Role Of Lipid Peroxidation Research Articles

Ferrostatin-1 inhibits osteoclast differentiation and prevents osteoporosis by suppressing lipid peroxidation

BackgroundOsteoporosis (OP) is a systemic disease characterized by low bone mass. New progress has been made in the study of OP, such as lipid peroxidation. However, the role of lipid peroxides in osteoclast differentiation is still unclear.MethodsBone marrow macrophages (BMMs) were extracted from C57BL/6J mice and induced to differentiate into osteoclasts, which were observed via TRAP staining, Phalloidin staining and bone pit assays. Related substances of lipid peroxidation were detected during osteoclastogenesis. The levels of osteoclastogenesis and lipid peroxides were measured by qRT-PCR, Western Blot and immunofluorescence. Activation of the p38/JNK/MAPK pathway was detected by Western Blot. The capacity for osteogenesis and angiogenesis of cells after treatment with supernatant of BMMs was evaluated. Furthermore, Ferrostatin-1 (Fer-1), from which femur and serum samples were comprehensively evaluated, was used in OVX mice.ResultsDuring osteoclastogenesis, the levels of ROS, MDA, ACSL4 and LPCAT3 increased with increasing duration of RANKL stimulation, while there were no significant changes in the levels of GSH or GPX4. Fer-1 inhibited osteoclast differentiation and decreased the level of lipid peroxides. In addition, Fer-1 inhibited osteoclast-related markers by inhibiting the p38/JNK/MAPK pathway. Furthermore, the supernatant of BMMs after Fer-1 treatment promoted osteogenesis and angiogenesis. Finally, Fer-1 successfully alleviated OP in OVX mice by reducing the level of lipid peroxidation in vivo.ConclusionFer-1 suppresses osteoclast differentiation by reducing lipid peroxidation levels regulated by ACSL4, which is mediated through the p38/JNK/MAPK signaling pathway. Additionally, Fer-1 enhances the coupling between osteogenesis and angiogenesis and has an anti-OP effect in vivo.

Single fluorescent probe reveals glutathione-viscosity crosstalk in the endoplasmic reticulum during ferroptosis and extracellular vesicles in synergistic ferroptosis-apoptosis

Ferroptosis is an iron-dependent cell death triggered by lipid peroxidation accumulation, representing a redox imbalance in cells. The increased knowledge of ferroptosis has led to various potential strategies to develop new cancer therapies, such as synergistic ferroptosis-apoptosis. The endoplasmic reticulum (ER) is the major hub for lipid metabolism in cells and plays a central role in lipid peroxidation. Glutathione (GSH) and viscosity levels in ER are important parameters for intracellular redox homeostasis, which remain unclear in ferroptosis and synergistic ferroptosis-apoptosis. This study developed an ER-targeting fluorescent probe (MMPY) with a dual-emission response to GSH and viscosity. Fluorescent cell imaging using MMPY revealed different GSH-viscosity crosstalk in the ER for the four ferroptosis pathways induced by erastin, RSL3, FIN56, and FINO2. GSH and viscosity changes in the ER during synergistic ferroptosis-apoptosis were also investigated. Interestingly, the new types of extracellular vesicles were observed during the synergistic process, which burdened the ER fragments with different GSH contents.

Effect of various physical and chemical stress conditions on the infectivity and survival of Heterorhabditis indica and Steinernema feltiae: Relationship with lipid oxidative stress

Entomopathogenic nematodes (EPNs) of the genera Heterorhabditis and Steinernema represent an alternative for the biological control of insects. The limited half-life of EPNs is still one of the most concerning issues in their commercialization. Lipid peroxidation (LPO) caused by reactive oxygen species (ROS) may be one of the most important causes of loss of infectivity and survival of EPNs when exposed to various physicochemical stress conditions (temperature, pH, hypoxia and osmotic pressure). Because LPO generates free radicals (FRs), it can trigger membrane peroxidation and lipid energy reserves of EPNs. However, in EPNs there is no data on the role of LPO on their physiology, making strategies for the conservation of derived biopreparations difficult. In this sense, the influence of LPO on the species of EPNs S. feltiae and H. indica under various conditions of physicochemical stress was studied. In both EPNs, the proposed stress conditions altered infectivity and survival over time, generating ROS associated with LPO with a variable tolerance depending on the species, type and time of exposure to stress. A relationship was observed between the LPO induced by stress conditions and infectivity-survival.

Lipid peroxidation triggered by the degradation of xCT contributes to gasdermin D-mediated pyroptosis in COPD

BackgroundPyroptosis is an inflammatory form of regulated necrosis that has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the role of lipid peroxidation in pyroptosis and its underlying mechanisms in COPD remain unclear. MethodsIn vitro, human bronchial epithelial cells (Beas-2b cells) were exposed to cigarette smoke extract (CSE) for 24 h. In vivo, mice were exposed to cigarette smoke (CS) for 4 weeks. To investigate the role of xCT, we used siRNA and AAV6 to conditionally knock down xCT in vitro and in vivo, respectively. ResultsThe administration of ferrostatin-1 (Fer-1), a ferroptosis inhibitor that inhibits lipid peroxidation, significantly reduced the cytotoxicity of CSE to Beas-2b cells and mitigated inflammatory exudation, lung injury and mucus hypersecretion in mice with CS-induced COPD. Fer-1 suppressed gasdermin D (GSDMD)-mediated pyroptosis caused by CS in vitro and in vivo. However, in Beas-2b cells and the lung epithelial cells of mice, conditional knockdown of xCT (a negative regulatory factor of lipid peroxidation) inhibited the xCT/GPx4 axis, leading to more severe lipid peroxidation and GSDMD-mediated pyroptosis during cigarette smoke exposure. Moreover, we found that CS promoted the degradation of xCT through the ubiquitin proteasome system (UPS) and that treatment with MG132 significantly inhibited the degradation of xCT and downregulated the expression of pyroptosis-related proteins. ConclusionThe results of this study suggested that the ubiquitination-mediated degradation of xCT drives GSDMD-mediated pyroptosis in COPD and is a potential therapeutic target for COPD.

Multiple oxidative modifications on hemoglobin are elevated in breast cancer patients as measured by nanoflow liquid chromatography-tandem mass spectrometry

Breast cancer is strongly connected with elevated oxidative stress. Oxidative modifications of hemoglobin can serve as biomarkers for monitoring oxidative stress status in vivo. The structure of hemoglobin modifications derived from malondialdehyde (MDA) in human blood hemoglobin exists as N-propenal and dihydropyridine (DHP). This study reports the simultaneous quantification of eleven modified peptides in hemoglobin derived from MDA and advanced histidine oxidation in 16 breast cancer patients and 16 healthy women using nanoflow liquid chromatography nanoelectrospray ionization tandem mass spectrometry. The results reveal statistically significant increases in the formation of MDA-derived N-propenal and DHP of lysine and advanced oxidation of histidine in hemoglobin of breast cancer patients with the Mann-Whitney U-test p values < 0.0001 and the AUC of ROC between 0.9277 and 1.0. Furthermore, the elevation in modified peptides is significant in patients with early stages of breast cancer. By measuring these oxidative modifications in hemoglobin from a drop of blood, the role of lipid peroxidation and oxidative stress in breast cancer can be assessed using this sensitive assay.

The role of lipid peroxidation in epithelial–mesenchymal transition of retinal pigment epithelial cells

Epithelial–Mesenchymal Transition (EMT) of retinal pigment epithelial (RPE) cells is recognized as pivotal in various retinal diseases. Previous studies have suggested a reciprocal regulation between reactive oxygen species (ROS) and EMT, though the involvement of peroxidized lipids or the effects of reducing them has remained unclear. The present study disclosed that EMT of ARPE-19 cells induced by TGF-β2 and TNF-α involves increased lipid peroxidation, and Ferrostatin-1 (Fer-1), a lipophilic antioxidative agent, successfully inhibited the increase in lipid peroxidation. Fer-1 suppressed the formation of EMT-associated fibrotic deposits, while EMT induction or Fer-1 treatment did not influence the cell viability or proliferation. Functionally, Fer-1 impeded EMT-driven cell migration and reduction in transepithelial electrical resistance. It demonstrated regulatory prowess by downregulating the mesenchymal marker fibronectin, upregulating the epithelial marker ZO-1, and inhibiting the EMT-associated transcriptional factor ZEB1. Additionally, VEGF, a major pathogenic cytokine in various retinal diseases, is also upregulated during EMT, and Fer-1 significantly mitigated the effect. The present study disclosed the involvement of lipid peroxidation in EMT of RPE cells, and suggests the suppression of lipid peroxidation may be a potential therapeutic target in retinal diseases in which EMT is implicated.

A Prooxidant and an Antioxidant Sow’s Status with Hepathopathy

The role of lipid peroxidation in the pathogenesis of liver diseases in sows was studied. The state of the antioxidant system in these diseases was also assessed. The liver of sows has been examined after slaughter. There were four groups formed: healthy, acute and chronic hepatosis (HS), and liver cirrhosis. An increase in the level of endogenous intoxication has established, the content of primary (diene conjugates), secondary (malondialdehyde, ketodienes, ketotrienes), and final (Schiff base) products of lipid peroxidation in the blood of sows with hepatopathy. Also noticed that sows with hepatopathy had decreased antioxidant protection, catalase activity, and concentration of tocopherol and ascorbic acid. The level of change was growing with a gravity of hepatopathy. The most expressed disturbance has been observed in sows with liver cirrhosis.

Dentoalveolar anomalies and modern views on the mechanisms of local stress-modeling effect of orthodontic appliances on the periodontal tissues (a literature review)

The aim of the study was to highlight the results of modern scientific developments in tracing the mechanisms of local stress-modeling effect of orthodontic appliances on the oral cavity and periodontal tissues during the active period of orthodontic treatment. Materials and methods. The research methodology was implemented in the collection and analysis of scientific results on the stress-modeling effect of orthodontic appliances in patients with dentoalveolar anomalies obtained from the processed sources – published full-text articles of original and fundamental research by national and foreign authors based on the evidential databases MEDLINE / PubMed, PMC, Scopus, Web of Science, Cochrane, Google Scholar, ResearchGate and other scientific and practical resources. Results. The main components of the stress-modeling effect of fixed orthodontic appliances on the oral cavity, and particularly on the periodontal tissues, were analyzed. The proportion of various complications is quite high and ranges from 32.7 % to 50.0 % of all cases. The development of oxidative stress during orthodontic treatment is potentiated by microcirculatory disorders and hypoxia of the periodontal tissues. The peculiarities of the periodontal cellular complex reaction, which has the ability to bear stress generated in the actin cytoskeleton by direct mechanical stimulation, to extracellular matrix proteins, affecting the three-dimensional organization of the extracellular matrix and its remodeling, have been traced. The role of lipid peroxidation, antioxidant system and enzymatic reaction of oral and crevicular fluids was also defined. Conclusions. The development of oxidative stress during orthodontic treatment can be caused by local and systemic exposure to metals, corrosion processes in particular; by inflammation of periodontal tissues due to poor oral hygiene and activation of periodontal pathogenic microflora; by aseptic inflammation in the periodontal ligament due to the use of mechanical force. Certain enzymes of the oral fluid, in particular lactate dehydrogenase, can act as a sensitive marker of changes in the periodontal ligament metabolism during orthodontic teeth movement. The localization and nature of free radical pathology are largely caused by the nature of an exogenous inducer of lipid peroxidation and the genotypic characteristics of antioxidant system. It is this ratio that determines the initiation and further chain branching of free radical reactions. Without normalization of all pathogenetic links, successful treatment of inflammatory and dystrophic-inflammatory diseases of the periodontal tissues, in particular in orthodontic patients, is impossible.

Association between F2-Isoprostane Metabolites and Weight Change in Older Women: A Longitudinal Analysis

Introduction: Theoretically, some metabolic traits may predispose older individuals to weight loss during aging, leading to increased all-cause mortality and many serious health issues. Biomarkers to robustly predict progressive weight loss during aging are, however, lacking. We prospectively assessed if urinary levels of F₂-isoprostanes and their peroxisomal β-oxidation metabolite, 2,3-dinor-5,6-dihydro-15-F_2t-isoprostane (F₂-IsoP-M), were associated with subsequent weight loss in middle-aged and older women. Methods: Included in the analysis were 2,066 women aged 40–70 years, a subset of a prospective cohort study. F₂-isoprostanes (F₂-IsoPs) and its β-oxidation metabolite, F₂-IsoP-M, were measured in urine using gas chromatography-mass spectrometry. Measurements of anthropometry and exposures to major determinants of body weight were performed at baseline and repeated thrice over 15-year follow-up. The longitudinal associations of F₂-IsoP-M and the F₂-IsoP-M to its parent compound, F₂-IsoP, ratio (MPR) with repeatedly measured weight changes were examined using linear mixed-effect models. Results: After adjusting for time-varying covariates: energy intake, physical activity, and comorbidity index, among others, levels of F₂-IsoP-M and the MPR were both inversely associated with percentage of weight change. Weight in the highest quartile of these two biomarkers was 1.33% (95% CI = −2.41, −0.24) and 1.09% (95% CI = −2.16, −0.02) lower than those in the lowest quartile group, with p for trend of 0.01 and 0.03, respectively. The inverse association was consistently seen across follow-up periods, although appearing stronger with prolonged follow-up. There was no association between the parent compound, F₂-IsoPs, and weight change. Conclusion: This study demonstrates the first piece of evidence to associate F₂-IsoP metabolism, peroxisomal β-oxidation, with weight loss in older women. Further investigations into the role of lipid peroxidation and peroxisomal β-oxidation in weight change among older individuals are warranted.

Treatment of cardiomyocytes isolated from left ventricular myocardium of dogs with chronic heart failure with ALDA-1, an activator of aldehyde dehydrogenase-2, improves mitochondrial function

Abstract Background Reactive oxygen species (ROS) generated by dysfunctional mitochondria (MITO) of the failing heart plays an important role in lipid peroxidation of polyunsaturated fatty acids in cell and MITO membranes resulting in the production of aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). MITO aldehyde dehydrogenase-2 (mALDH2) is a key enzyme for the detoxification of endogenous aldehyde substrates through NAD dependent oxidation. ALDH2 catalyzes toxic 4HNE to nontoxic 4HNA in cardiac cells. We previously showed that mALDH2 expression and activity are markedly reduced in MITO of failing LV cardiomyocytes (CM), a maladaptation that can lead to considerable accumulation of 4-HNE in MITO and ultimately to progressive LV systolic and diastolic dysfunction. In this study, we tested the hypothesis that exposure of failing cardiomyocytes to ALDA-1, an activator of mALDH2, improves MITO function. Methods Freshly isolated CM from LV myocardium of dogs (n = 7) with heart failure (HF, LV ejection fraction ≤35%) and of normal (NL) dogs (n = 4) were incubated for 1 hour in absence (baseline) and presence of Alda-1 at concentration of 10 µM. After incubation, ADP-stimulated respiration (ADPresp) and maximal rate of ATP synthesis (ATPmax) were measured using Strathklein respirometer and bioluminescence ATP assay kit. Results Treatment of isolated CM from HF dogs with 10 µM Alda-1 significantly increased ADPresp (277 ± 18 vs. 189 ± 12 nAtom O/min/mg, p&amp;lt;0.05) and ATPmax (30 ± 3 vs. 16 ± 3 nmoles/min/mg, p&amp;lt;0.05) compared to untreated CM of HF dogs. Treatment of CM from NL dogs with 10 µM Alda-1 had no effect on ADPresp (488 ± 18 vs. 484 ± 19 nAtom O/min/mg) or ATPmax (54 ± 3 vs. 52 ± 2 nmoles/min/mg) compared to untreated NL CM. Conclusions Treatment of CM from HF dogs with Alda-1 improved overall MITO function. Activation of mALDH2 represents a potential viable therapeutic target for treating HF.

Abstract P3173: Exposure Of Mitochondria Isolated From Left Ventricular Myocardium Of Dogs With Moderate Heart Failure To 4-hydroxy-2-nonenal (4-hne) Worsens Existing Mitochondrial Dysfunction

Background: Reactive oxygen species (ROS) generated by dysfunction of mitochondria (MITO) of the failing heart plays an important role in lipid peroxidation of polyunsaturated fatty acids in cell and MITO membranes resulting in the production of aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE). MITO aldehyde dehydrogenase-2 (mALDH2) is a key enzyme for the detoxification of endogenous aldehyde substrates through NAD dependent oxidation. We previously showed that mALDH2 expression and activity are markedly reduced in MITO of failing LV cardiomyocytes, a maladaptation that can lead to considerable accumulation of 4-HNE in MITO. It is unclear whether such an accumulation of 4-HNE can further exacerbate MITO dysfunction resulting in further limitation to ATP formation via oxidative phosphorylation. Hypothesis: This study tested the hypothesis that exposure of MITO isolated from failing hearts to exogenous 4-HNE can result in further deterioration of MITO function. Methods: Freshly isolated MITO from LV myocardium of dogs with moderate heart failure (HF, LV ejection fraction ~40%) were incubated for 1 hour in absence (baseline) and presence of 4-HNE at concentrations of 3 and 30 μM. MITO energetic parameters namely ADP-stimulated respiration (ADPresp), maximal respiratory capacity (MRC) and ATP-linked respiration (ATPresp) were evaluated using an XFe96 analyzer (Seahorse Biosciences). Results: Compared to baseline, exposure of MITO to 3 μM 4-HNE has no significant effects on any of the MITO energetic measures. However, exposure of MITO to 30 μM 4-HNE resulted in significant reduction of ADPresp (490 ± 37 vs. 179 ± 7 OCR pmols/O 2 /min, p&lt;0.05), significant reduction of MRC (334 ± 56 vs. 124 ± 18 OCR pmols/O 2 /min, p&lt;0.05), and significant reduction of ATPresp (48 ± 10 vs. 20 ± 12 OCR pmols/O 2 /min, p&lt;0.05). Conclusions: Exposure of MITO from failing myocardium to elevated levels of 4-HNE can lead to marked deterioration of MITO function that can result in a further reduction of ATP leading to progression of LV dysfunction. Limiting the accumulation of 4-HNE through pharmacologic normalization of ALDH2 activity can potentially represent a therapeutic target for retarding the progression of LV dysfunction toward intractable HF.

Hydroxysafflor yellow A inhibits endothelial cell ferroptosis in diabetic atherosclerosis mice by regulating miR-429/SLC7A11

Context Ferroptosis may play an essential role in lipid peroxidation and endothelial dysfunction of aortic endothelial cells (ECs) in type 2 diabetes mellitus (T2DM) with atherosclerosis (AS). Hydroxysafflor yellow A (HSYA) has shown substantial antioxidant stress and anti-ferroptosis. Objective This study confirms whether HSYA improves symptoms in a mouse model of T2DM/AS and elucidates the underlying mechanisms. Materials and methods ApoE-/- mice were fed with high fat combined with 30 mg/kg streptozotocin to establish a T2DM/AS model. Then mice were treated with intraperitoneal injections of 2.25 mg/kg HSYA for 12 weeks. Human Umbilical Vein Endothelial cells (HUVEC) induced by 33.3 mM d-glucose +100 μg/mL ox-LDL were used to construct a high lipid and high glucose cell model treated with 25 μM HSYA. The changes in oxidative stress- and ferroptosis-related markers were detected, and the regulatory effect of HSYA on the miR-429/SLC7A11 was also verified. Normal ApoE-/- mice or HUVEC cells were used as the control group. Results HSYA effectively reduced atherosclerotic plaque formation in the T2DM/AS mouse model and inhibited HUVEC ferroptosis, such as upregulating GSH-Px, SLC7A11 and GPX4, but inhibited ACSL4. Furthermore, HSYA also downregulated the expression of miR-429, which further regulated SLC7A11 expression. After miR-429 mimic or SLC7A11 siRNA transfection in the HUVEC, the antioxidative stress and anti-ferroptosis effects of HSYA were significantly abolished. Conclusions HSYA is expected to become an important health drug to prevent the occurrence and development of T2DM/AS.

1506-P: Effect of Beta-Agonist Treatment on Selenium Metabolism in Differentiated Brown Adipocytes

Selenium (Se) is an essential trace element important to several body processes such as metabolism, thyroid function, and curbing of oxidative stress. Se is utilized as the amino acid known selenocysteine (Sec), decomposed by the enzyme selenocysteine lyase (Scly). Selenoproteins have a broad range of functions, including protecting against lipid peroxidation and apoptosis, metabolic dysregulation such as glucose intolerance, and other immune responses. In brown adipocytes, the selenoprotein glutathione peroxidase 4 (GPX4) plays a key role in lipid peroxidation which in turn allows for proper thermogenic responses triggered by adrenergic signals. GPX4 removes toxic lipid peroxides by converting them into non-toxic alcohol and water. When Se levels are insufficient in brown adipocytes, the selenoprotein GPX4 may be downregulated, leading cells to accumulate a lethal amount of lipid peroxidases and triggering ferroptosis, a type of cell death. Ferroptosis activation, in turn, negatively impact pathways dependent on adrenergic responses in brown adipocytes, such as thermogenesis activation. To determine how Se levels regulate the expression of Scly and GPX4 upon treatment with adrenergic agonist in differentiated PAZ6 brown adipocytes. Human PAZ6 pre-adipocytes were differentiated for 21 days, then treated with insufficient (20 nM), adequate (80 nM), and high sodium selenite (160 nM) levels for 48h. Differentiated brown adipocytes were also treated with 1 μM CL-316243, a β3-adrenergic receptor agonist, for 24h after selenite treatment. Cells were then harvested for qPCR and Western blot analysis. Differentiated PAZ6 cells had an increase in UCP1 expression, a marker of brown adipocytes. Upon Se treatment, both Scly and GPX4 expression were unchanged in PAZ6 cells. Treatment with β3-adrenergic receptor agonist also did not affect the expression levels of both proteins. In differentiated brown adipocytes, expression of Scly and GPX4 is not dependent on Se nor β-agonist signals. Disclosure S.Swanson: None. Funding National Institutes of Health (R01DK128390)

Roles of glutathione peroxidase 4 on the mercury-triggered ferroptosis in renal cells: implications for the antagonism between selenium and mercury.

Understanding of how mercury species cause cellular impairments at the molecular level is critical for explaining the detrimental effects of mercury exposure on the human body. Previous studies have reported that inorganic and organic mercury compounds can induce apoptosis and necrosis in a variety of cell types, but more recent advances reveal that mercuric mercury (Hg2+) and methylmercury (CH3Hg+) may result in ferroptosis, a distinct form of programmed cell death. However, it is still unclear which protein targets are responsible for ferroptosis induced by Hg2+ and CH3Hg+. In this study, human embryonic kidney 293T cells were used to investigate how Hg2+ and CH3Hg+ trigger ferroptosis, given their nephrotoxicity. Our results demonstrate that glutathione peroxidase 4 (GPx4) plays a key role in lipid peroxidation and ferroptosis in renal cells induced by Hg2+ and CH3Hg+. The expression of GPx4, the only lipid repair enzyme in mammal cells, was downregulated in response to Hg2+ and CH3Hg+ stress. More importantly, the activity of GPx4 could be markedly inhibited by CH3Hg+, owing to the direct binding of the selenol group (-SeH) in GPx4 to CH3Hg+. Selenite supplementation was demonstrated to enhance the expression and activity of GPx4 in renal cells, and consequently relieve the cytotoxicity of CH3Hg+, suggesting that GPx4 is a crucial modulator implicated in the Hg-Se antagonism. These findings highlight the importance of GPx4 in mercury-induced ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.

Iron accumulation in ferroptosis and the role of lipid peroxidation in osteoarthritis

Ferroptosis is a recently discovered mode of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, which can reach lethal levels, but this process was found to be inhibited by ferroptosis inhibitor-specific reverse. Osteoarthritis (OA) is the most common degenerative joint disease characterized by complex pathogenesis including mechanical overload, elevated levels of inflammatory mediators, metabolic alterations, and cellular senescence and death. Since iron accumulation and oxidative stress are common pathological features of OA, the role of ferroptosis in OA has been extensively explored. Accumulating evidence indicates that iron homeostasis and lipid peroxidation are closely related to the pathogenesis of OA. This article will focus on the mechanisms of ferroptosis and the role of iron homeostasis and lipid peroxidation in the pathogenesis of OA, summarizing recent evidence.

Association between lipid peroxidation biomarkers and microRNA expression profiles

BackgroundIn-vitro and animal studies demonstrate that epigenetic regulation may play an important role in lipid peroxidation. No human study to date has directly evaluated microRNAs (miRNAs), as epigenetic modulators, in relation to systemic levels of lipid peroxidation. ObjectivesTo evaluate associations between systemic levels of lipid peroxidation and miRNA expression profiles in women. MethodsIncluded in the analysis were 92 women aged 40–70 years, a subset of the Shanghai Women’s Health Study (SWHS). Lipid peroxidation was assessed by urinary markers F2-isoprostanes (F2-IsoPs), the products of free radical-catalyzed peroxidation of arachidonic acid, and its major metabolite after β-oxidation, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), with GC/NICI-MS assays. Expression levels of 798 miRNAs were quantified in peripheral plasma with NanoString nCounter assays. A multivariable linear regression model was used to examine the association between lipid peroxidation and miRNA expression. ResultsAfter adjusting for potential confounders, 29 miRNAs and 213 miRNAs were associated with F2-IsoPs and F2-IsoP-M, respectively. When further controlling for multiple comparisons, none of these nominally significant associations with F2-IsoPs was retained, whereas 71 of 213 miRNAs associated with F2-IsoP-M remained. The predicted targets of the F2-IsoP-M associated miRNAs were enriched for several lipid peroxidation-related processes such as PI3K/AKT, MAPK, FOXO and HIF-1 signaling pathways. Moreover, 10 miRNAs (miR-93-5p, miR-761, miR-301b-3p, miR-497-5p, miR-141-3p, miR-186-5p, miR-126-3p, miR-200b-3p, miR-520d-3p, and miR-363-3p) exhibited functional interactions with 50 unique mRNAs targets involved in the regulation of β-oxidation. ConclusionsTo our knowledge, this study, for the first time, provides human data suggesting that miRNA expression may be linked to lipid peroxidation products and their metabolism.

Pro-thrombotic changes associated with exposure to ambient ultrafine particles in patients with chronic obstructive pulmonary disease: roles of lipid peroxidation and systemic inflammation

BackgroundExposure to particulate matter air pollution is associated with an increased risk of cardiovascular mortality in patients with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are not yet understood. Enhanced platelet and pro-thrombotic activity in COPD patients may explain their increased cardiovascular risk. We aim to explore whether short-term exposure to ambient particulate matter is associated with pro-thrombotic changes in adults with and without COPD, and investigate the underlying biological mechanisms in a longitudinal panel study. Serum concentration of thromboxane (Tx)B2 was measured to reflect platelet and pro-thrombotic activity. Lipoxygenase-mediated lipid peroxidation products (hydroxyeicosatetraenoic acids [HETEs]) and inflammatory biomarkers (interleukins [ILs], monocyte chemoattractant protein-1 [MCP-1], tumour necrosis factor alpha [TNF-α], and macrophage inflammatory proteins [MIPs]) were measured as potential mediating determinants of particle-associated pro-thrombotic changes.Results53 COPD and 82 non-COPD individuals were followed-up on a maximum of four visits conducted from August 2016 to September 2017 in Beijing, China. Compared to non-COPD individuals, the association between exposure to ambient ultrafine particles (UFPs) during the 3–8 days preceding clinical visits and the TxB2 serum concentration was significantly stronger in COPD patients. For example, a 103/cm3 increase in the 6-day average UFP level was associated with a 25.4% increase in the TxB2 level in the COPD group but only an 11.2% increase in the non-COPD group. The association in the COPD group remained robust after adjustment for the levels of fine particulate matter and gaseous pollutants. Compared to the non-COPD group, the COPD group also showed greater increases in the serum concentrations of 12-HETE (16.6% vs. 6.5%) and 15-HETE (9.3% vs. 4.5%) per 103/cm3 increase in the 6-day UFP average. The two lipid peroxidation products mediated 35% and 33% of the UFP-associated increase in the TxB2 level of COPD patients. UFP exposure was also associated with the increased levels of IL-8, MCP-1, MIP-1α, MIP-1β, TNF-α, and IL-1β in COPD patients, but these inflammatory biomarkers did not mediate the TxB2 increase.ConclusionsShort-term exposure to ambient UFPs was associated with a greater pro-thrombotic change among patients with COPD, at least partially driven by lipoxygenase-mediated pathways following exposure.Trial registrationChiCTR1900023692. Date of registration June 7, 2019, i.e. retrospectively registered.

Functional Deficits of 5×FAD Neural Stem Cells Are Ameliorated by Glutathione Peroxidase 4.

Alzheimer’s disease (AD) is the most common cause of dementia affecting millions of people around the globe. Impaired neurogenesis is reported in AD as well as in AD animal models, although the underlying mechanism remains unclear. Elevated lipid peroxidation products are well-documented in AD. In current study, the role of lipid peroxidation on neural stem cell (NSCs) function is tested. Neural stem cells (NSCs) from 5×FAD mice, a widely used AD model with impaired neurogenesis, were observed to have increased levels of lipid reactive oxygen species compared to NSCs from control WT mice. 5×FAD NSCs exhibited altered differentiation potential as revealed by their propensity to differentiate into astrocytic lineage instead of neuronal lineage compared to WT NSCs. In addition, 5×FAD NSCs showed a reduced level of Gpx4, a key enzyme in reducing hydroperoxides in membrane lipids, and this reduction appeared to be caused by enhanced autophagy-lysosomal degradation of Gpx4 protein. To test if increasing Gpx4 could restore differentiation potential, NSCs from 5×FAD and Gpx4 double transgenic mice, i.e., 5×FAD/GPX4 mice were studied. Remarkably, upon differentiation, neuronal linage cells increased significantly in 5×FAD/GPX4 cultures compared to 5×FAD cultures. Taken together, the findings suggest that deficiency of lipid peroxidation defense contributes to functional decline of NSCs in AD.

The role of ALOX15B in heat stress-induced apoptosis of porcine sertoli cells

Heat stress reduces the number of Sertoli cells and impairs spermatogenesis. Mounting evidence indicates that lipid homeostasis is fundamental to cell survival. However, little is known about the role of lipid peroxides in the heat stress-induced apoptosis of Sertoli cells. In the present study, we used metabolomics to explore the changes of lipid peroxides in porcine Sertoli cells under heat stress using liquid chromatograph-mass spectrometry. These results showed a notable increase in the content of 8-hydroxyeicosatetraenoic acid (8-HETE), and 15-hydroxyeicosatetraenoic acid (15-HETE). Furthermore, we found that among arachidonate lipoxygenases, heat stress significantly increased the expression of arachidonate 15-lipoxygenase type B (ALOX15B). Moreover, baicalein, a specific inhibitor of ALOX15B, reduced the content of 8-HETE and 15-HETE, and decreased the apoptosis rate in heat stress-treated porcine Sertoli cells. In addition, baicalein and small interfering RNAs targeting ALOX15B increased the content of 8-HETE and 15-HETE, and activated the p38-p53 pathway, causing apoptosis in heat stress treated porcine Sertoli cells. Interestingly, a p38 inhibitor decreased the expression of ALOX15B, reduced the content of 8-HETE and 15-HETE, and decreased the expression of p53 and the apoptosis rate in heat stress treated porcine Sertoli cells. A p53 inhibitor had similar effect on Sertoli cells. These results indicated that heat stress enhanced the expression of ALOX15B, increased the content of 8-HETE and 15-HETE, and activated the p38-p53 pathway to cause apoptosis. ALOX15B and lipid peroxides obtained feedback from the p38-p53 pathway. Our findings will help to reveal the mechanism of lipid metabolism in Sertoli cells, and could provide a new targeted substrate for anti-heat stress strategies.

Роль перекисного окисления липидов в патогенезе гипертонической болезни у лиц первого периода зрелости, работающих в ночное время

В статье представлен результат исследования состояния системы перекисного окисления липидов у лиц первого периода зрелости, страдающих гипертонической болезнью, длительное время работающих в ночную смену. Показано наличие нарушений деятельности системы перекисного окисления липидов (снижение активности супероксиддисмутазы, повышение содержания малонового альдегида и диеновых коньюгатов в мембранах эритроцитов) у данной группы лиц. Выявлена прямая зависимость между содержанием продуктов ПОЛ в мембранах эритроцитов, активностью супероксиддисмутазы и тяжестью течения гипертонической болезни у молодых людей, работающих в ночное время. Выраженность нарушений деятельности системы ПОЛ коррелирует с продолжительностью ночного характера труда.