Oxidized phospholipids
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Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive therapeutic modality acknowledged for augmenting neurological function recovery following stroke. Nonetheless, uncertainties remain regarding its efficacy in promoting cognitive function recovery in patients diagnosed with vascular dementia (VD). In this study, VD was experimentally induced in a rat model utilizing the bilateral common carotid artery occlusion method. Following a recuperation period of seven days, rats were subjected to high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) at a frequency of 10 Hz. Cognitive function was assessed utilizing the Morris water maze test, and the levels of IL-6, TNF-alpha, SOD, GSH, MDA, and Fe2+ in cerebral tissue were quantitatively analyzed through enzyme-linked immunosorbent assay. Moreover, the gene and protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPx4) were meticulously investigated via quantitative polymerase chain reaction (qPCR) and Western blotting techniques. The use of HF-rTMS notably augmented cognitive function in rats with VD, concomitantly reducing neuroinflammation, oxidative stress, and ferroptosis within the brain. The group subjected to HF-rTMS demonstrated an increase in the levels of both proteins and genes associated with Nrf2 and GPx4, in comparison to the VD group. These results highlight the potential of HF-rTMS treatment in enhancing cognitive function in rats diagnosed with VD through the modulation of the Nrf2/GPx4 signaling pathway. This modulation, in turn, mitigates processes linked with neuroinflammation, oxidative stress, and ferroptosis. Nevertheless, additional studies are essential to comprehensively elucidate the underlying mechanisms and clinical implications of HF-rTMS treatment in the treatment of VD.
- MeSH
- faktor 2 související s NF-E2 * metabolismus MeSH
- fosfolipidová hydroperoxidglutathionperoxidasa * metabolismus MeSH
- kognice * fyziologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- oxidační stres MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- signální transdukce * MeSH
- transkraniální magnetická stimulace * metody MeSH
- vaskulární demence * metabolismus terapie psychologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cylindrospermopsin, a potent hepatotoxin produced by harmful cyanobacterial blooms, poses environmental and human health concerns. We used a 3D human liver in vitro model based on spheroids of HepG2 cells, in combination with molecular and biochemical assays, automated imaging, targeted LC-MS-based proteomics, and lipidomics, to explore cylindrospermopsin effects on lipid metabolism and the processes implicated in hepatic steatosis. Cylindrospermopsin (1 μM, 48 h) did not significantly affect cell viability but partially reduced albumin secretion. However, it increased neutral lipid accumulation in HepG2 spheroids while decreasing phospholipid levels. Simultaneously, cylindrospermopsin upregulated genes for lipogenesis regulation (SREBF1) and triacylglycerol synthesis (DGAT1/2) and downregulated genes for fatty acid synthesis (ACLY, ACCA, FASN, SCD1). Fatty acid uptake, oxidation, and lipid efflux genes were not significantly affected. Targeted proteomics revealed increased levels of perilipin 2 (adipophilin), a major hepatocyte lipid droplet-associated protein. Lipid profiling quantified 246 lipid species in the spheroids, with 28 significantly enriched and 15 downregulated by cylindrospermopsin. Upregulated species included neutral lipids, sphingolipids (e.g., ceramides and dihexosylceramides), and some glycerophospholipids (phosphatidylethanolamines, phosphatidylserines), while phosphatidylcholines and phosphatidylinositols were mostly reduced. It suggests that cylindrospermopsin exposures might contribute to developing and progressing towards hepatic steatosis or metabolic dysfunction-associated steatotic liver disease (MASLD).
- MeSH
- alkaloidy * farmakologie MeSH
- bakteriální toxiny * metabolismus MeSH
- buněčné sféroidy účinky léků metabolismus MeSH
- buňky Hep G2 MeSH
- homeostáza účinky léků MeSH
- játra * metabolismus účinky léků MeSH
- lidé MeSH
- lipidomika MeSH
- lipogeneze účinky léků MeSH
- metabolismus lipidů * účinky léků MeSH
- proteomika MeSH
- toxiny kmene Cyanobacteria * MeSH
- uracil * analogy a deriváty metabolismus MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
CD36/FAT (translokáza mastných kyselin) hraje centrální roli v kardiovaskulárních onemocněních, má nezměněnou strukturu u různých živočišných druhů. Jeho vyjádření v tukové tkáni, kosterním svalu, játrech a makrofázích arteriální stěny zdůrazňuje tento význam. Kromě fagocytace oxidovaných LDL (oxLDL) receptor CD36 akceleruje prozánětlivý proces v celém organismu. Specificita mikroprostředí tukové tkáně s vysokou koncentrací volných mastných kyselin, inzulinu a glukózy indukuje polarizaci specifickými metabolickými cestami k produkci metabolicky aktivovaných prozánětlivých makrofágů (MAPIM) s výraznou expresí CD36. Proporce MAPIM v lidské tukové tkáni výrazně koreluje se dvěma hlavními rizikovými faktory kardiovaskulárních nemocí – hypercholesterolemií a obezitou. Polarizace MAPIM v tukové tkáni je dána složením mastných kyselin fosfolipidů celulární membrány a vzrůstá s proporcí palmitátu a palmitooleátu a naopak klesá s proporcí n-3 mastných kyselin, zejména kyseliny -linolenové a eikosapentaenové. Při analýze tohoto vlivu odděleně v adipocytech a makrofázích jsme prokázali, že adipocyty tvoří vhodné mikroprostředí polarizace (s podobnými vztahy k mastným kyselinám celulární membrány). Naproti tomu polarizace vlastních makrofágů je určena kompeticí nasyceného palmitátu a cholesterolových molekul v raftu celulární membrány. CD36 hraje klíčovou roli v rozvoji aterosklerózy pohlcováním oxLDL, tvorbou tukových proužků a pěnových buněk až ke vzniku komplikovaných lézí. Nedostatek receptorů CD36 brzdí aterogenní proces jak v experimentu, tak u osob s jeho genetickým snížením. Komplexní role CD36 v zánětu, lipidovém metabolismu a angiogenezi hraje klíčovou roli v celulární a orgánové komunikaci s aktivací aterogenního procesu.
The CD36/FAT (fatty acid translocator) receptor is a crucial player in cardiovascular diseases, featuring a consistent structure across species. Its expression in adipose tissue, skeletal muscle, liver, and arterial wall macrophages underscores its importance. Beyond scavenging oxidized LDL (oxLDL), CD36 accelerates the pro-inflammatory processes in all these organs. Specific microenvironments of adipose tissue with high concentrations of free long-chain fatty acids, insulin, and glucose induce polarization by tissue-specific path- ways producing metabolically activated pro-inflammatory macrophages (MAPIMs) with high CD36 expres- sion. The proportion of MAPIMs in human adipose tissue correlates significantly with the two main risk predictors of cardiovascular diseases - hypercholesterolemia and obesity. Polarization of MAPIMs in adipose tissue is defined by the fatty acid composition of cell membrane phospholipids, and increases with the proportion of palmitic, and mainly palmitoleate, fatty acids and decreases with the presence of n-3 polyenic fatty acids, specifically α-linolenic and eicosapentaenoic fatty acids. When analysing this effect separately for adipocytes and macrophages, we found that adipocytes create a microenvironment (with a relationship similar to the effects of individual fatty acids of membrane phospholipids) beneficial for pro-inflammatory polarization. On the contrary, macrophage polarization is related to the competition of unsaturated palmitate and cholesterol molecules in the membrane raft. CD36 is crucial for the development of atherosclerosis within the arterial wall, scavenging oxLDL producing fatty streaks and foam cells until the formation of complicated atherosclerotic lesions. CD36 deficiency attenuates atherosclerotic lesion development both in experimental models and individuals with genetic defects of this receptor. The complex role of CD36 in inflammation, lipid metabolism, and angiogenesis makes it a key player in cell- and organ-level communication, activating the atherogenic process.
Plasmalogens (vinyl-ether phospholipids) are an emergent class of lipid drugs against various diseases involving neuro-inflammation, oxidative stress, mitochondrial dysfunction, and altered lipid metabolism. They can activate neurotrophic and neuroprotective signaling pathways but low bioavailabilities limit their efficiency in curing neurodegeneration. Here, liquid crystalline lipid nanoparticles (LNPs) are created for the protection and non-invasive intranasal delivery of purified scallop-derived plasmalogens. The in vivo results with a transgenic mouse Parkinson's disease (PD) model (characterized by motor impairments and α-synuclein deposition) demonstrate the crucial importance of LNP composition, which determines the self-assembled nanostructure type. Vesicle and hexosome nanostructures (characterized by small-angle X-ray scattering) display different efficacy of the nanomedicine-mediated recovery of motor function, lipid balance, and transcriptional regulation (e.g., reduced neuro-inflammation and PD pathogenic gene expression). Intranasal vesicular and hexosomal plasmalogen-based LNP treatment leads to improvement of the behavioral PD symptoms and downregulation of the Il6, Il33, and Tnfa genes. Moreover, RNA-sequencing and lipidomic analyses establish a dramatic effect of hexosomal nanomedicines on PD amelioration, lipid metabolism, and the type and number of responsive transcripts that may be implicated in neuroregeneration.
- MeSH
- aplikace intranazální * MeSH
- liposomy MeSH
- metabolismus lipidů účinky léků MeSH
- modely nemocí na zvířatech * MeSH
- myši transgenní MeSH
- myši MeSH
- nanočástice * chemie MeSH
- nanomedicína * metody MeSH
- Parkinsonova nemoc * metabolismus farmakoterapie MeSH
- plasmalogeny * chemie farmakologie MeSH
- regulace genové exprese účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid with promising anticancer potential. Anaemia is a frequent adverse effect of anticancer treatment caused in part by eryptosis and haemolysis. Thus, it is important to investigate the role of DHA in red blood cell (RBC) death. RBCs were treated with anticancer concentrations (10-100 μM) of DHA under different physiological conditions, and fluorescence-assisted cell sorting was employed to measure eryptotic markers. Cell membrane scrambling was detected by annexin-V-FITC labelling, cytoplasmic Ca2+ by Fluo4/AM, cell size by forward scatter (FSC), and oxidative stress by H2DCFDA. Haemolytic markers were also assayed by photometric methods. DHA caused significant phospholipid scrambling with Ca2+ accumulation, loss of cellular volume, and oxidative stress. These changes were associated with dacrocyte formation, as revealed by electron microscopy. Moreover, DHA exhibited a dual effect on membrane integrity: it was haemolytic under isotonic conditions and anti-haemolytic in hypotonic environments. Importantly, inhibition of Rac1 GTPase activity with NSC23766 significantly reduced DHA-mediated haemolysis, as did co-administration of either sucrose or polyethylene glycol 8,000. Conversely, the presence of 125 mM KCl and urea without extracellular Ca2+ significantly exacerbated DHA toxicity. In conclusion, this is the first report that identifies key biochemical mechanisms underlying the cytotoxic effects of DHA in RBCs, promoting further development and validation of DHA in anticancer therapy.
- MeSH
- eryptóza * účinky léků MeSH
- erytrocyty účinky léků metabolismus MeSH
- hemolýza * účinky léků MeSH
- kyseliny dokosahexaenové * farmakologie MeSH
- lidé MeSH
- oxidační stres * účinky léků MeSH
- signální transdukce účinky léků MeSH
- vápník * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) can progress to more severe stages, such as steatohepatitis and fibrosis. Thermoneutral housing together with high-fat diet promoted NAFLD progression in C57BL/6J mice. Due to possible differences in steatohepatitis development between different C57BL/6 substrains, we examined how thermoneutrality affects NAFLD progression in C57BL/6N mice. METHODS: Male mice were fed standard or high-fat diet for 24 weeks and housed under standard (22°C) or thermoneutral (30°C) conditions. RESULTS: High-fat feeding promoted weight gain and hepatic steatosis, but the effect of thermoneutral environment was not evident. Liver expression of inflammatory markers was increased, with a modest and inconsistent effect of thermoneutral housing; however, histological scores of inflammation and fibrosis were generally low (<1.0), regardless of ambient temperature. In standard diet-fed mice, thermoneutrality increased weight gain, adiposity, and hepatic steatosis, accompanied by elevated de novo lipogenesis and changes in liver metabolome characterized by complex decreases in phospholipids and metabolites involved in urea cycle and oxidative stress defense. CONCLUSION: Thermoneutrality appears to promote NAFLD-associated phenotypes depending on the C57BL/6 substrain and/or the amount of dietary fat.
- MeSH
- bydlení MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- hmotnostní přírůstek MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nealkoholová steatóza jater * metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Thermal reactions can significantly alter the metabolomic and lipidomic content of biofluids and tissues during storage. In this study, we investigated the stability of polar metabolites and complex lipids in dry human serum and mouse liver extracts over a three-day period under various temperature conditions. Specifically, we tested temperatures of -80 °C (freezer), -24 °C (freezer), -0.5 °C (polystyrene box with gel-based ice packs), +5 °C (refrigerator), +23 °C (laboratory, room temperature), and +30 °C (thermostat) to simulate the time between sample extraction and analysis, shipping dry extracts to different labs as an alternative to dry ice, and document the impact of higher temperatures on sample integrity. The extracts were analyzed using five fast liquid chromatography-mass spectrometry (LC-MS) methods to screen polar metabolites and complex lipids, and over 600 metabolites were annotated in serum and liver extracts. We found that storing dry extracts at -24 °C and partially at -0.5 °C provided comparable results to -80 °C (reference condition). However, increasing the storage temperatures led to significant changes in oxidized triacylglycerols, phospholipids, and fatty acids within three days. Polar metabolites were mainly affected at storage temperatures of +23 °C and +30 °C.
- Publikační typ
- časopisecké články MeSH
In this work oleuropein and lentisk oil have been co-loaded in different phospholipid vesicles (i.e., liposomes, transfersomes, hyalurosomes and hyalutransfersomes), to obtain a formulation capable of both inhibiting the production of different markers connected with inflammation and oxidative stress and promoting the skin repair. Liposomes were prepared using a mixture of phospholipids, oleuropein and lentisk oil. Tween 80, sodium hyaluronate or their combination have been added to the mixture to obtain transfersomes, hyalurosomes and hyalutransfersomes. Size, polydispersity index, surface charge and stability on storage was evaluated. The biocompatibility, anti-inflammatory activity and wound healing effect were tested using normal human dermal fibroblasts. Vesicles were small (mean diameter ∼ 130 nm) and homogeneously dispersed (polydispersity index ∼ 0.14), highly negatively charged (zeta potential 02053-64 mV) and capable of loading 20 mg/mL of oleuropein and 75 mg/mL of lentisk oil. The freeze-drying of dispersions with a cryoprotectant permitted to improve their stability on storage. The co-loading of oleuropein and lentisk oil in vesicles inhibited the overproduction of inflammatory markers, especially MMP-1 and IL-6, counteracted the oxidative stress induced in cells using hydrogen peroxide, and promoted the healing of a wounded area performed in vitro in a cell monolayer of fibroblasts. The proposed co-loading of oleuropein and lentisk oil in natural-based phospholipid vesicles may hold promising therapeutic value especially for the treatment of a wide variety of skin disorders.
- MeSH
- cytokiny metabolismus MeSH
- fosfolipidy * metabolismus MeSH
- hojení ran MeSH
- kůže metabolismus MeSH
- lidé MeSH
- liposomy * metabolismus MeSH
- oxidační stres MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.
- MeSH
- fosfáty metabolismus MeSH
- kyseliny dokosahexaenové * MeSH
- lidé MeSH
- lysofosfolipidy metabolismus MeSH
- lyzozomy metabolismus MeSH
- myši MeSH
- nádory prsu * patologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased.
