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE2.ResultsIn this study, we designed and synthesized a new PGE2 release matrix by chemically bonding PGE2 to collagen. Our results revealed that the PGE2 matrix effectively extends the half-life of PGE2 in vitro and in vivo. Moreover, the PGE2 matrix markedly improved neovascularization by increasing angiogenesis, as confirmed by bioluminescence imaging (BLI). Furthermore, the PGE2 matrix exhibits superior therapeutic efficacy in the hindlimb ischemia model through the activation of MyoD1-mediated muscle stem cells, which is consistent with accelerated structural recovery of skeletal muscle, as evidenced by histological analysis.ConclusionsOur findings highlight the chemical bonding strategy of chemical bonding PGE2 to collagen for sustained release and may facilitate the development of PGE2-based therapies to significantly improve tissue regeneration.Graphical

Glomerular Biomechanical Stress and Lipid Mediators during Cellular Changes Leading to Chronic Kidney Disease.

Hyperfiltration is an important underlying cause of glomerular dysfunction associated with several systemic and intrinsic glomerular conditions leading to chronic kidney disease (CKD). These include obesity, diabetes, hypertension, focal segmental glomerulosclerosis (FSGS), congenital abnormalities and reduced renal mass (low nephron number). Hyperfiltration-associated biomechanical forces directly impact the cell membrane, generating tensile and fluid flow shear stresses in multiple segments of the nephron. Ongoing research suggests these biomechanical forces as the initial mediators of hyperfiltration-induced deterioration of podocyte structure and function leading to their detachment and irreplaceable loss from the glomerular filtration barrier. Membrane lipid-derived polyunsaturated fatty acids (PUFA) and their metabolites are potent transducers of biomechanical stress from the cell surface to intracellular compartments. Omega-6 and ω-3 long-chain PUFA from membrane phospholipids generate many versatile and autacoid oxylipins that modulate pro-inflammatory as well as anti-inflammatory autocrine and paracrine signaling. We advance the idea that lipid signaling molecules, related enzymes, metabolites and receptors are not just mediators of cellular stress but also potential targets for developing novel interventions. With the growing emphasis on lifestyle changes for wellness, dietary fatty acids are potential adjunct-therapeutics to minimize/treat hyperfiltration-induced progressive glomerular damage and CKD.

Wound Healing Properties of Exosomes - A Review and Modelling of Combinatorial Analysis Strategies.

Wound healing is an elaborated process, well-regulated via cell migration and proliferation. Although the physiological basics of wound healing have been thoroughly investigated and reported, much remains to be studied. Particularly, various studies have demonstrated the immunomodulatory roles of exosomes derived from plant cells, mammalian cells, and mesenchymal stem cells (MSCs) in the healing and repairing system. The paracrine and therapeutic effects of exosomes are mainly associated with the broad exosomal cargo content comprising growth factors, cytokines, enzymes, nucleic acids, proteins, and lipid signaling molecules. Nevertheless, the functional or mechanism pathway of exosomes with reference to overall exosomal cargo remains undetermined. To date, combinatorial analysis strategies employing Database for Annotation, Visualization, and Integrated Discovery (DAVID), STRING tools, Gene Ontology (GO), Kyoto Encyclopedia of Genes, Genomes (KEGG) pathway enrichment analysis, as well as Ingenuity Pathway Analysis (IPA) have been applied in elucidating network interaction and functional pathway of exosomes. In this review paper, the application of combinatorial analysis strategies is demonstrated to better understand the therapeutic potentials of exosomes in the wound healing process. In conclusion, functional modulation of exosomal cargo for specific biological treatment is achievable, and modelling of combinatorial analysis strategies will hopefully bridge the research gap and provide a paradigm shift to regenerative processes.

Identification of ritanserin analogs that display DGK isoform specificity

The diacylglycerol kinase (DGK) family of lipid enzymes catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Both DAG and PA are lipid signaling molecules that are of notable importance in regulating cell processes such as proliferation, apoptosis, and migration. There are ten mammalian DGK enzymes that appear to have distinct biological functions. DGKα has emerged as a promising therapeutic target in numerous cancers including glioblastoma (GBM) and melanoma as treatment with small molecule DGKα inhibitors results in reduced tumor sizes and prolonged survival. Importantly, DGKα has also been identified as an immune checkpoint due to its promotion of T cell anergy, and its inhibition has been shown to improve T cell activation. There are few small molecule DGKα inhibitors currently available, and the application of existing compounds to clinical settings is hindered by species-dependent variability in potency, as well as concerns regarding isotype specificity particularly amongst other type I DGKs. In order to resolve these issues, we have screened a library of compounds structurally analogous to the DGKα inhibitor, ritanserin, in an effort to identify more potent and specific alternatives. We identified two compounds that more potently and selectively inhibit DGKα, one of which (JNJ-3790339) demonstrates similar cytotoxicity in GBM and melanoma cells as ritanserin. Consistent with its inhibitor profile towards DGKα, JNJ-3790339 also demonstrated improved activation of T cells compared with ritanserin. Together our data support efforts to identify DGK isoform-selective inhibitors as a mechanism to produce pharmacologically relevant cancer therapies.

Cannabinoids accumulate in mouse breast milk and differentially regulate lipid composition and lipid signaling molecules involved in infant development

Maternal cannabis use during lactation may expose developing infants to cannabinoids (CBs) such as ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBs modulate lipid signaling molecules in the central nervous system in age- and cell-dependent ways, but their influence on the lipid composition of breast milk has yet to be established. This study investigates the effects of THC, CBD, or their combination on milk lipids by analyzing the stomach contents of CD1 mouse pups that have been nursed by dams injected with CBs on postnatal days (PND) 1 -10. Stomach contents were collected 2 hours after the last injection on PND10 and HPLC/MS/MS was used to identify and quantify over 80 endogenous lipid species and cannabinoids in the samples. We show that CBs differentially accumulate in milk, lead to widespread decreases in free fatty acids, decreases in N-acyl methionine species, increases N-linoleoyl species, as well as modulate levels of endogenous CBs (eCBs) AEA, 2-AG, and their structural congeners. Our data indicate the passage of CBs to pups through breast milk and that maternal CB exposure alters breast milk lipid compositions.