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International Journal of Molecular... May 2024Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer's disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble...
Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer's disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show red blood cell (RBC) membrane-binding capacity and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Ab-treated RBCs. In RBCs following different treatments, the ATP, 2,3 DPG and cAMP levels and caspase 3 activity were determined by spectrophotometric and immunoassay. S1P rescued the inhibition of ATP release from RBCs triggered by Ab, through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. These findings reveal the molecular basis of S1P protection against Aβ in RBCs and suggest new therapeutic avenues in AD.
Topics: Lysophospholipids; Sphingosine; Amyloid beta-Peptides; Erythrocytes; Humans; Cyclic AMP; Adenosine Triphosphate; Caspase 3; Alzheimer Disease; 2,3-Diphosphoglycerate; Signal Transduction
PubMed: 38791223
DOI: 10.3390/ijms25105184 -
Antioxidants (Basel, Switzerland) Apr 2024() is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the...
() is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson's disease pathology.
PubMed: 38790613
DOI: 10.3390/antiox13050508 -
Membranes May 2024The role of aromatic amino acids in peripheral protein membrane binding has been reported to involve cation-π interactions with choline lipids. In this study, we have...
The role of aromatic amino acids in peripheral protein membrane binding has been reported to involve cation-π interactions with choline lipids. In this study, we have investigated the interactions of the model pentapeptide Ac-WL-X-LL-OH (where X = L, Y, F, or W) with the phospholipid membrane using solid-state NMR. The effect of guest residue X on the peptide-lipid interactome was complementary to the seminal report on the interfacial hydrophobicity scale by Wimley and White. We found that the phospholipids retained a lamellar phase in the presence of each of the peptides with an aromatic X residue, whereas the Leu peptide perturbed the bilayer to an extent where an additional isotropic phase was observed. The solid-state NMR C and P data provide additional information on the influence of these short peptides on the membrane that has not been previously reported. The magnitude of membrane perturbation was in the order of guest residue X = L > Y~F > W, which is consistent with the relative amino acid interfacial affinity reported by Wimley and White. Further work is, however, required to uncover the behavior of the peptide and localization in the membrane domain due to ambiguity of the C NMR data. We have launched efforts in this regard for the objective of better understanding the role of aromatic amino acids in peripheral membrane protein binding.
PubMed: 38786939
DOI: 10.3390/membranes14050105 -
Biology May 2024() is a frequent gram-negative bacterium that causes nosocomial infections, affecting more than 100 million patients annually worldwide. Bacterial lipopolysaccharide...
Lysophosphatidylcholine Acetyltransferase 2 () Influences the Gene Expression of the Lipopolysaccharide Receptor Complex in Infected RAW264.7 Macrophages, Depending on the Lipopolysaccharide Serotype.
() is a frequent gram-negative bacterium that causes nosocomial infections, affecting more than 100 million patients annually worldwide. Bacterial lipopolysaccharide (LPS) from binds to toll-like receptor 4 (TLR4) and its co-receptor's cluster of differentiation protein 14 (CD14) and myeloid differentiation factor 2 (MD2), collectively known as the LPS receptor complex. LPCAT2 participates in lipid-raft assembly by phospholipid remodelling. Previous research has proven that LPCAT2 co-localises in lipid rafts with TLR4 and regulates macrophage inflammatory response. However, no published evidence exists of the influence of LPCAT2 on the gene expression of the LPS receptor complex induced by smooth or rough bacterial serotypes. We used RAW264.7-a commonly used experimental murine macrophage model-to study the effects of LPCAT2 on the LPS receptor complex by transiently silencing the gene, infecting the macrophages with either smooth or rough LPS, and quantifying gene expression. LPCAT2 only significantly affected the gene expression of the LPS receptor complex in macrophages infected with smooth LPS. This study provides novel evidence that the influence of LPCAT2 on macrophage inflammatory response to bacterial infection depends on the LPS serotype, and it supports previous evidence that LPCAT2 regulates inflammatory response by modulating protein translocation to lipid rafts.
PubMed: 38785798
DOI: 10.3390/biology13050314 -
Redox Biology Jul 2024Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in...
Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA-sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.
Topics: Ferroptosis; Humans; PTEN Phosphohydrolase; Drug Resistance, Neoplasm; Pancreatic Neoplasms; Mice; DNA-Binding Proteins; Transcription Factors; Animals; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gemcitabine; Carcinoma, Pancreatic Ductal; Deoxycytidine; Cell Proliferation; Xenograft Model Antitumor Assays; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 38781729
DOI: 10.1016/j.redox.2024.103200 -
The Journal of Cell Biology Sep 2024The mitochondria-ER-cortex anchor (MECA) forms a tripartite membrane contact site between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM). The...
The mitochondria-ER-cortex anchor (MECA) forms a tripartite membrane contact site between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM). The core component of MECA, Num1, interacts with the PM and mitochondria via two distinct lipid-binding domains; however, the molecular mechanism by which Num1 interacts with the ER is unclear. Here, we demonstrate that Num1 contains a FFAT motif in its C-terminus that interacts with the integral ER membrane protein Scs2. While dispensable for Num1's functions in mitochondrial tethering and dynein anchoring, the FFAT motif is required for Num1's role in promoting mitochondrial division. Unexpectedly, we also reveal a novel function of MECA in regulating the distribution of phosphatidylinositol-4-phosphate (PI(4)P). Breaking Num1 association with any of the three membranes it tethers results in an accumulation of PI(4)P on the PM, likely via disrupting Sac1-mediated PI(4)P turnover. This work establishes MECA as an important regulatory hub that spatially organizes mitochondria, ER, and PM to coordinate crucial cellular functions.
Topics: Cell Membrane; Cytoskeletal Proteins; Endoplasmic Reticulum; Membrane Proteins; Mitochondria; Mitochondrial Dynamics; Phosphatidylinositol Phosphates; Protein Binding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 38781029
DOI: 10.1083/jcb.202308144 -
Frontiers in Endocrinology 2024Polycystic Ovary Syndrome (PCOS) is a heritable condition with an as yet unclear etiology. Various factors, such as genetics, lifestyle, environment, inflammation,...
BACKGROUND
Polycystic Ovary Syndrome (PCOS) is a heritable condition with an as yet unclear etiology. Various factors, such as genetics, lifestyle, environment, inflammation, insulin resistance, hyperandrogenism, iron metabolism, and gut microbiota, have been proposed as potential contributors to PCOS. Nevertheless, a systematic assessment of modifiable risk factors and their causal effects on PCOS is lacking. This study aims to establish a comprehensive profile of modifiable risk factors for PCOS by utilizing a two-sample Mendelian Randomization (MR) framework.
METHODS
After identifying over 400 modifiable risk factors, we employed a two-sample MR approach, including the Inverse Variance Weighted (IVW) method, Weighted Median method, and MR-Egger, to investigate their causal associations with PCOS. The reliability of our estimates underwent rigorous examination through sensitivity analyses, encompassing Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots.
RESULTS
We discovered that factors such as smoking per day, smoking initiation, body mass index, basal metabolic rate, waist-to-hip ratio, whole body fat mass, trunk fat mass, overall health rating, docosahexaenoic acid (DHA) (22:6n-3) in blood, monounsaturated fatty acids, other polyunsaturated fatty acids apart from 18:2 in blood, omega-3 fatty acids, ratio of bisallylic groups to double bonds, omega-9 and saturated fatty acids, total lipids in medium VLDL, phospholipids in medium VLDL, phospholipids in very large HDL, triglycerides in very large HDL, the genus , the genus , the genus 9, the class , and the phylum , showed a significant effect on heightening genetic susceptibility of PCOS. In contrast, factors including fasting insulin interaction with body mass index, sex hormone-binding globulin, iron, ferritin, SDF1a, college or university degree, years of schooling, household income, the genus , the family , the order , the class , and the phylum were determined to reduce risk of PCOS.
CONCLUSION
This study innovatively employs the MR method to assess causal relationships between 400 modifiable risk factors and the susceptibility of PCOS risk. It supports causal links between factors like smoking, BMI, and various blood lipid levels and PCOS. These findings offer novel insights into potential strategies for the management and treatment of PCOS.
Topics: Polycystic Ovary Syndrome; Humans; Female; Mendelian Randomization Analysis; Risk Factors; Body Mass Index; Insulin Resistance
PubMed: 38779450
DOI: 10.3389/fendo.2024.1348368 -
International Journal of Biological... Jun 2024The rapid activation of phosphatidylinositol-specific phospholipase C (PI-PLC) occurs early after the stimulation of biotic and abiotic stress in plants, which directly...
Phosphatidylinositol-specific phospholipase C-associated phospholipid metabolism mediates DcGLRs channel to promote calcium influx under CaCl treatment in shredded carrots during storage.
The rapid activation of phosphatidylinositol-specific phospholipase C (PI-PLC) occurs early after the stimulation of biotic and abiotic stress in plants, which directly associated with the calcium channel-induced calcium ion (Ca) influx. Exogenous calcium chloride (CaCl) mediates the calcium signaling transduction to promote the γ-aminobutyric acid accumulation and nutritional quality in shredded carrots whereas the generation mechanism remains uncertain. Therefore, the involvement of PI-PLC-associated phospholipid metabolism was investigated in present study. Our result revealed that CaCl treatment promoted the expression and activity of PI-PLC and increased the inositol 1,4,5-trisphosphate and hexakisphosphate content in shredded carrots. The transcripts of multi-glutamate receptor-like channels (DcGLRs), the glutamate and γ-aminobutyric acid (GABA) content, and Ca influx were induced by CaCl treatment in shredded carrots during storage. However, PI-PLC inhibitor (U73122) treatment inhibited the activation of PI-PLC, the increase of many DcGLRs family genes expression levels, and Ca influx. Moreover, the identification of DcPI-PLC4/6 and DcGLRs proteins, along with the analysis of characteristic domains such as PLCXc, PLCYc, C2 domain, transmembranous regions, and ligand binding domain, suggests their involvement in phospholipid catalysis and calcium transport in carrots. Furthermore, DcPI-PLC4/6 overexpression in tobacco leaves induced the Ca influx by activating the expressions of NtGLRs and the accumulation of glutamate and GABA. These findings collectively indicate that CaCl treatment-induced PI-PLC activation influences DcGLRs expression levels to mediate cytosolic Ca influx, thus, highlighting the "PI-PLC-GLRs-Ca" pathway in calcium signaling generation and GABA biosynthesis in shredded carrots.
Topics: Calcium; Daucus carota; Calcium Chloride; Phospholipids; Phosphoinositide Phospholipase C; Gene Expression Regulation, Plant; Plant Proteins
PubMed: 38777008
DOI: 10.1016/j.ijbiomac.2024.132517 -
The Journal of Pharmacology and... Jun 2024The high prevalence of breast cancer is a global health concern, compounded by the lack of safe or effective treatments for its advanced stages. These facts urge the...
The high prevalence of breast cancer is a global health concern, compounded by the lack of safe or effective treatments for its advanced stages. These facts urge the development of novel treatment strategies. Annexin A5 (ANXA5) is a natural human protein that binds with high specificity to phosphatidylserine, a phospholipid tightly maintained in the inner leaflet of the cell membrane on most healthy cells but externalized in tumor cells and the tumor vasculature. Here, we have developed a targeted photosensitizer for photothermal therapy (PTT) of solid tumors through the functionalization of single-walled carbon nanotubes (SWCNTs) to ANXA5-the SWCNT-ANXA5 conjugate. The ablation of tumors through the SWCNT-ANXA5-mediated PTT synergizes with checkpoint inhibition, creating a systemic anticancer immune response. In vitro ablation of cells incubated with the conjugate promoted cell death in a dose-dependent and targeted manner. This treatment strategy was tested in vivo with the orthotopic EMT6 breast tumor model in female balb/cJ mice. Enhanced therapeutic effects were achieved by using intratumoral injection of the conjugate and treating tumors at a lower PTT temperature (45°C). Intratumoral injection prevented the accumulation of the SWCNTs in major clearance organs. When combined with checkpoint inhibition of anti-programmed cell death protein-1, SWCNT-ANXA5-mediated PTT increased survival and 80% of the mice survived for 100 days. Evidence of immune system activation by flow cytometry of splenic cells strengthens the hypothesis of an abscopal effect as a mechanism of prolonged survival. SIGNIFICANCE STATEMENT: This study demonstrated a relatively high survival rate (80% at 100 days) of mice with aggressive breast cancer when treated with photothermal therapy using the SWCNT-ANXA5 conjugate injected intratumorally and combined with immune stimulation using the anti-programmed cell death protein-1 checkpoint inhibitor. Photothermal therapy was accomplished by maintaining the tumor temperature at a relatively low level of 45°C and avoiding accumulation of the nanotubes in the clearance organs by using intratumoral administration.
Topics: Nanotubes, Carbon; Animals; Female; Mice; Breast Neoplasms; Mice, Inbred BALB C; Photothermal Therapy; Cell Line, Tumor; Programmed Cell Death 1 Receptor; Humans; Neoplasm Metastasis; Immunotherapy; Photosensitizing Agents; Phototherapy
PubMed: 38772718
DOI: 10.1124/jpet.123.001796 -
MSphere Jun 2024OLE (ornate, large, extremophilic) RNAs are members of a noncoding RNA class present in many Gram-positive, extremophilic bacteria. The large size, complex structure,...
OLE (ornate, large, extremophilic) RNAs are members of a noncoding RNA class present in many Gram-positive, extremophilic bacteria. The large size, complex structure, and extensive sequence conservation of OLE RNAs are characteristics consistent with the hypothesis that they likely function as ribozymes. The OLE RNA representative from is known to localize to the phospholipid membrane and requires at least three essential protein partners: OapA, OapB, and OapC. However, the precise biochemical functions of this unusual ribonucleoprotein (RNP) complex remain unknown. Genetic disruption of OLE RNA or its partners revealed that the complex is beneficial under diverse stress conditions. To search for additional links between OLE RNA and other cellular components, we used phylogenetic profiling to identify proteins that are either correlated or anticorrelated with the presence of OLE RNA in various bacterial species. This analysis revealed strong correlations between the essential protein-binding partners of OLE RNA and organisms that carry the gene. Similarly, proteins involved in sporulation are correlated, suggesting a potential role for the OLE RNP complex in spore formation. Intriguingly, the Mg transporter MpfA is strongly anticorrelated with OLE RNA. Evidence indicates that MpfA is structurally related to OapA and therefore MpfA may serve as a functional replacement for some contributions otherwise performed by the OLE RNP complex in species that lack this device. Indeed, OLE RNAs might represent an ancient RNA class that enabled primitive organisms to sense and respond to major cellular stresses.IMPORTANCEOLE (ornate, large, extremophilic) RNAs were first reported nearly 20 years ago, and they represent one of the largest and most intricately folded noncoding RNA classes whose biochemical function remains to be established. Other RNAs with similar size, structural complexity, and extent of sequence conservation have proven to catalyze chemical transformations. Therefore, we speculate that OLE RNAs likewise operate as ribozymes and that they might catalyze a fundamental reaction that has persisted since the RNA World era-a time before the emergence of proteins in evolution. To seek additional clues regarding the function of OLE RNA, we undertook a computational effort to identify potential protein components of the OLE ribonucleoprotein (RNP) complex or other proteins that have functional links to this device. This analysis revealed known protein partners and several additional proteins that might be physically or functionally linked to the OLE RNP complex. Finally, we identified a Mg transporter protein, MpfA, that strongly anticorrelates with the OLE RNP complex. This latter result suggests that MpfA might perform at least some functions that are like those carried out by the OLE RNP complex.
Topics: Ribonucleoproteins; Computational Biology; Bacterial Proteins; RNA, Bacterial; Phylogeny; RNA, Untranslated
PubMed: 38771028
DOI: 10.1128/msphere.00159-24