Mechanism Of Peroxidation Research Articles

Integrated transcriptomic and metabolomic analysis reveals the effects and potential mechanism of hydrogen peroxide on pigment metabolism in postharvest broccoli.

To understand the effects and related potential mechanism of H2O2 on pigment metabolism in postharvest broccoli, an integrated analysis of transcriptome and metabolome was performed. Results suggested that 65 differentially expressed genes and 26 differentially accumulated metabolites involved in chlorophyll, carotenoid, and flavonoid metabolism were identified. H2O2 treatment delayed the decrease of chlorophyll content by upregulating the expressions of chlorophyll synthetic genes, thylakoid synthetic genes, and 15 light-harvesting complex genes compared with the control and diphenylene iodonium treatments. H2O2 treatment decreased the accumulation of 11 flavonoids and 5 flavonols by downregulating the flavonoid synthetic genes. In addition, H2O2 treatment promoted carotenoid biosynthesis to eliminate reactive oxygen species in thylakoids, thereby protecting chlorophyll molecules from degradation. The inhibition of flavonoids and flavonols accumulation and chlorophyll decrease was the crucial reason for the delayed yellowing in H2O2 treatment. This study provides a new method and theoretical support for delaying the yellowing process in postharvest broccoli.

Mitochondrial targeted modification and anticancer mechanism of natural product ergosterol peroxide

Ergosterol peroxide (EP) isolated from the edible medicinal fungus Pleurotus ferulae has a wide range of anti-tumor activity, but poor water solubility and low bioavailability limit further application. In this study, EP was structurally modified using triphenylphosphine (TPP+), which combines mitochondrial targeting, amphiphilicity, and cytotoxicity. A series of TPP+-conjugated ergosterol peroxide derivatives (TEn) with different length linker arms were synthesized. The structure–activity relationship showed that the anticancer activity of TEn gradually decreased with the elongation of the linker arm. The compound TE3 has the optimal and broadest spectrum of antitumor effects. It mainly through targeting mitochondria, inducing ROS production, disrupting mitochondrial function, and activating mitochondria apoptosis pathway to exert anti-cervical cancer activity. Among them, TPP+ only acted as a mitochondrial targeting group, while EP containing peroxide bridge structure served as an active group to induce ROS. In vivo experiments have shown that TE3 has better anti-cervical cancer activity and safety than the first-line anticancer drug cisplatin, and can activate the immune response in mice. Although TE3 exhibits some acute toxicity, it is not significant at therapeutic doses. Therefore, TE3 has the potential for further development as an anti-cervical cancer drug.

Mechanism of ergosterol peroxide on MCF-7 breast cancer cells based on network pharmacology and in vitro experiments

This study investigated the effects of ergosterol peroxide(EP) on the proliferation and apoptosis of MCF-7 breast cancer cells, explored its possible mechanisms of action, and verified the effects and mechanisms by in vitro experiments. Network pharmaco-logy was used to screen the target proteins of EP and construct target networks and protein-protein interaction(PPI) networks to predict the potential target proteins and related pathways involved in EP anti-breast cancer effects. The MTT assay was performed to measure the inhibitory effect of EP on MCF-7 cell proliferation, and the colony formation assay was used to assess the cell cloning ability. Flow cytometry and laser confocal microscopy were employed to evaluate cell apoptosis, mitochondrial membrane potential and reactive oxygen species(ROS) levels. Western blot analysis was conducted to examine the expression levels of B-cell lymphoma 2(Bcl-2), Bcl-2-associated X protein(Bax), cytochrome C(Cyt C), caspase-7, cleaved caspase-7, phosphatidylinositol 3-kinase(PI3K), and se-rine/threonine kinase B(AKT) in MCF-7 cells treated with EP. The results of network pharmacology prediction yielded 173 common targets between EP and breast cancer; the results of Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis showed that EP treatment for breast cancer mainly affected the signaling pathways such as cancer pathway, PI3K-AKT signaling pathway, cellular senescence signaling pathway, and viral carcinogenesis pathway; and the MTT assay results showed that the viability of MCF-7 cells in the EP group was significantly lower than that in the control group, exhibiting a time-and concentration-dependent trend, and EP can inhibit colony formation of MCF-7 breast cancer cells. Treatment with 10, 20, and 40 μmol·L~(-1) EP for 24 h resulted in a significant increase in the total apoptosis rate of MCF-7 cells, a significant decrease in mitochondrial membrane potential, and a significant increase in ROS levels. In addition, treatment with EP led to an upregulation of Cyt C, Bax, and cleaved caspase-7 protein expression, and a downregulation of p-PI3K, p-AKT, and Bcl-2 protein expression in MCF-7 cells. Studies have shown that EP inhibits MCF-7 breast cancer cell proliferation and reduces colony formation by a mechanism that may be related to the PI3K-AKT pathway mediating the mitochondrial apoptotic pathway.

MiRNA-142-3p aggravates hydrogen peroxide-induced human umbilical vein endothelial cell premature senescence by targeting SIRT1.

Vascular endothelial cell premature senescence plays an important part in stroke. Many microRNAs (miRNAs) are known to be involved in the pathological process of vascular endothelial cell premature senescence. The present study aimed to investigate the mechanism of hydrogen peroxide (H2O2)-induced premature senescence in human umbilical vein endothelial cells (HUVECs) and effect of miR-142-3p on hydrogen peroxide (H2O2)-induced premature senescence. HUVECs were exposed to H2O2 to establish a model premature senescence in endothelial cells. CCK-8 assay was performed to detect cell viability. Senescence-associated β-galactosidase staining assay and senescence-related proteins p16 and p21 were used to detect changes in the degree of cell senescence. RT-qPCR and Western blot were conducted to measure mRNA and protein levels, respectively. The scratch wound-healing assay, transwell assay, and EdU assay were performed to evaluate the ability of migration and proliferation, respectively. miRNA-142-3p and silencing information regulator 2 related enzyme 1 (SIRT1) binding was verified using Targetscan software and a dual-luciferase assay. We found that miRNA-142-3p is abnormally up-regulated in HUVECs treated with H2O2. Functionally, miRNA-142-3p inhibition may mitigate the degree of HUVEC senescence and improve HUVEC migration and proliferation. Mechanistically, SIRT1 was validated to be targeted by miRNA-142-3p in HUVECs. Moreover, SIRT1 inhibition reversed the effects of miRNA-142-3p inhibition on senescent HUVECs exposed to H2O2. To our knowledge, this is the first study to show that miRNA-142-3p ameliorates H2O2-induced HUVECs premature senescence by targeting SIRT1 and may shed light on the role of the miR-142-3p/SIRT1 axis in stroke treatment.

Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production.

This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring in breast cancer are described, ranging from nonspecific, at first glance, and strictly biochemical to hormone-induced reactions, genetic and epigenetic regulation, which allows for a broader and deeper understanding of the principles of oncogenesis, as well as maintaining the viability of cancer cells in the mammary gland. Specific pathways of the activation of oxidative stress have been studied as a response to the overproduction of stress hormones and estrogens, and specific ways to reduce its negative impact have been described. The diversity of participants that trigger redox reactions from different sides is considered more fully: glycolytic activity in breast cancer, and the nature of consumption of amino acids and metals. The role of metals in oxidative stress is discussed in detail. They can act as both co-factors and direct participants in oxidative stress, since they are either a trigger mechanism for lipid peroxidation or capable of activating signaling pathways that affect tumorigenesis. Special attention has been paid to the genetic and epigenetic regulation of breast tumors. A complex cascade of mechanisms of epigenetic regulation is explained, which made it possible to reconsider the existing opinion about the triggers and pathways for launching the oncological process, the survival of cancer cells and their ability to localize.

Effects of sulfur‐ and Fe‐deficient defects on the decomposition of hydrogen peroxide H2O2 on pyrite surface

AbstractThere is still a lack of research on the effect of the S and Fe vacancy on the adsorption mechanism of peroxide (H2O2) on the pyrite surface. In this work, the adsorption of H2O2 molecules on the perfect and defective pyrite surface is simulated based on density functional theory (DFT). The results indicated that the adsorption energy of H2O2 molecules on the S‐vacancy surface is relatively lower than that on the perfect surface and dissociative adsorption entirely occurs, while the adsorption behavior of H2O2 molecules on the S‐rich pyrite surface has not occurred. When the H2O2 molecules are adsorbed on the Fe‐rich pyrite surface, two products appear, one with two OH− species and the other with an H2O molecule and an O atom. The analysis of the transition state (TS) found that the dissociation of the H2O2 molecule producing two OH− species that bond with two Fe atoms is more likely to occur. In addition, based on the coordination chemistry, it is demonstrated that Fe atoms are more reactive around an S vacancy than on a perfect surface.

Study on the Mechanism of Lipid Peroxidation Induced by Carbonate Radicals.

Based on the reported research, hydroxyl radicals can be rapidly transformed into carbonate radicals in the carbonate-bicarbonate buffering system in vivo. Many of the processes considered to be initiated by hydroxyl radicals may be caused by carbonate radicals, which indicates that lipid peroxidation initiated by hydroxyl radicals can also be caused by carbonate radicals. To date, theoretical research on reactions of hydrogen abstraction from and radical addition to polyunsaturated fatty acids (PUFAs) of carbonate radicals has not been carried out systematically. This paper employs (3Z,6Z)-nona-3,6-diene (NDE) as a model for polyunsaturated fatty acids (PUFAs). Density functional theory (DFT) with the CAM-B3LYP method at the 6-311+g(d,p) level was used to calculate the differences in reactivity of carbonate radicals abstracting hydrogen from different positions of NDE and their addition to the double bonds of NDE under lipid solvent conditions with a dielectric constant of 4.0 (CPCM model). Grimme's empirical dispersion correction was taken into account through the D3 scheme. The energy barrier, reaction rate constants, internal energy, enthalpy and Gibbs free energy changes in these reactions were calculated With zero-point vibrational energy (ZPVE) corrections. The results indicated that carbonate radicals initiate lipid peroxidation primarily through hydrogen abstraction from diallyl carbon atoms. The reaction of hydrogen abstraction from diallyl carbon atoms exhibits the highest reaction rate, with a reaction rate constant approximately 43-fold greater than the second-ranked hydrogen abstraction from allyl carbon atoms. This process has the lowest energy barrier, internal energy, enthalpy, and Gibbs free energy changes, indicating that it is also the most spontaneous process.

Oxygen-18 Labeling Defines a Ferric Peroxide (Compound 0) Mechanism in the Oxidative Deformylation of Aldehydes by Cytochrome P450 2B4.

Most cytochrome P450 (P450) oxidations are considered to occur with the active oxidant being a perferryl oxygen (FeO3+, Compound I). However, a ferric peroxide (FeO2®, Compound 0) mechanism has been proposed, as well, particularly for aldehyde substrates. We investigated three of these systems, the oxidative deformylation of the model substrates citronellal, 2-phenylpropionaldehyde, and 2-methyl-2-phenylpropionaldehyde by rabbit P450 2B4, using 18O labeling. The formic acid product contained one 18O derived from 18O2, which is indicative of a dominant Compound 0 mechanism. The formic acid also contained only one 18O derived from H218O, which ruled out a Compound I mechanism. The possibility of a Baeyer-Villiger reaction was examined by using synthesized possible intermediates, but our data do not support its presence. Overall, these findings unambiguously demonstrate the role of the Compound 0 pathway in these aldehyde oxidative deformylation reactions.

Free Radical Lipid Peroxidation Induced by Reactive Halogen Species.

The review is devoted to the mechanisms of free radical lipid peroxidation (LPO) initiated by reactive halogen species (RHS) produced in mammals, including humans, by heme peroxidase enzymes, primarily myeloperoxidase (MPO). It has been shown that RHS can participate in LPO both in the initiation and branching steps of the LPO chain reactions. The initiation step of RHS-induced LPO mainly involves formation of free radicals in the reactions of RHS with nitrite and/or with amino groups of phosphatidylethanolamine or Lys. The branching step of the oxidative chain is the reaction of RHS with lipid hydroperoxides, in which peroxyl and alkoxyl radicals are formed. The role of RHS-induced LPO in the development of human inflammatory diseases (cardiovascular and neurodegenerative diseases, cancer, diabetes, rheumatoid arthritis) is discussed in detail.

Mechanism of lipid peroxidation of liposomes by cold atmospheric pressure plasma jet irradiation

Mechanism of lipid peroxidation of liposomes by cold atmospheric pressure plasma jet irradiation

Increase of OH radical yields due to the decomposition of hydrogen peroxide by gold nanoparticles under X-ray irradiation.

We elucidate the decomposition mechanism of hydrogen peroxide, which is formed by water radiolysis, by gold nanoparticles (GNPs) under X-ray irradiation. The variations in yields of hydrogen peroxide generated in the presence of GNPs are evaluated using the Ghormley technique. The increase of yields of OH radicals has been quantified using Ampliflu® Red solutions. Almost all hydrogen peroxide generated by irradiation of <25 Gy is decomposed by GNPs, while the yield of OH radicals increases by 1.6 times. The amount of OH radicals thus obtained is almost equivalent to that of the decomposed hydrogen peroxide. The decomposition of hydrogen peroxide is an essential reaction to produce additional OH radicals efficiently in the vicinity of GNPs.

Density functional theory studies on the oleic acid thermal oxidation into volatile compounds.

Oleic acid oxidation is one of the main sources of food flavor compounds. Volatile profiling was investigated using thermal desorption cryo-trapping combined with gas chromatography-mass spectrometry to analyze the volatile composition of oleic acid oxidation. A total of 43 volatile compounds, including aldehydes (11), ketones (2), alcohols (5), furans (2), acids (8), ester (12) and alkane (3) were identified from oleic acid during heating. Then, density functional theory (DFT) was applied to analyze the oxidative mechanism of oleic acid during heating. A total of 30 reactions were obtained and grouped into the peroxide (ROOH), alkoxy radical (RO•), and peroxide radical (ROO•) pathways. The structures of intermediates, transition states (TS), and products in each reaction were also determined. Results show that the branch chemical reactions were the key reactions in different reaction pathway. Moreover, the reaction priority of the thermal oxidation reaction of oleic acid was the peroxide radical mechanism>the peroxide mechanism>the alkoxy radical mechanism.

Damage mechanism of calcium peroxide on Microcystis aeruginosa PCC7806 and its potential application

Calcium peroxide (CP) is an oxidizing agent that can gradually release hydrogen peroxide (HP) to achieve selective killing of cyanobacteria in water blooms, and reduce the phosphorus content in the water column. Despite the potential of CP for use in cyanobacterial water bloom disposal, there is a lack of research on the mechanism of oxidative damage on cyanobacterial cells by calcium peroxide. Further studies are required to comprehend the underlying scientific principles and potential risks and benefits of applying this approach to cyanobacteria disposal. In this investigation, we employed varying doses of CP for the treatment of Microcystis aeruginosa (M. aeruginosa), which resulted in the following findings: (1) the HP released from CP can damage the photosystem II of M. aeruginosa, reduce cell photosynthetic pigment content, intensify the degree of membrane lipid peroxidation, and increase the extracellular protein content; (2) CP significantly increased the soluble extracellular polysaccharide (sEPS) and bound extracellular polysaccharide (bEPS) content of cells (p < 0.05), causing the cells to exist as agglomerates and effectively allowing them to flocculate and precipitate, reducing the turbidity of the water body; (3) The increased dose elevated the pH and calcium ions significantly decreased the orthophosphate content, resulting in an increase in extracellular alkaline phosphatase activity, but possibly increasing the total extracellular nitrogen content. These results suggested that CP is an effective chemical algaecide for cyanobacteria, and has the potential to be applied to dispose of cyanobacterial blooms while reducing the phosphorus content of the water column and further inhibiting the growth and proliferation of cells.

Novel mechanism of hydrogen peroxide for promoting efficient natamycin synthesis in Streptomyces.

The mechanism of regulation of natamycin biosynthesis by Streptomyces in response to oxidative stress is unclear. Here, we first show cholesterol oxidase SgnE, which catalyzes the formation of H2O2 from sterols, triggered a series of redox-dependent interactions to stimulate natamycin production in S. gilvosporeus. In response to reactive oxygen species, residues Cys212 and Cys221 of the H2O2-sensing consensus sequence of OxyR were oxidized, resulting in conformational changes in the protein: OxyR extended its DNA-binding domain to interact with four motifs of promoter p sgnM . This acted as a redox-dependent switch to turn on/off gene transcription of sgnM, which encodes a cluster-situated regulator, by controlling the affinity between OxyR and p sgnM , thus regulating the expression of 12 genes in the natamycin biosynthesis gene cluster. OxyR cooperates with SgnR, another cluster-situated regulator and an upstream regulatory factor of SgnM, synergistically modulated natamycin biosynthesis by masking/unmasking the -35 region of p sgnM depending on the redox state of OxyR in response to the intracellular H2O2 concentration. IMPORTANCE Cholesterol oxidase SgnE is an indispensable factor, with an unclear mechanism, for natamycin biosynthesis in Streptomyces. Oxidative stress has been attributed to the natamycin biosynthesis. Here, we show that SgnE catalyzes the formation of H2O2 from sterols and triggers a series of redox-dependent interactions to stimulate natamycin production in S. gilvosporeus. OxyR, which cooperates with SgnR, acted as a redox-dependent switch to turn on/off gene transcription of sgnM, which encodes a cluster-situated regulator, by masking/unmasking its -35 region, to control the natamycin biosynthesis gene cluster. This work provides a novel perspective on the crosstalk between intracellular ROS homeostasis and natamycin biosynthesis. Application of these findings will improve antibiotic yields via control of the intracellular redox pressure in Streptomyces.

Transcriptome and metabolome integrated analysis revealed the effects and potential mechanism of hydrogen peroxide on antioxidant system in postharvest broccoli

To investigate the effects and potential mechanism of exogenous H2O2 on antioxidant metabolism and yellowing in postharvest broccoli, the transcriptome and metabolome integrated analysis were performed. A total of 61 differentially expressed genes and 6 differentially accumulated metabolites identified among of H2O2 and diphenylene iodonium (DPI) treatments on 2 and 4 d. Exogenous H2O2 promoted the accumulation of endogenous H2O2 within 1 d by activating RBOHs expressions·H2O2 treatment up-regulated the expressions of SOD, CAT and peroxiredoxin (Prx) genes and APX, DHAR and GPX genes involved in ascorbic acid-glutathione (AsA-GSH) cycle, thereby promoting the scavenging of O2-. and H2O2 and alleviating the oxidative damage. Additionally, H2O2 treatment promoted the biosynthesis of AsA and GSH, and increased the content of AsA, GSH, oxidized glutathione, and γ-glutamylcysteine·H2O2 treatment also promoted glucosinolate biosynthesis, the accumulation of 3-(6′-methylthio)hexylmalic acid, and the production of sulforaphane by up-regulating MYS expression, thereby enhancing the health-care function of postharvest broccoli. This study provided the new insights into regulatory mechanism of H2O2 on antioxidant system.

2D redox-active COF with the anthraquinone structure for photocatalytic reduction of uranium

Photocatalysis can be an effective technology for the conversion of U(VI) to U(IV) because it is efficient, facile and free of secondary pollution. In this work, anthraquinone-functionalized covalent organic framework (DQTP) was fabricated by an irreversible tautomerization of 2,6-diaminoanthraquinone (DQ) and 2, 4, 6-triformylphloroglucinol (TP) in the β-ketoenamine structure. The resultant DQTP could be effectively used as a metal-free heterogeneous catalyst for the photoreduction of U(VI) (k = 0.00287 min−1). The pivotal role of anthraquinone moieties as the active sites for U(VI) reduction was evidenced, i.e., to promote charge separation and thus enhance photocatalytic activity, as well as the production of H2O2 followed by the formation of (UO2)O2·2H2O with U(VI) through in-situ reactions. Additionally, free radical capture experiments and spectrometry analysis were conducted to determine the synergistic reduction mechanism of photogenerated electrons, superoxide radicals and hydrogen peroxide. It was reassuring that this work could provide the research basis for the subsequent development of more practical metal-free photocatalysts for the purification of U(VI)-containing wastewater.

Elucidating the Influence of Intercalated Anions in NiFe LDH on the Electrocatalytic Behavior of OER: A Kinetic Study

AbstractThe oxygen evolution reaction (OER) as one half‐cell reaction of electrochemical water splitting has a fundamental impact on water splitting efficiency and thus on the competitiveness of electrochemically generated hydrogen in the energy market. Nickel‐iron layered double hydroxides (NiFe LDH) are among the most promising electrocatalysts for efficient OER under alkaline conditions. Despite intensive research, correlations of the material properties and the resulting kinetically limiting surface processes are poorly investigated. This work focuses on the kinetic behavior of NiFe LDH catalysts containing different anions in the basal spacing in alkaline OER. Steady‐state Tafel plots, impedance measurements as well as reaction order plots were used to elucidate differences in the catalytic performance. All catalysts showed a dual Tafel behavior and fractional reaction orders. For kinetic modelling, the physisorbed hydrogen peroxide mechanism and Temkin adsorption model were adopted to fit experimental data. Our study showed that the intercalated anions affect the kinetics of rate determining steps. The hypophosphite intercalated LDH possessed the highest OER activity and the first step as rate determining. While for both carbonate and borate intercalated NiFe LDH, the second step proved to be rate determining in the low Tafel region, while the first step was found to be rate‐limiting in the high Tafel region.

Performance and mechanism of calcium peroxide reducing H2S production from sludge anaerobic fermentation

Calcium peroxide (CaO2) addition is widely regarded as a high-efficient sludge treatment method to degrade pollutants and enhance resource recovery. In this study, it was further found that CaO2 addition changed sulfur distribution during sludge anaerobic treatment, which promoted sulfur flow from sludge solid to liquid phase but significantly inhibited toxic hydrogen sulfide (H2S) gas production. With CaO2 addition increased from 0 to 0.25 g/g VSS, the accumulated H2S yield decreased from 314.6 × 10−4 to 61.3 × 10−4 mg/g VSS while the accumulated SCFAs and hydrogen yields increased from 46.2 to 266.5 mg COD/g VSS, and 0.9 to 10.2 mL/g VSS. Mechanism analysis showed that the released OH– and oxidizing substances (e.g., ·OH and ·O2–) firstly destroyed functional groups and hydrogen bonding networks contained in sludge EPS, with the contents of C=O group, β-sheet and α-Helix being reduced by 24%, 19.7%, and 23.2%, respectively. This caused the cracking of sludge EPS and releases of soluble metal ions (e.g., Al, Mg, and Fe). The released metal ions in alkaline environment promoted the transformation of H2S gas and dissolved sulfide to metal sulfide, which was one important reason to reduce H2S gas release. Then, the free radicals further attacked sludge cells without EPS protection and caused cell lysis. Flow cytometry analysis showed that 0.25 g/g VSS CaO2 reduced the rate of living cells from 90.7% to 81.4%. Microbial analysis unveiled that CaO2 reduced the content of S2− producers (e.g., Desulfobulbus and Desulfovibrio) and the expression of related genes (e.g., PepD and Sat). Moreover, the activities of S2− producers, e.g., methionine lyase and adenosine-5′-phosphosulfate reductase also reduced by 41.3% and 64.8% with 0.25 g/g VSS CaO2 addition. These findings provide new insights into CaO2-based sludge treatment and might have significant implications for sludge treatment.

Acrolein Exposure Impaired Glucose Homeostasis and Increased Risk of Type 2 Diabetes: An Urban Adult Population-Based Cohort Study with Repeated Measures

Acrolein is an identified high-priority hazardous air pollutant ubiquitous in daily life and associated with cardiometabolic risk that attracts worldwide attention. However, the etiology role of acrolein exposure in glucose dyshomeostasis and type 2 diabetes (T2D) is unclear. This repeated-measurement prospective cohort study included 3522 urban adults. Urine/blood samples were repeatedly collected for determinations of acrolein metabolites (N-acetyl-S-(3-hydroxypropyl)-l-cysteine, N-acetyl-S-(2-carboxyethyl)-l-cysteine; acrolein exposure biomarkers), glucose homeostasis, and T2D at baseline and a three-year follow-up. We found that each 3-fold increment in acrolein metabolites was cross-sectionally associated with 5.91-6.52% decrement in homeostasis model assessment-insulin sensitivity (HOMA-IS) and 0.07-0.14 mmol/L, 4.02-4.57, 5.91-6.52, 19-20, 18-19, and 23-31% increments in fasting glucose (FPG), fasting insulin (FPI), HOMA-insulin resistance (HOMA-IR), risks of prevalent IR, impaired fasting glucose (IFG), and T2D, respectively; longitudinally, participants with sustained-high acrolein metabolite levels had increased risks of incident IR, IFG, and T2D by 63-80, 87-99, and 120-154%, respectively (P < 0.05). In addition, biomarkers of heme oxygenase-1 activity (exhaled carbon monoxide), lipid peroxidation (8-iso-prostaglandin-F2α), protein carbonylation (protein carbonyls), and oxidative DNA damage (8-hydroxy-deoxyguanosine) mediated 5.00-38.96% of these associations. Our study revealed that acrolein exposure may impair glucose homeostasis and increase T2D risk via mediating mechanisms of heme oxygenase-1 activation, lipid peroxidation, protein carbonylation, and oxidative DNA damage.

Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis.

Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Lipid peroxidation can propagate through either the hydrogen-atom transfer (HAT) or peroxyl radical addition (PRA) mechanism. However, the contribution of the PRA mechanism to the induction of ferroptosis has not been studied. In this study, we aim to elucidate the relationship between the reactivity and mechanisms of lipid peroxidation and ferroptosis induction. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we found that conjugated PUFAs, including conjugated linolenic acid (CLA 18:3) and conjugated linoleic acid (CLA 18:2), can induce or potentiate ferroptosis much more potently than nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. The different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.