Lipid Signaling Research Articles

Progressive alterations in lipid distribution and composition in a murine Alzheimer’s disease model visualized by label‐free Raman microscopy

AbstractBackgroundAlzheimer’s disease (AD) is accompanied by severe alterations in the brain lipid profile, affecting both the type and the distribution of lipids in the tissue. Moreover, literature also suggests a close association of Aβ plaques and lipids, exacerbating amyloidogenesis and plaque deposition. Thus, a spatially resolved approach is eminently important to understand the chemical nature of the progressive relationship between Aβ plaques and surrounding lipids. In the here presented study, Raman microscopy, a label‐free, chemically selective technique, was used in combination with state‐of‐the‐art statistics to analyze Aβ plaques and the surrounding tissue in a murine Alzheimer’s disease model. By encompassing differently aged diseased and healthy mice, this study aimed to generate knowledge on the alterations of Aβ plaque surrounding lipids during disease progression, whilst advancing the application of Raman microscopy within a neurodegenerative context.MethodRegions of interest in brain sections of APP/PS1 (Amyloid‐Precursor‐Protein / Presenilin‐1) mice aged 50 days, 5 months, and 10 months, as well as healthy non‐transgenic mice were imaged using a confocal Raman microscope (WITec GmbH, Ulm, Germany). The hyperspectral Raman data sets were processed using Project 4 software (WITec GmbH, Ulm, Germany), in‐house written Matlab scripts (The Mathworks, Inc., Natick, USA) and the Matlab‐integrated RamanLight App.ResultUsing multivariate analysis, Raman signatures of the Aβ plaques, cell nuclei, mitochondria, and lipids were identified in the tissue, characterized, and compared to each other (Figure 1). Subsequently, the lipid signal was semi‐quantitatively analyzed. The results of this analysis indicate an increasing, massive abundance of lipids in the direct vicinity of the Aβ plaques with disease progression, and the biochemical Raman spectra also reveal the growing presence of long‐chained lipids around the Aβ plaque. Overall, a distinct shift of the lipid spectra and abundance, starting with disease manifestation, is observed in the proximity of the plaques.ConclusionThe presented study shows progressive alterations in the distribution and type of lipids surrounding Aβ plaques in an AD model, spatially resolving lipid alterations and providing valuable additional biochemical insight to more established imaging methods such as fluorescence microscopy.

Bile acids inform about a sex‐specific resilience phenotype against Alzheimer’s disease implicating a role for the gut microbiome and the exposome

AbstractBackgroundBile acids (BAs) are byproducts of cholesterol metabolism involved in lipid absorption, signaling and energy homeostasis. BA synthesis and metabolism, regulated by human and gut bacteria co‐metabolism, are influenced by the exposome. Our prior studies at a population level illustrated a correlation between altered BA profiles and cognitive and brain imaging changes in MCI and AD. More information is needed to determine if these are causal in sub‐populations, and if their modulation can impact disease course.MethodAbsolute serum levels of 33 primary, secondary, and conjugated BAs were measured on a targeted mass spectrometry‐based platform in 1117 fasted subjects (502 women) drawn from the AD Neuroimaging Initiative (ADNI‐1/GO‐2; AD (N = 180), MCI (N = 607) and CN (N = 330). Analysis centered on adjusted and/or stratified linear models with an interpretative focus emphasizing individual‐level granularity.ResultIn stratified analysis, men but not women showed strong association between levels and ratios of BAs and diagnosis. Inclusion of two (informative) bile acids and their ratios increases AUCs for AD vs control from ∼0.72 to ∼0.82‐0.85 (p<0.001) in APOEε4 genotype‐stratified analyses. Some specific associations were APOEε4 genotype‐dependent; some specific microbiome‐mediated ratios in BAs were associated with AD diagnosis in APOEε4− only and secondary bile acid synthesis was associated with AD diagnosis in APOEε4+ only. Other associations were APOEε4 genotype‐independent ‐ higher ratios of primary BAs to total BAs were associated with reduced AD prevalence. Levels of cholic acid below sharp thresholds 25 or 50 nM (in APOEε4+ and APOEε4−, respectively) at 24 months were associated with 5‐ to 7‐fold increased relative risk of MCI to AD progression, establishing a potential biomarker for a resilience phenotype.ConclusionLeveraging the combined power of ADNI and metabolomics with a focus on granularity and complementarity revealed previously unobserved relationships between BAs, sex, APOEε4 genotype, and AD etiology. These data identify a resilience class and provide a roadmap for stratifying subjects and targeting therapies in a precision medicine approach while gaining deeper insights linking peripheral‐central metabolism influenced by the exposome. BAs are a potential modifiable factor that mediates causal linkages between endogenous and exogenous factors in the susceptibility or resilience against AD.

Gene‐level Association Study of Alzheimer’s Disease on CHS and FRAM cohorts

AbstractBackgroundExperimental, clinical, and genetic epidemiological studies continue clarifying important aspects of Alzheimer’s disease (AD) pathological development. Despite this progress the genetic mechanisms of AD regulation remain unclear. One problem that may contribute to slowing further progress in better understanding of these mechanisms deals with difficulties in replication of the results of genetic association studies. To overcome this problem the idea of using a gene‐based analysis in which all common variation within a candidate gene is considered jointly has been suggested. In this paper we investigate to what extent the use of gene‐based analyses resolves the non‐replication problem.MethodWe performed gene‐level and meta‐analysis association studies for two cohorts: Cardiovascular Heart Study (CHS) and Framingham (FRAM) using Alzheimer’s disease as a primary outcome. To support our findings, we also performed meta‐analysis following gene‐enrichment study for both cohorts. Analysis was performed separately for males and females and for both sexes. Additional covariates were age, smoking. Gene‐level analysis was performed with fastBAT and enrichment analysis with ClusterProfiler on KEGG database.ResultOur analysis identified a list of highly significant genes, such as TOMM40, APOC1 (all with FDR‐adjusted p‐value < 0.05) and pathways, such as Cholesterol metabolism, Fluid shear stress and atherosclerosis, Proteoglycans in cancer, Lipid and atherosclerosis showed statistically significant associations (FDR‐adjusted p‐value < 0.05) in both datasets and sexes.Meta‐analysis revealed TOMM40 (p‐value = 2.35E‐16), APOC1 (p‐value 4.46E‐13), ENSG00000259648 (p‐value = 8.88E‐06), PEX7 (p‐value = 4.40E‐05), ENSG00000287274 (p‐value = 5.38E‐05) genes for men and women combined; men exclusively revealed ENSG00000259648, TOMM40, and APOC1 (p‐value<1.75E‐05) and women TOMM40 and APOC1 (p‐value<6E‐08).Gene‐enrichment meta‐analysis revealed NOD‐like receptor signaling pathway (adjusted p‐value 3.23E‐07), Lipid and atherosclerosis (p‐value = 5.93E‐05), Yersinia (p‐value = 1.17E‐04) for men and women combined; for men only the pathways are Lipid and atherosclerosis (p‐value = 3.61E‐03), TGF‐beta signaling pathway (p‐value = 3.61E‐03), AGE‐RAGE signaling pathway in diabetic complications (p‐value = 5.18E‐03); and for women Cholesterol metabolism (p‐value = 3.49E‐07), Fatty acid degradation (p‐value = 1.04E‐06), PPAR signaling pathway (p‐value = 1.23E‐05).ConclusionIn this work we were able to identify statistically significant genes and pathways showed replication across the studies and are potentially useful for uncovering genetic mechanisms of AD. However, other things such as genetic heterogeneity may influence disease developing and needed further exploration.

Noninvasive in vivo application of confocal Raman spectroscopy in identifying age-related biochemical changes in human stratum corneum and epidermis

Stratum corneum, and epidermis, regions of human skin were analyzed in vivo using confocal Raman spectroscopy to evaluate age-related biochemical and spectral changes. The data consisted of two defined age groups comprising 71 volunteers (27 ± 3 and 55 ± 4 years old). Multivariate statistical analyses were used to interpret and classify the average spectral data for each skin layer. The analyses demonstrated the measurement of two different groups of skin with different ages and revealed the most representative peaks for both the stratum corneum and epidermis. The Amide III and Amide I, both in α-helix conformation, exhibited increased signals in the spectra of the epidermis and stratum corneum of the younger group, and it was observed that an increased crosslinking of keratin filaments with age is a potential contributor to the stiffness increment, which consequently leads to a decrease in the Raman signal in the older group. The opposite occurred for the lipids signal, as changes in the lateral packing of lipids indicate skin ageing and an increase in the Raman signal. The disparity in the means of total natural moisturizing factor, was statistically significant between the two age groups. The statistical results demonstrated the emergence of distinct groups pertaining to the epidermis and stratum corneum, as well as pertaining to group I or II.

The role of extended synaptotagmin at membrane contact sites in cancer research

Membrane contact sites (MCSs) are adjacent locations between the membranes of two different organelles and play important roles in various physiological processes, including cellular calcium and lipid signaling. In cancer research, MCSs have been proposed to regulate tumor metabolism and fate, contributing to tumor progression, and this function could be exploited for tumor therapy. However, there is little evidence on how MCSs are involved in cancer progression. In this review, we use extended synaptotagmins (E-Syts) as an entry point to describe how MCSs affect cancer progression and may be used as new diagnostic biomarkers. We then introduced the role of E-Syt and its related pathways in calcium and lipid signaling, aiming to explain how MCSs affect tumor proliferation, progression, metastasis, apoptosis, drug resistance, and treatment through calcium and lipid signaling. Generally, this review will facilitate the understanding of the complex contact biology of cancer cells.

Lipid signaling and proline catabolism are activated in barley roots (Hordeum vulgare L.) during recovery from cold stress

Previous findings have shown that phospholipase D (PLD) contributes to the response to long-term chilling stress in barley by regulating the balance of proline (Pro) levels. Although Pro accumulation is one of the most prominent changes in barley roots exposed to this kind of stress, the regulation of its metabolism during recovery from stress remains unclear. Research has mostly focused on the responses to stress per se, and not much is known about the dynamics and mechanisms underlying the subsequent recovery. The present study aimed to evaluate how PLD, its product phosphatidic acid (PA), and diacylglycerol pyrophosphate (DGPP) modulate Pro accumulation in barley during recovery from long-term chilling stress. Pro metabolism involves different pathways and enzymes. The rate-limiting step is mediated by pyrroline-5-carboxylate synthetase (P5CS) in its biosynthesis, and by proline dehydrogenase (ProDH) in its catabolism. We observed that Pro levels decreased in recovering barley roots due to an increase in ProDH activity. The addition of 1-butanol, a PLD inhibitor, reverted this effect and altered the relative gene expression of ProDH. When barley tissues were treated with PA before recovery, the fresh weight of roots increased and ProDH activity was stimulated. These data contribute to our understanding of how acidic membrane phospholipids like PA help to control Pro degradation during recovery from stress.

Long noncoding RNAs and their complex role in shaping and regulating arachidonic acid metabolism: Learning to love the (not-really) junk.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators in numerous biological processes. The arachidonic acid (AA) metabolic pathway is a fundamental biochemical pathway responsible for the enzymatic conversion of AA, a 20-carbon omega-six polyunsaturated fatty acid, into a variety of potent lipid signaling molecules known as eicosanoids. Eicosanoids are produced through the cyclooxygenase and lipoxygenase arms of the AA pathway and have diverse biological roles in both healthy and disease states, including cancer and inflammatory diseases. Cyclooxygenase 2 (COX-2), the inducible, rate-limiting enzyme of the cyclooxygenase arm, produces two main forms of eicosanoids: prostaglandins and thromboxanes. AA metabolized through the lipoxygenase arm by the action of 5-lipoxygenase (ALOX5) produces eicosanoids known as leukotrienes. COX-2 and ALOX5 gene expression are regulated through many different lncRNAs and microRNA (miRNA)-mediated mechanisms. As previously reviewed, noncoding RNAs affect transcription, splicing, alternative polyadenylation, messenger RNA stability, translation, and miRNA regulation of COX-2 and ALOX5 (Lutz and Cornett, 2013, Wiley Interdisciplinary Reviews. RNA, 4(5), 593-605). This current review discusses the intricate roles of lncRNAs, including MALAT1, NEAT1, HOTAIR, PACER, and others, in modulating the AA pathway. In this review update, we will delve into advancements in our understanding of AA gene expression regulation. We will explore the mechanisms of lncRNAs and their associated miRNAs and proteins known to regulate key components of the AA signaling pathway. We will also discuss the therapeutic potential of targeting lncRNA-mediated regulation, with a focus on modulating COX-2 and ALOX5 activity and downstream eicosanoid production for applications in inflammatory and oncological conditions. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease.

Unraveling the Cave: A Seventy-Year Journey into the Caveolar Network, Cellular Signaling, and Human Disease.

In the mid-1950s, a groundbreaking discovery revealed the fascinating presence of caveolae, referred to as flask-shaped invaginations of the plasma membrane, sparking renewed excitement in the field of cell biology. Caveolae are small, flask-shaped invaginations in the cell membrane that play crucial roles in diverse cellular processes, including endocytosis, lipid homeostasis, and signal transduction. The structural stability and functionality of these specialized membrane microdomains are attributed to the coordinated activity of scaffolding proteins, including caveolins and cavins. While caveolae and caveolins have been long appreciated for their integral roles in cellular physiology, the accumulating scientific evidence throughout the years reaffirms their association with a broad spectrum of human disorders. This review article aims to offer a thorough account of the historical advancements in caveolae research, spanning from their initial discovery to the recognition of caveolin family proteins and their intricate contributions to cellular functions. Furthermore, it will examine the consequences of a dysfunctional caveolar network in the development of human diseases.

Quantifying single-cell diacylglycerol signaling kinetics after uncaging

Studying the role of molecularly distinct lipid species in cell signaling remains challenging due to a scarcity of methods for performing quantitative lipid biochemistry in living cells. We have recently used lipid uncaging to quantify lipid-protein affinities and rates of lipid trans-bilayer movement and turnover in the diacylglycerol signaling pathway. This approach is based on acquiring live-cell dose-response curves requiring light dose titrations and experimental determination of uncaging photoreaction efficiency. We here aimed to develop a methodological approach that allows us to retrieve quantitative kinetic data from uncaging experiments that 1) require only typically available datasets without the need for specialized additional constraints and 2) should in principle be applicable to other types of photoactivation experiments. Our new analysis framework allows us to identify model parameters such as diacylglycerol-protein affinities and trans-bilayer movement rates, together with initial uncaged diacylglycerol levels, using noisy single-cell data for a broad variety of structurally different diacylglycerol species. We find that lipid unsaturation degree and side-chain length generally correlate with faster lipid trans-bilayer movement and turnover and also affect lipid-protein affinities. In summary, our work demonstrates how rate parameters and lipid-protein affinities can be quantified from single-cell signaling trajectories with sufficient sensitivity to resolve the subtle kinetic differences caused by the chemical diversity of cellular signaling lipid pools.

Review of molecular biological research on the treatment of membranous nephropathy with Tripterygium glycosides based on TCM theory.

To explore the mechanism of Tripterygium wilfordii polyglycoside (TWP) in the treatment of membranous nephropathy (MN) by network pharmacology. TCMSP and DrugBank databases were used to screen the main targets of the main active components of Tripterygium glycosides, and OMIM and Gene Cards databases were used to search the gene targets of MN. UniProt database was used to normalize all the targets to get the intersection targets of TGs and MNs. Synergistic genes were uploaded to the STRING platform to construct a protein-protein interaction network and screen related core targets. Gene Ontology and Kyoto Genome Encyclopedia analyses of core targets were performed using the DAVID database. AutoDockTools software was used to verify the molecular docking between the active components of TGs and the synergistic genes. We identified 126 potential targets for the active component of Tripterygium glycosides, 584 MN-associated disease targets, and 28 co-acting genes. It mainly involves AGE-RAGE signaling pathway, lipid and atherosclerosis, IL-17 signaling pathway, fluid shear stress and atherosclerosis, NF-kappa B signaling pathway and other pathways and biological pathways in diabetic complications. The active component of that Tripterygium glycosides and the active site of the synergistic core target can the bond energy is less than -5kJ/mol. Tripterygium glycosides can regulate the release of inflammatory factors to treat MN through multiple active components, multiple disease targets, multiple biological pathways and multiple pathways, which provides a basis for broadening the clinical use of traditional Chinese medicine in the treatment of MN.

Pulled Flowprobe for Ambient Liquid Extraction-Based High Spatial Resolution Mass Spectrometry Imaging with Enhanced Sensitivity and Stability.

Ambient liquid extraction techniques enable direct mass spectrometry imaging (MSI) under ambient conditions with minimal sample preparation. However, currently an integrated probe for ambient liquid extraction-based MSI with high spatial resolution, high sensitivity, and stability is still lacking. In this work, we developed a new integrated probe made of pulled coaxial capillaries, named pulled flowprobe, and compared it with the previously reported single-probe. Mass transfer kinetics in probes was first investigated. The extraction kinetic curves during probe sampling indicate a narrower and higher peak shape for the pulled flowprobe than single-probe. Computational fluid dynamics analysis reveals that in the pulled flowprobe flow velocities are lower in liquid microjunction and higher in the transferring channels, resulting in higher extraction efficiencies and reduced band diffusion compared with single-probe and other probes with a similar flow route. Results of ambient liquid extraction-based MSI of lipids in rat cerebrum show that signals of low-abundance lipids were 2-5 times higher via a pulled flowprobe than via a single-probe, and 26 more lipid species were detected on brain tissue via a pulled flowprobe than via a single-probe. The stability of MSI with the pulled flowprobe was found to be higher than that with single-probe (averaged relative standard deviation = 18% vs 80%) by imaging a lab-made uniform ink coating. Moreover, in the pulled flowprobe, no retraction of the inner capillary from outer capillary is optimal for both sensitivity and stability. The spatial resolution of the pulled flowprobe (30-40 μm) was measured to be higher than that of a comparable size single-probe by calculation with the "80-20" rule. Finally, the new pulled flowprobe was applied to high-resolution MSI of lipids in the hippocampus, and localization of several lipids to the specific cell layers in the hippocampus region was observed. Thus, this work provides an alternative easily fabricated sampling probe with enhanced sensitivity, stability, and spatial resolution, promoting the use of ambient liquid extraction-based MSI in biological and clinical research.

Enhancement of peripheral fatty acyl ethanolamide signaling prevents stress-induced social avoidance and anxiety-like behaviors in male rats

Abstract Rationale Exposure to traumatic events can lead to alterations in social and anxiety-related behaviors. Emerging evidence suggests that peripheral host-defense processes are implicated in the expression of stress-induced behavioral responses and may be targeted to mitigate the negative sequalae of stress exposure. Objectives In this study, we used the peripherally restricted FAAH inhibitor URB937 to investigate the effects of the fatty acyl ethanolamide (FAE) family of lipid mediators – which include the endocannabinoid anandamide and the endogenous PPAR-α agonists, oleoylethanolamide and palmitoylethanolamide – on behavioral and peripheral biochemical responses to two ethologically distinct rat models of stress. Methods Male adult rats were exposed to acute social defeat, a model of psychological stress (Experiment 1), or to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a test of innate predator-evoked fear (Experiment 2), and subsequently treated with URB937 (1 or 3 mg/kg, intraperitoneal) or vehicle. Behavioral analyses were conducted 24 h (Experiment 1) or 7 days (Experiment 2) after exposure. Results URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat Conclusions Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure.

Peroxisome population control by phosphoinositide signaling at the endoplasmic reticulum-plasma membrane interface.

Phosphoinositides are lipid signaling molecules acting at the interface of membranes and the cytosol to regulate membrane trafficking, lipid transport and responses to extracellular stimuli. Peroxisomes are multicopy organelles that are highly responsive to changes in metabolic and environmental conditions. In yeast, peroxisomes are tethered to the cell cortex at defined focal structures containing the peroxisome inheritance protein, Inp1p. We investigated the potential impact of changes in cortical phosphoinositide levels on the peroxisome compartment of the yeast cell. Here we show that the phosphoinositide, phosphatidylinositol-4-phosphate (PI4P), found at the junction of the cortical endoplasmic reticulum and plasma membrane (cER-PM) acts to regulate the cell's peroxisome population. In cells lacking a cER-PM tether or the enzymatic activity of the lipid phosphatase Sac1p, cortical PI4P is elevated, peroxisome numbers and motility are increased, and peroxisomes are no longer firmly tethered to Inp1p-containing foci. Reattachment of the cER to the PM through an artificial ER-PM "staple" in cells lacking the cER-PM tether does not restore peroxisome populations to the wild-type condition, demonstrating that integrity of PI4P signaling at the cell cortex is required for peroxisome homeostasis.

Nitrogen Oxide-derived Anti-inflammatory Lipid Signaling Mediators

Nitrogen Oxide-derived Anti-inflammatory Lipid Signaling Mediators

Exploring the pharmacological mechanisms of Biyan Qingdu Granula in the treatment after nasopharyngeal carcinoma radiotherapy based on UPLC/Q-TOF MS, network pharmacology and molecular docking

BackgroundBiyan Qingdu Granula (BYQD) is a traditional Chinese medicine (TCM) formula commonly used for post-radiotherapy treatment of nasopharyngeal carcinoma (NPC). Despite its extensive use, the underlying pharmacological mechanisms have yet to be fully elucidated. MethodsUPLC/Q-TOF MS was used to comprehensively analyze the chemical composition of BYQD. Additionally, an everted gut sac model, coupled with UPLC/Q-TOF MS, was used to screen and identify the active ingredients. Subsequently, we conducted a network pharmacological analysis to delve into the potential mechanisms of these active ingredients. Molecular docking experiments were also performed to assess the interactions between active ingredients and potential core targets. ResultsThe findings revealed the identification of 62 identical ingredients upon comparing the sample solution and intestinal absorbed solution of BYQD. We constructed a protein-protein interaction (PPI) network, which led to the identification of five core targets, namely, TP53, STAT3, MAPK1, SRC and AKT1. Through the construction of a drug-active ingredient-intersection target network, we identified Quercetin, Luteolin, Eupatilin, Magnoflorine, Acacetin and other compound as potential active ingredients. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that pathways in cancer, PI3K-Akt signaling pathway, lipid and atherosclerosis, proteoglycans in cancer, and the MAPK signaling pathway might play the key roles in the treatment of NPC after radiotherapy using BYQD. Molecular docking results corroborated strong binding activity between the putative core targets and the corresponding key active ingredients. ConclusionThis study provides a preliminary revelation of the active ingredients and potential pharmacological mechanisms of BYQD in the post-radiotherapy treatment of NPC. These findings establish a vital theoretical basis and serve as a scientific reference for the future investigating the pharmacological mechanisms and clinical application of BYQD.

Network pharmacology-based and molecular docking-based analysis of You-Gui-Yin for the treatment of osteonecrosis of the femoral head.

You-Gui-Yin (YGY) is a classic prescription for warming up kidney-Yang and filling in kidney essence in traditional Chinese medicine, and has been used to treat osteonecrosis of the femoral head (ONFH) effectively. However, the underlying mechanisms are still unknown. This study is aimed at exploring the possible mechanisms of action of the YGY in the treatment of ONFH based on network pharmacology and molecular docking. TCMSP was used to screen the active components and targets of YGY. The disease targets of ONFH were collected in several public databases. The protein-protein interaction (PPI) Network was constructed using the STRING platform. The Metascape database platform was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The key active components and core target proteins of YGY in the treatment of ONFH were verified by the molecular docking. 120 active components were obtained from YGY, among which 73 components were hit by the 117 drug-disease intersection targets. Key effective components included quercetin, kaempferol, beta-sitosterol, glycitein, beta-carotene, and so on. Core target proteins included ALB, AKT1, TNF, IL6, TP53, and so on. According to GO and KEGG analyses, there were 1762 biological processes, 94 cellular component, 138 molecular function and 187 signaling pathways involved. we selected the top 20 biological processes (BP), cellular components (CC), molecular functions (MF) and signaling pathways to draw the heat maps, showing that Lipid and atherosclerosis signaling pathway, IL-17 signaling pathway, HIF-1 signaling pathway, relaxin signaling pathway and MAPK signaling pathway and other pathways may play a key role in the treatment of ONFH by YGY. The results of molecular docking showed that key effective components and corresponding core target proteins exhibited the good binding activity. YGY can treat ONFH through multicomponents, multitargets, and multipathways, which provides a reference for the subsequent research, development of targeted drugs and clinical application.

Self-DNA Inhibition in Drosophila melanogaster Development: Metabolomic Evidence of the Molecular Determinants.

We investigated the effects of dietary delivered self-DNA in the model insect Drosophila melanogaster. Self-DNA administration resulted in low but significant lethality in Drosophila larvae and considerably extended the fly developmental time. This was characterized by the abnormal persistence of the larvae in the L2 and L3 stages, which largely accounted for the average 72 h delay observed in pupariation, as compared to controls. In addition, self-DNA exposure affected adult reproduction by markedly reducing both female fecundity and fertility, further demonstrating its impact on Drosophila developmental processes. The effects on the metabolites of D. melanogaster larvae after exposure to self-DNA were studied by NMR, LC-MS, and molecular networking. The results showed that self-DNA feeding reduces the amounts of all metabolites, particularly amino acids and N-acyl amino acids, which are known to act as lipid signal mediators. An increasing amount of phloroglucinol was found after self-DNA exposure and correlated to developmental delay and egg-laying suppression. Pidolate, a known intermediate in the γ-glutamyl cycle, also increased after exposure to self-DNA and correlated to the block of insect oogenesis.

CD36 as a gatekeeper of myocardial lipid metabolism and therapeutic target for metabolic disease.

The multifunctional membrane glycoprotein CD36 is expressed in different types of cells and plays a key regulatory role in cellular lipid metabolism, especially in cardiac muscle. CD36 facilitates the cellular uptake of long-chain fatty acids, mediates lipid signaling, and regulates storage and oxidation of lipids in various tissues with active lipid metabolism. CD36 deficiency leads to marked impairments in peripheral lipid metabolism, which consequently impact on the cellular utilization of multiple different fuels because of the integrated nature of metabolism. The functional presence of CD36 at the plasma membrane is regulated by its reversible subcellular recycling from and to endosomes and is under the control of mechanical, hormonal, and nutritional factors. Aberrations in this dynamic role of CD36 are causally associated with various metabolic diseases, in particular insulin resistance, diabetic cardiomyopathy, and cardiac hypertrophy. Recent research in cardiac muscle has disclosed the endosomal proton pump vacuolar-type H+-ATPase (v-ATPase) as a key enzyme regulating subcellular CD36 recycling and being the site of interaction between various substrates to determine cellular substrate preference. In addition, evidence is accumulating that interventions targeting CD36 directly or modulating its subcellular recycling are effective for the treatment of metabolic diseases. In conclusion, subcellular CD36 localization is the major adaptive regulator of cellular uptake and metabolism of long-chain fatty acids and appears a suitable target for metabolic modulation therapy to mend failing hearts.

Nutrient-regulated control of lysosome function by signaling lipid conversion

Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated in response to cellular nutrient status is poorly understood. We show here that lysosome morphology and function are reversibly controlled by a nutrient-regulated signaling lipid switch that triggers the conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active and static mTORC1-inactive degradative lysosomes clustered at the cell center. Starvation-triggered relocalization of phosphatidylinositol 4-phosphate (PI(4)P)-metabolizing enzymes reshapes the lysosomal surface proteome to facilitate lysosomal proteolysis and to repress mTORC1 signaling. Concomitantly, lysosomal phosphatidylinositol 3-phosphate (PI(3)P), which marks motile signaling-active lysosomes in the cell periphery, is erased. Interference with this PI(3)P/PI(4)P lipid switch module impairs the adaptive response of cells to altering nutrient supply. Our data unravel a key function for lysosomal phosphoinositide metabolism in rewiring organellar membrane dynamics in response to cellular nutrient status.

CB₂R ligands to treat inflammatory diabetes

CB₂R ligands to treat inflammatory diabetes Researchers discuss how scientific innovations might influence the discovery of future tailor-made CB2R-based anti-inflammatory treatments. The G-protein-coupled receptor (GPCR) type-2 cannabinoid receptor (CB2R) is a 2 highly promising pharmacological target for novel anti-inflammatory medicines. (1) CB2R is an essential component of a vital lipid signaling system that tremendously influences multiple human health and disease states ranging from metabolic disorders to neurodegenerative diseases and is termed endocannabinoid system (ECS). Few CB2R-activation-based drugs have been launched. (2) Several candidates are under active clinical development, aiming at treating diseases in which inflammatory processes play a significant role or are the underlying reason. Recent scientific innovations in ECS research and drug discovery in general (Figure 1) are now being incorporated into the design, synthesis and evaluation of novel ligands targeting CB2R. They will impact the generation of further improved tailor-made medicines for inflammatory diseases.