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The Journal of Biological Chemistry Sep 2023Sphingomyelin synthase (SMS)-related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) that is conserved and ubiquitous in mammals. However, its...
Sphingomyelin synthase (SMS)-related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) that is conserved and ubiquitous in mammals. However, its biological function is still not clear. We previously observed that SMS1 deficiency-mediated glucosylceramide accumulation caused nonalcoholic fatty liver diseases (NAFLD), including nonalcoholic steatohepatitis (NASH) and liver fibrosis. Here, first, we evaluated high-fat diet/fructose-induced NAFLD in Smsr KO and WT mice. Second, we evaluated whether SMSr deficiency can reverse SMS1 deficiency-mediated NAFLD, using Sms1/Sms2 double and Sms1/Sms2/Smsr triple KO mice. We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructose-induced fatty liver and NASH, and attenuated glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation. Further, we found that SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors, and PE supplementation in vitro or in vivo mimicked the condition of SMSr/PE-PLC deficiency. Furthermore, we demonstrated that SMSr/PE-PLC deficiency or PE supplementation effectively prevented membrane-bound β-catenin transfer to the nucleus, thereby preventing tumor-related gene expression. Finally, we observed that patients with NASH had higher SMSr protein levels in the liver, lower plasma PE levels, and lower plasma PE/phosphatidylcholine ratios, and that human plasma PE levels are negatively associated with tumor necrosis factor-α and transforming growth factor β1 levels. In conclusion, SMSr/PE-PLC deficiency causes PE accumulation, which can attenuate fatty liver, NASH, and fibrosis. These results suggest that SMSr/PE-PLC inhibition therapy may mitigate NAFLD.
Topics: Animals; Humans; Mice; Fructose; Glucosylceramides; Liver; Liver Cirrhosis; Neoplasms; Non-alcoholic Fatty Liver Disease; Phosphatidylethanolamines; Transferases (Other Substituted Phosphate Groups); Mice, Knockout; Male; Female; Diet, High-Fat
PubMed: 37586586
DOI: 10.1016/j.jbc.2023.105162 -
Communications Biology Jan 2024Our previous work has shown that D-ribose (RIB)-induced depressive-like behaviors in mice. However, the relationship between variations in RIB levels and depression as...
Our previous work has shown that D-ribose (RIB)-induced depressive-like behaviors in mice. However, the relationship between variations in RIB levels and depression as well as potential RIB participation in depressive disorder is yet unknown. Here, a reanalysis of metabonomics data from depressed patients and depression model rats is performed to clarify whether the increased RIB level is positively correlated with the severity of depression. Moreover, we characterize intestinal epithelial barrier damage, gut microbial composition and function, and microbiota-gut-brain metabolic signatures in RIB-fed mice using colonic histomorphology, 16 S rRNA gene sequencing, and untargeted metabolomics analysis. The results show that RIB caused intestinal epithelial barrier impairment and microbiota-gut-brain axis dysbiosis. These microbial and metabolic modules are consistently enriched in peripheral (fecal, colon wall, and serum) and central (hippocampus) glycerophospholipid metabolism. In addition, three differential genera (Lachnospiraceae_UCG-006, Turicibacter, and Akkermansia) and two types of glycerophospholipids (phosphatidylcholine and phosphatidylethanolamine) have greater contributions to the overall correlations between differential genera and glycerophospholipids. These findings suggest that the disturbances of gut microbiota by RIB may contribute to the onset of depressive-like behaviors via regulating glycerophospholipid metabolism, and providing new insight for understanding the function of microbiota-gut-brain axis in depression.
Topics: Humans; Animals; Mice; Rats; Brain-Gut Axis; Ribose; Lipid Metabolism; Gastrointestinal Microbiome; Glycerophospholipids
PubMed: 38195757
DOI: 10.1038/s42003-023-05759-1 -
The Journal of Physiology Sep 2023Well-regulated placental palmitic acid (PA) and oleic acid (OA) metabolism is vital for optimal placental function and fetal development, but dysregulation occurs with...
Well-regulated placental palmitic acid (PA) and oleic acid (OA) metabolism is vital for optimal placental function and fetal development, but dysregulation occurs with gestational diabetes (GDM). We hypothesized that such dysregulation might arise from increased maternofetal glucose, leptin or insulin concentrations present in GDM, and that dysregulated PA and OA lipid metabolism could be moderated by myo-inositol, a natural polyol and potential GDM intervention. Placental explants from 21 women were incubated with stable isotope-labelled C-PA or C-OA for 48 h. Explants were treated with glucose (5, 10 mm) or leptin (13 nm) or insulin (150 nm) in combination with myo-inositol (0.3, 30, 60 μm). Forty-seven C-PA lipids and 37 C-OA lipids were measured by liquid chromatography-mass spectrometry (LCMS). Compared with controls (5 mm glucose), glucose (10 mm) increased 19 C-OA lipids and nine C-PA lipids, but decreased C-OA phosphatidylethanolamine 38:5 and C-PA phosphatidylethanolamine 36:4. The effects of leptin and insulin were less prominent than glucose, with leptin increasing C-OA acylcarnitine 18:1, and insulin increasing four C-PA triacylglycerides. Most glucose, leptin and insulin-induced alterations in lipids were attenuated by co-incubation with myo-inositol (30 or 60 μm), with attenuation also occurring in all subgroups stratified by GDM status and fetal sex. However, glucose-induced increases in acylcarnitine were not attenuated by myo-inositol and were even exaggerated in some instances. Myo-inositol therefore appears to generally act as a moderator, suppressing the perturbation of lipid metabolic processes by glucose, leptin and insulin in placenta in vitro. Whether myo-inositol protects the fetus and pregnancy from unfavourable outcomes requires further research. KEY POINTS: Incubation of placental explants with additional glucose, or to a lesser extent insulin or leptin, alters the placental production of C-lipids from C-palmitic acid (PA) and C-oleic acid (OA) in vitro compared with untreated controls from the same placenta. Co-incubation with myo-inositol attenuated most alterations induced by glucose, insulin or leptin in C-lipids, but did not affect alterations in C-acylcarnitines. Alterations induced by glucose and leptin in C-PA triacylglycerides and C-PA phospholipids were influenced by fetal sex and gestational diabetes status, but were all still attenuated by myo-inositol co-incubation. Insulin differently affected C-PA triacylglycerides and C-PA phospholipids depending on fetal sex, with alterations also attenuated by myo-inositol co-incubation.
Topics: Pregnancy; Female; Humans; Insulin; Oleic Acid; Palmitic Acid; Phosphatidylethanolamines; Leptin; Diabetes, Gestational; Placenta; Glucose
PubMed: 37602663
DOI: 10.1113/JP285036 -
The Journal of Cell Biology Feb 2024Cancer cells harness lipid metabolism to promote their own survival. We screened 47 cancer cell lines for survival dependency on phosphatidylserine (PS) synthesis using...
Cancer cells harness lipid metabolism to promote their own survival. We screened 47 cancer cell lines for survival dependency on phosphatidylserine (PS) synthesis using a PS synthase 1 (PTDSS1) inhibitor and found that B cell lymphoma is highly dependent on PS. Inhibition of PTDSS1 in B cell lymphoma cells caused a reduction of PS and phosphatidylethanolamine levels and an increase of phosphoinositide levels. The resulting imbalance of the membrane phospholipidome lowered the activation threshold for B cell receptor (BCR), a B cell-specific survival mechanism. BCR hyperactivation led to aberrant elevation of downstream Ca2+ signaling and subsequent apoptotic cell death. In a mouse xenograft model, PTDSS1 inhibition efficiently suppressed tumor growth and prolonged survival. Our findings suggest that PS synthesis may be a critical vulnerability of malignant B cell lymphomas that can be targeted pharmacologically.
Topics: Animals; Humans; Mice; Apoptosis; Lymphoma, B-Cell; Phosphatidylserines; Receptors, Antigen, B-Cell; Signal Transduction; Phosphatidylinositols; Nitrogenous Group Transferases
PubMed: 38048228
DOI: 10.1083/jcb.202212074 -
Scientific Reports Aug 2023The occurrence of methyl carbamates of phosphatidylethanolamines and phosphatidylserines in the lipid extract of mitochondria obtained from mouse embryonic fibroblasts...
The occurrence of methyl carbamates of phosphatidylethanolamines and phosphatidylserines in the lipid extract of mitochondria obtained from mouse embryonic fibroblasts was ascertained by hydrophilic interaction liquid chromatography with electrospray ionization single and multi-stage mass spectrometry, performed using sinergically a high resolution (quadrupole-Orbitrap) and a low resolution (linear ion trap) spectrometer. Two possible routes to the synthesis of methyl carbamates of phospholipids were postulated and evaluated: (i) a chemical transformation involving phosgene, occurring as a photooxidation by-product in the chloroform used for lipid extraction, and methanol, also used for the latter; (ii) an enzymatic methoxycarbonylation reaction due to an accidental bacterial contamination, that was unveiled subsequently on the murine mitochondrial sample. A specific lipid extraction performed on a couple of standard phosphatidyl-ethanolamines/-serines, based on purposely photo-oxidized chloroform and deuterated methanol, indicated route (i) as negligible in the specific case, thus highlighting the enzymatic route related to bacterial contamination as the most likely source of methyl carbamates. The unambiguous recognition of the latter might represent the starting point toward a better understanding of their generation in biological systems and a minimization of their occurrence when an artefactual formation is ascertained.
Topics: Animals; Mice; Phosphatidylethanolamines; Chloroform; Fibroblasts; Methanol; Phosphatidylserines; Carbamates; Mitochondria
PubMed: 37633960
DOI: 10.1038/s41598-023-40357-5 -
International Journal of Systematic and... Nov 2023A milky-white-coloured, aerobic, Gram-stain-positive, rod-shaped and motile bacterial strain (GW78) was isolated from forest soil. GW78 was catalase-positive and...
A milky-white-coloured, aerobic, Gram-stain-positive, rod-shaped and motile bacterial strain (GW78) was isolated from forest soil. GW78 was catalase-positive and oxidase-negative. The strain was able to grow optimally at 37 °C and at pH 7.0 in Reasoner's 2A media. The phylogenetic and 16S rRNA gene sequence analysis of GW78 showed its affiliation with the genus . The 16S rRNA gene sequence of GW78 revealed 98.3 % similarity to its nearest neighbour VKPM B-7519. Its chemotaxonomic properties included MK-7 as the sole menaquinone, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylmonomethylethanolamine and phosphatidylethanolamine as major polar lipids, and anteiso-C, C 11 and anteiso-C as predominant fatty acids. Digital DNA-DNA hybridization and average nucleotide identity results with its closest relatives were <74.0 % and <14.0 %, respectively. Overall, 16S rRNA gene sequence comparisons, phylogenetic and genomic evidence, and phenotypic and chemotaxonomic data allow the differentiation of GW78 from other members of the genus . Thus, we propose that strain GW78 represents a novel species of the genus , with the name sp. nov. The type strain is GW78 (=KCTC 43430=NBRC 116023).
Topics: Fatty Acids; Phospholipids; Phylogeny; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Base Composition; DNA, Bacterial; Bacterial Typing Techniques; Soil Microbiology; Paenibacillus; Forests
PubMed: 37982814
DOI: 10.1099/ijsem.0.006171 -
Advanced Healthcare Materials Mar 2024Lipid-based nanocarriers have demonstrated high interest in delivering genetic material, exemplified by the success of Onpattro and COVID-19 vaccines. While PEGylation...
Lipid-based nanocarriers have demonstrated high interest in delivering genetic material, exemplified by the success of Onpattro and COVID-19 vaccines. While PEGylation imparts stealth properties, it hampers cellular uptake and endosomal escape, and may trigger adverse reactions like accelerated blood clearance (ABC) and hypersensitivity reactions (HSR). This work highlights the great potential of amphiphilic poly(N-methyl-N-vinylacetamide) (PNMVA) derivatives as alternatives to lipid-PEG for siRNA delivery. PNMVA compounds with different degrees of polymerization and hydrophobic segments, are synthesized. Among them, DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine)-PNMVA efficiently integrates into lipoplexes and LNP membranes and prevents protein corona formation around these lipid carriers, exhibiting stealth properties comparable to DSPE-PEG. However, unlike DSPE-PEG, DSPE-PNMVA shows no adverse impact on lipoplexes cell uptake and endosomal escape. In in vivo study with mice, DSPE-PNMVA lipoplexes demonstrate no liver accumulation, indicating good stealth properties, extended circulation time after a second dose, reduced immunological reaction, and no systemic pro-inflammatory response. Safety of DSPE-PNMVA is confirmed at the cellular level and in animal models of zebrafish and mice. Overall, DSPE-PNMVA is an advantageous substitute to DSPE-PEG for siRNA delivery, offering comparable stealth and toxicity properties while improving efficacy of the lipid-based carriers by minimizing the dilemma effect and reducing immunological reactions, meaning no ABC or HSR effects.
Topics: Mice; Humans; Animals; Liposomes; Polyethylene Glycols; COVID-19 Vaccines; Zebrafish; RNA, Small Interfering; Phosphatidylethanolamines; Polyvinyls
PubMed: 37994483
DOI: 10.1002/adhm.202302712 -
Advanced Science (Weinheim,... May 2024Ferroptosis and apoptosis are key cell-death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron-dependent lipid peroxidation...
Ferroptosis and apoptosis are key cell-death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron-dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis-to-apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of the GGS is associated with poor prognosis in breast cancer patients and PDXs and contains different ferroptosis repressors. Depletion of one representative, PDGFA-assaociated protein 1(PDAP1), is found to suppress basal-like breast tumor growth in a mouse model. Omics and mechanistic studies revealed that ferroptosis is associated with enhanced lysosomal function, glutaminolysis, and the tricarboxylic acid (TCA) cycle, while its transition into apoptosis is attributed to enhanced endoplasmic reticulum(ER)-stress and phosphatidylethanolamine (PE)-to-phosphatidylcholine (PC) metabolic shift. Collectively, this study highlights molecular mechanisms underlying ferroptosis execution, identified a highly predictive ferroptosis gene signature with prognostic value, ferroptosis versus apoptosis biomarkers, and ferroptosis repressors for breast cancer therapy.
Topics: Ferroptosis; Humans; Animals; Mice; Apoptosis; Female; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Biomarkers
PubMed: 38441406
DOI: 10.1002/advs.202307263 -
Nuclear Medicine and Biology 2023Cell death is fundamental in health and disease and resisting cell death is a hallmark of cancer. Treatment of malignancy aims to cause cancer cell death, however... (Review)
Review
Cell death is fundamental in health and disease and resisting cell death is a hallmark of cancer. Treatment of malignancy aims to cause cancer cell death, however current clinical imaging of treatment response does not specifically image cancer cell death but assesses this indirectly either by changes in tumor size (using x-ray computed tomography) or metabolic activity (using 2-[F]fluoro-2-deoxy-glucose positron emission tomography). The ability to directly image tumor cell death soon after commencement of therapy would enable personalised response adapted approaches to cancer treatment that is presently not possible with current imaging, which is in many circumstances neither sufficiently accurate nor timely. Several cell death pathways have now been identified and characterised that present multiple potential targets for imaging cell death including externalisation of phosphatidylserine and phosphatidylethanolamine, caspase activation and La autoantigen redistribution. However, targeting one specific cell death pathway carries the risk of not detecting cell death by other pathways and it is now understood that cancer treatment induces cell death by different and sometimes multiple pathways. An alternative approach is targeting the cell death phenotype that is "agnostic" of the death pathway. Cell death phenotypes that have been targeted for cell death imaging include loss of plasma membrane integrity and dissipation of the mitochondrial membrane potential. Targeting the cell death phenotype may have the advantage of being a more sensitive and generalisable approach to cancer cell death imaging. This review describes and summarises the approaches and radiopharmaceuticals investigated for imaging cell death by targeting cell death pathways or cell death phenotype.
Topics: Humans; Fluorodeoxyglucose F18; Neoplasms; Positron-Emission Tomography; Tomography, X-Ray Computed; Radiopharmaceuticals
PubMed: 37598518
DOI: 10.1016/j.nucmedbio.2023.108380 -
CNS Neuroscience & Therapeutics Oct 2023Mid-gestational sevoflurane exposure may induce notable long-term neurocognitive impairment in offspring. This study was designed to investigate the role and potential...
AIMS
Mid-gestational sevoflurane exposure may induce notable long-term neurocognitive impairment in offspring. This study was designed to investigate the role and potential mechanism of ferroptosis in developmental neurotoxicity induced by sevoflurane in the second trimester.
METHODS
Pregnant rats on day 13 of gestation (G13) were treated with or without 3.0% sevoflurane, Ferrostatin-1 (Fer-1), PD146176, or Ku55933 on three consecutive days. Mitochondrial morphology, ferroptosis-relative proteins, malondialdehyde (MDA) levels, total iron content, and glutathione peroxidase 4 (GPX4) activities were measured. Hippocampal neuronal development in offspring was also examined. Subsequently, 15-lipoxygenase 2 (15LO2)-phosphatidylethanolamine binding protein 1 (PEBP1) interaction and expression of Ataxia telangiectasia mutated (ATM) and its downstream proteins were also detected. Furthermore, Morris water maze (MWM) and Nissl's staining were applied to estimate the long-term neurotoxic effects of sevoflurane.
RESULTS
Ferroptosis mitochondria were observed after maternal sevoflurane exposures. Sevoflurane elevated MDA and iron levels while inhibiting GPX4 activity, and resultant long-term learning and memory dysfunction, which were alleviated by Fer-1, PD146176, and Ku55933. Sevoflurane could enhance 15LO2-PEBP1 interaction and activate ATM and its downstream P53/SAT1 pathway, which might be attributed to excessive p-ATM nuclear translocation.
CONCLUSION
This study proposes that 15LO2-mediated ferroptosis might contribute to neurotoxicity induced by maternal sevoflurane anesthesia during the mid-trimester in the offspring and its mechanism may be ascribed to hyperactivation of ATM and enhancement of 15LO2-PEBP1 interaction, indicating a potential therapeutic target for ameliorating sevoflurane-induced neurotoxicity.
Topics: Pregnancy; Female; Rats; Animals; Sevoflurane; Ferroptosis; Rats, Sprague-Dawley; Brain; Iron
PubMed: 37287422
DOI: 10.1111/cns.14236