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Frontiers in Veterinary Science 2024This study aims to explore the important factors affecting the characteristics of different parts of pork.
INTRODUCTION
This study aims to explore the important factors affecting the characteristics of different parts of pork.
METHODS
Lipidomics and proteomics methods were used to analyze DAL (differential lipids) and DAPs (differential proteins) in five different parts (longissimus dorsi, belly meat, loin, forelegs and buttocks) of Duhua pig (Duroc × Guangdong small spotted pig), to identify potential pathways affecting meat quality, investigating fat deposition in pork and its lipid-protein interactions.
RESULTS
The results show that TG (triglyceride) is the lipid subclass with the highest proportion in muscle, and the pathway with the most significantly enriched lipids is GP. DAP clustered on several GO terms closely related to lipid metabolism and lipogenesis (lipid binding, lipid metabolism, lipid transport, and lipid regulation). In KEGG analysis, there are two main DAP aggregation pathways related to lipid metabolism, namely Fatty acid degradation and oxidative phosphorylation. In PPI analysis, we screened out 31 core proteins, among which NDUFA6, NDUFA9 and ACO2 are the most critical.
DISCUSSION
PC (phosphatidylcholine) is regulated by SNX5, THBS1, ANXA7, TPP1, CAVIN2, and VDAC2 in the phospholipid binding pathway. TG is regulated by AUH/HADH/ACADM/ACADL/HADHA in the lipid oxidation and lipid modification pathways. Potential biomarkers are rich in SFA, MUFA and PUFA respectively, the amounts of SFA, MUFA and PUFA in the lipid measurement results are consistent with the up- and down-regulation of potential biomarker lipids. This study clarified the differences in protein and lipid compositions in different parts of Duhua pigs and provided data support for revealing the interactions between pork lipids and proteins. These findings provide contributions to the study of intramuscular fat deposition in pork from a genetic and nutritional perspective.
PubMed: 38659450
DOI: 10.3389/fvets.2024.1361441 -
Free Radical Biology & Medicine Aug 2024Fusobacterium (F.) nucleatum is a carcinogenesis microbiota in colorectal cancer (CRC). Growing evidence shows that F. nucleatum contributes to chemoresistance....
Fusobacterium (F.) nucleatum is a carcinogenesis microbiota in colorectal cancer (CRC). Growing evidence shows that F. nucleatum contributes to chemoresistance. Ferroptosis is reported to restore the susceptibility of resistant cells to chemotherapy. However, the role of gut microbiota affecting ferroptosis in chemoresistance remains unclear. Here, we examined the CRC tissues of patients using 16S rRNA sequencing to investigate the possible connection between gut microbiota dysbiosis and the relapse of CRC. We found that a high abundance of F. nucleatum in CRC tissue is associated with relapse. We further demonstrated that F. nucleatum induced oxaliplatin resistance in vitro and in vivo. The transcriptome of an F. nucleatum-infected cell revealed ferroptosis was associated with F. nucleatum infection. We perform malondialdehyde, ferrous iron, and glutathione assays to verify the effect of F. nucleatum on ferroptosis under oxaliplatin treatment in vivo and in vitro. Mechanistically, F. nucleatum promoted oxaliplatin resistance by overexpressing GPX4 and then inhibiting ferroptosis. E-cadherin/β-catenin/TCF4 pathway conducted the GPX4 overexpression effect of F. nucleatum. The chromatin immuno-precipitation quantitative PCR (CHIP-qPCR) and dual-luciferase reporter assay showed that F. nucleatum promoted TCF4 binding with GPX4. We also determined the E-cadherin/β-catenin/TCF4/GPX4 axis related to tumor tissue F. nucleatum status and CRC relapse clinically. Here, we revealed the contribution of F. nucleatum to oxaliplatin resistance by inhibiting ferroptosis in CRC. Targeting F. nucleatum and ferroptosis will provide valuable insight into chemoresistance management and may improve outcomes for patients with CRC.
Topics: Ferroptosis; Humans; Colorectal Neoplasms; Drug Resistance, Neoplasm; Cadherins; Oxaliplatin; beta Catenin; Phospholipid Hydroperoxide Glutathione Peroxidase; Animals; Fusobacterium nucleatum; Mice; Gastrointestinal Microbiome; Xenograft Model Antitumor Assays; Gene Expression Regulation, Neoplastic; Male; Antigens, CD; Female; Cell Line, Tumor; Fusobacterium Infections; Dysbiosis; Transcription Factor 4; Mice, Nude
PubMed: 38657754
DOI: 10.1016/j.freeradbiomed.2024.04.226 -
Materials Today. Bio Jun 2024The complex genomics, immunosuppressive tumor microenvironment (TME), and chemotherapeutic resistance of osteosarcoma (OS) have resulted in limited therapeutic effects...
The complex genomics, immunosuppressive tumor microenvironment (TME), and chemotherapeutic resistance of osteosarcoma (OS) have resulted in limited therapeutic effects in the clinic. Ferroptosis is involved in tumor progression and is regulated mainly by glutathione peroxidase 4 (GPX4). Small interfering RNA (siRNA)-based RNA interference (RNAi) can precisely target any gene. However, achieving effective siRNA delivery is highly challenging. Here, we fabricated a TME-responsive metal-organic framework (MOF)-based biomimetic nanosystem (mFeP@si) with siGPX4 delivery and sonodynamic therapy (SDT) to treat OS by targeting ferroptosis. Under ultrasound (US) irradiation, mFeP@si achieves lysosomal escape via singlet oxygen (O)-mediated lysosomal membrane disruption and then accelerates ROS generation and glutathione (GSH) depletion. Meanwhile, siGPX4 silences GPX4 expression by binding to GPX4 mRNA and leads to the accumulation of toxic phospholipid hydroperoxides (PL-OOH), further magnifying the ROS storm and triggering ferroptosis. Notably, synergistic therapy remarkably enhances antitumor effects, improves the immunosuppressive TME by inducing potent immunogenic cell death (ICD), and increases the sensitivity of chemotherapy-resistant OS cells to cisplatin. Overall, this novel nanosystem, which targets ferroptosis by integrating RNAi and SDT, exhibits strong antitumor effects both in vitro and in vivo, providing new insights for treating OS.
PubMed: 38654934
DOI: 10.1016/j.mtbio.2024.101053 -
Journal of Molecular Medicine (Berlin,... Jun 2024Annexins, a group of Ca-dependent phospholipid-binding proteins, exert diverse roles in neuronal development, normal central nervous system (CNS) functioning,... (Review)
Review
Annexins, a group of Ca-dependent phospholipid-binding proteins, exert diverse roles in neuronal development, normal central nervous system (CNS) functioning, neurological disorders, and CNS tumors. This paper reviews the roles of individual annexins (A1-A13) in these contexts. Annexins possess unique structural and functional features, such as Ca-dependent binding to phospholipids, participating in membrane organization, and modulating cell signaling. They are implicated in various CNS processes, including endocytosis, exocytosis, and stabilization of plasma membranes. Annexins exhibit dynamic roles in neuronal development, influencing differentiation, proliferation, and synaptic formation in CNS tissues. Notably, annexins such as ANXA1 and ANXA2 play roles in apoptosis and blood-brain barrier (BBB) integrity. Neurological disorders, including Alzheimer's disease, multiple sclerosis, and depression, involve annexin dysregulation, influencing neuroinflammation, blood-brain barrier integrity, and stress responses. Moreover, annexins contribute to the pathogenesis of CNS tumors, either promoting or suppressing tumor growth, angiogenesis, and invasion. Annexin expression patterns vary across different CNS tumor types, providing potential prognostic markers and therapeutic targets. This review underscores the multifaceted roles of annexins in the CNS, highlighting their importance in normal functioning, disease progression, and potential therapeutic interventions.
Topics: Humans; Annexins; Animals; Central Nervous System; Blood-Brain Barrier; Central Nervous System Diseases; Central Nervous System Neoplasms
PubMed: 38639785
DOI: 10.1007/s00109-024-02443-7 -
Cell Reports May 2024Phosphatidylinositol 3-kinase α (PI3Kα) is a heterodimer of p110α catalytic and p85 adaptor subunits that is activated by agonist-stimulated receptor tyrosine...
Phosphatidylinositol 3-kinase α (PI3Kα) is a heterodimer of p110α catalytic and p85 adaptor subunits that is activated by agonist-stimulated receptor tyrosine kinases. Although p85α recruits p110α to activated receptors on membranes, p85α loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. p110α localizes to microtubules via microtubule-associated protein 4 (MAP4), facilitating its interaction with activated receptor kinases on endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85α knockdown, the residual p110α, coupled predominantly to p85β, exhibits enhanced recruitment with receptor tyrosine kinases to endosomes. Moreover, the p110α C2 domain binds PI3-phosphate, and this interaction is also required to recruit p110α to endosomes and for PI3K/Akt signaling. Stable knockdown of p85α, which mimics the reduced p85α levels observed in cancer, enhances cell growth and tumorsphere formation, and these effects are abrogated by MAP4 or p85β knockdown, underscoring their role in the tumor-promoting activity of p85α loss.
Topics: Animals; Humans; Cell Proliferation; Class Ia Phosphatidylinositol 3-Kinase; Endosomes; Enzyme Activation; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Protein Binding; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 38630589
DOI: 10.1016/j.celrep.2024.114119 -
Clinical and Experimental Nephrology Jun 2024Inflammation plays a crucial role in the pathophysiology of various kidney diseases. Kidney perivascular cells (pericytes/fibroblasts) are responsible for producing... (Review)
Review
Inflammation plays a crucial role in the pathophysiology of various kidney diseases. Kidney perivascular cells (pericytes/fibroblasts) are responsible for producing proinflammatory molecules, promoting immune cell infiltration, and enhancing inflammation. Vascular adhesion protein-1, expressed in kidney perivascular cells, is an ectoenzyme that catalyzes the oxidative deamination of primary amines with the production of hydrogen peroxide in the extracellular space. Our study demonstrated that blocking this enzyme suppressed hydrogen peroxide production and neutrophil infiltration, thereby reducing renal ischemia-reperfusion injury. Sphingosine 1-phosphate (S1P) signaling was also observed to play an essential role in the regulation of perivascular inflammation. S1P, which is produced in kidney perivascular cells, is transported into the extracellular space via spinster homolog 2, and then binds to S1P receptor-1 expressed in perivascular cells. Upon injury, inflammatory signaling in perivascular cells is enhanced by this pathway, thereby promoting immune cell infiltration and subsequent fibrosis. Furthermore, inhibition of S1P transport by spinster homolog 2 reduces kidney fibrosis. Hypoxia-inducible factor-prolyl hydroxylase inhibitors can restore the capacity for erythropoietin production in kidney perivascular cells. Animal data suggested that these drugs could also alleviate kidney and lipid inflammation although the precise mechanism is still unknown. Neuroimmune interactions have been attracting significant attention due to their potential to benefit patients with inflammatory diseases. Vagus nerve stimulation is one of the most promising strategies for harnessing neuroimmune interactions and attenuating inflammation associated with various diseases, including kidney disease. Using cutting-edge tools, the vagal afferents-C1 neurons-sympathetic nervous system-splenic nerve-spleen-kidney axis responsible for kidney protection induced by vagus nerve stimulation was identified in our study. Further research is required to decipher other crucial systems that control kidney inflammation and to determine whether these novel strategies can be applied to patients with kidney disease.
Topics: Humans; Animals; Lysophospholipids; Sphingosine; Neuroimmunomodulation; Kidney Diseases; Kidney; Inflammation; Signal Transduction; Vascular Cell Adhesion Molecule-1
PubMed: 38630367
DOI: 10.1007/s10157-024-02494-7 -
Nature Communications Apr 2024Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent...
Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent further peroxidation. Here we identify the upregulation of lipopolysaccharide-binding protein (LBP) and its trafficking through LDs as a mechanism for modulating LD homeostasis in response to oxidative stress. Our results suggest that LBP induces lipid accumulation by controlling lipid-redox homeostasis through its lipid-capture activity, sorting unsaturated triglycerides into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated triglycerides accumulation by phospholipid/triglycerides competition and Peroxiredoxin 4, a redox state sensor of LBP that regulates the shuttle of LBP from LDs. Furthermore, chronic stress upregulates LBP expression, leading to insulin resistance and obesity. Our findings contribute to the understanding of the role of LBP in regulating LD homeostasis and against cellular peroxidative injury. These insights could inform the development of redox-based therapies for alleviating oxidative stress-induced metabolic dysfunction.
Topics: Acute-Phase Proteins; Carrier Proteins; Homeostasis; Lipid Droplets; Lipopolysaccharides; Membrane Glycoproteins; Oxidative Stress; Triglycerides
PubMed: 38615060
DOI: 10.1038/s41467-024-47553-5 -
International Journal of Molecular... Mar 2024Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step in triacylglycerol synthesis. Understanding its substrate recognition mechanism may help to design...
Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step in triacylglycerol synthesis. Understanding its substrate recognition mechanism may help to design drugs to regulate the production of glycerol lipids in cells. In this work, we investigate how the native substrate, glycerol-3-phosphate (G3P), and palmitoyl-coenzyme A (CoA) bind to the human GPAT isoform GPAT4 via molecular dynamics simulations (MD). As no experimentally resolved GPAT4 structure is available, the AlphaFold model is employed to construct the GPAT4-substrate complex model. Using another isoform, GPAT1, we demonstrate that once the ligand binding is properly addressed, the AlphaFold complex model can deliver similar results to the experimentally resolved structure in MD simulations. Following the validated protocol of complex construction, we perform MD simulations using the GPAT4-substrate complex. Our simulations reveal that R427 is an important residue in recognizing G3P via a stable salt bridge, but its motion can bring the ligand to different binding hotspots on GPAT4. Such high flexibility can be attributed to the flexible region that exists only on GPAT4 and not on GPAT1. Our study reveals the substrate recognition mechanism of GPAT4 and hence paves the way towards designing GPAT4 inhibitors.
Topics: Humans; Molecular Dynamics Simulation; Glycerol; Ligands; Glycerol-3-Phosphate O-Acyltransferase; Protein Isoforms; Phosphates; Glycerophosphates
PubMed: 38612541
DOI: 10.3390/ijms25073729 -
Journal of the American Chemical Society Apr 2024Lipopolysaccharide (LPS) is vital for maintaining the outer membrane barrier in Gram-negative bacteria. LPS is also frequently obtained in complex with the inner...
Lipopolysaccharide (LPS) is vital for maintaining the outer membrane barrier in Gram-negative bacteria. LPS is also frequently obtained in complex with the inner membrane proteins after detergent purification. The question of whether or not LPS binding to inner membrane proteins not involved in outer membrane biogenesis reflects native lipid environments remains unclear. Here, we leverage the control of the hydrophilic-lipophilic balance and packing parameter concepts to chemically tune detergents that can be used to qualitatively differentiate the degree to which proteins copurify with phospholipids (PLs) and/or LPS. Given the scalable properties of these detergents, we demonstrate a detergent fine-tuning that enables the facile investigation of intact proteins and their complexes with lipids by native mass spectrometry (nMS). We conclude that LPS, a lipid that is believed to be important for outer membranes, can also affect the activity of membrane proteins that are currently not assigned to be involved in outer membrane biogenesis. Our results deliver a scalable detergent chemistry for a streamlined biophysical characterization of protein-lipid interactions, provide a rationale for the high affinity of LPS-protein binding, and identify noncanonical associations between LPS and inner membrane proteins with relevance for membrane biology and antibiotic research.
PubMed: 38604609
DOI: 10.1021/jacs.3c14358 -
Communications Biology Apr 2024The ability of the Torpedo nicotinic acetylcholine receptor (nAChR) to undergo agonist-induced conformational transitions requires the presence of cholesterol and/or...
The ability of the Torpedo nicotinic acetylcholine receptor (nAChR) to undergo agonist-induced conformational transitions requires the presence of cholesterol and/or anionic lipids. Here we use recently solved structures along with multiscale molecular dynamics simulations to examine lipid binding to the nAChR in bilayers that have defined effects on nAChR function. We examine how phosphatidic acid and cholesterol, lipids that support conformational transitions, individually compete for binding with phosphatidylcholine, a lipid that does not. We also examine how the two lipids work synergistically to stabilize an agonist-responsive nAChR. We identify rapidly exchanging lipid binding sites, including both phospholipid sites with a high affinity for phosphatidic acid and promiscuous cholesterol binding sites in the grooves between adjacent transmembrane α-helices. A high affinity cholesterol site is confirmed in the inner leaflet framed by a key tryptophan residue on the MX α-helix. Our data provide insight into the dynamic nature of lipid-nAChR interactions and set the stage for a detailed understanding of the mechanisms by which lipids facilitate nAChR function at the neuromuscular junction.
Topics: Animals; Receptors, Nicotinic; Torpedo; Phospholipids; Muscles; Phosphatidylcholines; Cholesterol
PubMed: 38600247
DOI: 10.1038/s42003-024-06106-8