Peroxidation Of Polyunsaturated Fatty Acids Research Articles

Dietary docosahexaenoic acid plays an opposed role in ferroptotic and non-ferroptotic acute kidney injury

Ferroptosis due to polyunsaturated fatty acid (PUFA) peroxidation has been implicated in the pathogenesis of acute kidney injury (AKI), suggesting the risk of dietary intake of PUFA for people susceptible to AKI. Clinically, however, in addition to ferroptosis, other mechanisms also contribute to different types of AKI such as inflammation associated necroptosis and pyroptosis. Therefore, the role of PUFA, especially ω3 PUFA which is a common food supplement, in various AKIs deserves further evaluation. In this study, rhabdomyolysis- and folic acid-induced AKI (Rha-AKI and FA-AKI) were established in mice fed with different fatty acids Histology of kidney, blood urea nitrogen and creatinine, lipid peroxidation, and inflammatory factors were examined. Results showed that these two types of AKIs had diametrically different pathogenesis indicated by that ferrostatin-1 (Fer-1), a lipid antioxidant, can attenuate FA-AKI rather than Rha-AKI. Further, dietary DHA (provided by fish oil) reduced tubular injury and renal lesion by inhibiting peroxidation and inflammation in mice with Rha-AKI while increasing cell death, tissue damage, peroxidation and inflammation in mice with FA-AKI. In human renal tubular epithelial cell line HK-2, MTT assay and DHE staining showed that both myoglobin and ferroptosis inducers can cause cell death and oxidative stress. Ferroptosis inducer-induced cell death was promoted by DHA, while such result was not observed in myoglobin-induced cell death when adding DHA. This study illustrates that the mechanisms of AKI might be either ferroptosis dependent or -independent and the deterioration effect of dietary DHA depends on whether ferroptosis is involved.

Detoxification of the Lipid Peroxidation Aldehyde, 4-Hydroxynonenal, by Apple Phloretin In Vitro and in Mice.

4-Hydroxy-2-nonenal (4-HNE) is a secondary cytotoxic product generated from lipid peroxidation of polyunsaturated fatty acids (PUFAs). The accumulation of 4-HNE can covalently modify biomolecules, such as DNA and proteins, leading to various pathological conditions. Apple phloretin has been shown to be able to trap 4-HNE in vitro, but the trapping mechanisms of 4-HNE by phloretin are not fully understood. Moreover, whether the in vitro trapping efficacy of phloretin toward 4-HNE could be transferred into in vivo environments has never been investigated. In the present study, we observed the formation of 4-HNE conjugates of phloretin increased as phloretin decreased during the in vitro incubation. We then purified and characterized three mono-4-HNE-conjugates of phloretin using NMR and LC-MS/MS techniques. We thereafter demonstrated that apple phloretin could scavenge in vivo 4-HNE via the formation of at least three mono-4-HNE-conjugates of phloretin in a dose-dependent manner in mice after oral administration of three doses of phloretin (25, 100, and 400 mg/kg). The findings from this study pave the way to understanding how dihydrochalcones could act as effective scavengers of 4-HNE by working as sacrificial nucleophiles in vivo, thereby preventing or reducing the risk of 4-HNE-associated chronic diseases.

Circular RNAs in ferroptosis: regulation mechanism and potential clinical application in disease.

Ferroptosis, an iron-dependent non-apoptotic form of cell death, is reportedly involved in the pathogenesis of various diseases, particularly tumors, organ injury, and degenerative pathologies. Several signaling molecules and pathways have been found to be involved in the regulation of ferroptosis, including polyunsaturated fatty acid peroxidation, glutathione/glutathione peroxidase 4, the cysteine/glutamate antiporter system Xc-, ferroptosis suppressor protein 1/ubiquinone, and iron metabolism. An increasing amount of evidence suggests that circular RNAs (circRNAs), which have a stable circular structure, play important regulatory roles in the ferroptosis pathways that contribute to disease progression. Hence, ferroptosis-inhibiting and ferroptosis-stimulating circRNAs have potential as novel diagnostic markers or therapeutic targets for cancers, infarctions, organ injuries, and diabetes complications linked to ferroptosis. In this review, we summarize the roles that circRNAs play in the molecular mechanisms and regulatory networks of ferroptosis and their potential clinical applications in ferroptosis-related diseases. This review furthers our understanding of the roles of ferroptosis-related circRNAs and provides new perspectives on ferroptosis regulation and new directions for the diagnosis, treatment, and prognosis of ferroptosis-related diseases.

Striking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in Alzheimer's Disease.

Significance: The lack of disease-modifying treatments for Alzheimer's disease (AD) that substantially alter the course of the disease highlights the need for new biological models of disease progression and neurodegeneration. Oxidation of macromolecules within the brain, including lipids, proteins, and DNA, is believed to contribute to AD pathophysiology, concomitant with dysregulation of redox-active metals, such as iron. Creating a unified model of pathogenesis and progression underpinned by iron dysregulation and redox dysregulation in AD could lead to new therapeutic targets with disease-modifying potential. Recent Advances: Ferroptosis, which was named in 2012, is a necrotic form of regulated cell death that depends on both iron and lipid peroxidation. While it is distinct from other types of regulated cell death, ferroptosis is regarded as being mechanistically synonymous with oxytosis. The ferroptosis paradigm has great explanatory potential in describing how neurons degenerate and die in AD. At the molecular level, ferroptosis is executed by the lethal accumulation of phospholipid hydroperoxides generated by the iron-dependent peroxidation of polyunsaturated fatty acids, while the major defensive protein against ferroptosis is the selenoenzyme, glutathione peroxidase 4 (GPX4). An expanding network of protective proteins and pathways have also been identified to complement GPX4 in the protection of cells against ferroptosis, with a central role emerging for nuclear factor erythroid 2-related factor 2 (NRF2). Critical Issues: In this review, we provide a critical overview of the utility of ferroptosis and NRF2 dysfunction in understanding the iron- and lipid peroxide-associated neurodegeneration of AD. Future Directions: Finally, we discuss how the ferroptosis paradigm in AD is providing a new spectrum of therapeutic targets. Antioxid. Redox Signal. 39, 141-161.

Common weeds as heavy metal bioindicators: a new approach in biomonitoring

Environmental pollution by heavy metals affects both urban and non-urban areas of Europe and the world. The use of bioindicator plants for the detection of these pollutants is a common practice. An important property of potential bioindicators is their easy availability and wide distribution range, which means that they can be practically used over a wide area. Therefore, common and widely distributed weeds: Trifolium pratense L., Rumex acetosa L., Amaranthus retroflexus L., Plantago lanceolata L., ornamental species Alcea rosea L., and Lolium multiflorum L. var. Ponto were selected as a potential bioindicators of heavy metals (Cd, Pb, Cu, Zn). Plants were exposed in the same soil conditions in three sample sites in the Poznań city. It was found that all species had heavy metal accumulation potential, especially A. rosea, P. lanceolata and L. multiflorum for Zn (BCF = 6.62; 5.17; 4.70) and A. rosea, P. lanceolata for Cd (BCF = 8.51; 6.94). Translocation of Cu and Zn was the most effective in T. pratense (TFCu = 2.55; TFZn = 2.67) and in A. retroflexus (TFCu = 1.50; TFZn = 2.23). Cd translocation was the most efficient in T. pratense (TFCd = 1.97), but PB was the most effective translocated in A. retroflexus (TFPb = 3.09).. Based on physiological response to stress, it was detected an increasing level of hydrogen peroxide (H2O2) in roots and leaves of all samples, with the highest in all organs of A. rosea. Enzymatic activity levels of CAT, APOX, and also the marker of polyunsaturated fatty acid peroxidation MDA, were higher after 6 weeks of exposure in comparison to control samples and varied in time of exposure and between species and exposure. After the experiment, in almost all samples we detected a reduction of chlorophyll content and relative water content, but in efficiency of photosynthesis parameters: net photosynthesis rate, intercellular CO2 concentration and stomatal conductance, we noted increased values, which proved the relatively good condition of the plants. The examined weeds are good bioindicators of heavy metal contamination, and their combined use makes it possible to comprehensively detection of environmental threats.

Carvacrol-A Natural Phenolic Compound with Antimicrobial Properties.

The main purpose of this article is to present the latest research related to selected biological properties of carvacrol, such as antimicrobial, anti-inflammatory, and antioxidant activity. As a monoterpenoid phenol, carvacrol is a component of many essential oils and is usually found in plants together with its isomer, thymol. Carvacrol, either alone or in combination with other compounds, has a strong antimicrobial effect on many different strains of bacteria and fungi that are dangerous to humans or can cause significant losses in the economy. Carvacrol also exerts strong anti-inflammatory properties by preventing the peroxidation of polyunsaturated fatty acids by inducing SOD, GPx, GR, and CAT, as well as reducing the level of pro-inflammatory cytokines in the body. It also affects the body's immune response generated by LPS. Carvacrol is considered a safe compound despite the limited amount of data on its metabolism in humans. This review also discusses the biotransformations of carvacrol, because the knowledge of the possible degradation pathways of this compound may help to minimize the risk of environmental contamination with phenolic compounds.

New Insights into the Role of Ferroptosis in Cardiovascular Diseases

Cardiovascular diseases (CVDs) are the principal cause of disease burden and death worldwide. Ferroptosis is a new form of regulated cell death mainly characterized by altered iron metabolism, increased polyunsaturated fatty acid peroxidation by reactive oxygen species, depletion of glutathione and inactivation of glutathione peroxidase 4. Recently, a series of studies have indicated that ferroptosis is involved in the death of cardiac and vascular cells and has a key impact on the mechanisms leading to CVDs such as ischemic heart disease, ischemia/reperfusion injury, cardiomyopathies, and heart failure. In this article, we reviewed the molecular mechanism of ferroptosis and the current understanding of the pathophysiological role of ferroptosis in ischemic heart disease and in some cardiomyopathies. Moreover, the comprehension of the machinery governing ferroptosis in vascular cells and cardiomyocytes may provide new insights into preventive and therapeutic strategies in CVDs.

Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis.

Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell death. Here, we review the involvement of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), lipid remodeling enzymes and lipid peroxidation in ferroptosis, highlighting studies revealing how using the multicellular model organism Caenorhabditis elegans contributes to the understanding of the roles of specific lipids and lipid mediators in ferroptosis.

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.

Transcriptomics and metabolomics analysis reveal the anti-oxidation and immune boosting effects of mulberry leaves in growing mutton sheep.

Currently, the anti-oxidation of active ingredients in mulberry leaves (MLs) and their forage utilization is receiving increasing attention. Here, we propose that MLs supplementation improves oxidative resistance and immunity. We conducted a trial including three groups of growing mutton sheep, each receiving fermented mulberry leaves (FMLs) feeding, dried mulberry leaves (DMLs) feeding or normal control feeding without MLs. Transcriptomic and metabolomic analyses revealed that promoting anti-oxidation and enhancing disease resistance of MLs is attributed to improved tryptophan metabolic pathways and reduced peroxidation of polyunsaturated fatty acids (PUFAs). Furthermore, immunity was markedly increased after FMLs treatment by regulating glycolysis and mannose-6-phosphate pathways. Additionally, there was better average daily gain in the MLs treatment groups. These findings provide new insights for understanding the beneficial effects of MLs in animal husbandry and provide a theoretical support for extensive application of MLs in improving nutrition and health care values.

Polyunsaturated fatty acids changes during electroconvulsive therapy in major depressive disorder

Polyunsaturated fatty acids (PUFAs) have important electrochemical properties and have been implicated in the pathophysiology of major depressive disorder (MDD) and its treatment. However, the relation of PUFAs with electroconvulsive therapy (ECT) has never been investigated. Therefore, we aimed to explore the associations between PUFA concentrations and response to ECT in patients with MDD. We included 45 patients with unipolar MDD in a multicentre study. To determine PUFA concentrations, we collected blood samples at the first (T0) and twelfth (T12) ECT-session. We assessed depression severity using the Hamilton Rating Scale for Depression (HAM-D) at T0, T12 and at the end of the ECT-course. ECT-response was defined as ‘early response’ (at T12), ‘late response’ (after ECT-course) and ‘no’ response (after the ECT-course). The PUFA chain length index (CLI), unsaturation index (UI) and peroxidation index (PI) and three individual PUFAs (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and nervonic acid [NA]) were associated with response to ECT using linear mixed models. Results showed a significant higher CLI in ‘late responders’ compared to ‘non responders’. For NA, ‘late responders’ showed significantly higher concentrations compared to ‘early’- and ‘non responders’. In conclusion, this study provides the first indication that PUFAs are associated with the efficacy of ECT. This indicates that PUFAs' influence on neuronal electrochemical properties and neurogenesis may affect ECT outcomes. Thereby, PUFAs form a potentially modifiable factor predicting ECT outcomes, that warrants further investigation in other ECT-cohorts.

The Use of Ozone Technology: An Eco-Friendly Method for the Sanitization of the Dairy Supply Chain.

The dairy field has considerable economic relevance in the agri-food system, but also has the need to develop new 'green' supply chain actions to ensure that sustainable products are in line with consumer requirements. In recent years, the dairy farming industry has generally improved in terms of equipment and product performance, but innovation must be linked to traditional product specifications. During cheese ripening, the storage areas and the direct contact of the cheese with the wood must be carefully managed because the proliferation of contaminating microorganisms, parasites, and insects increases significantly and product quality quickly declines, notably from a sensory level. The use of ozone (as gas or as ozonated water) can be effective for sanitizing air, water, and surfaces in contact with food, and its use can also be extended to the treatment of waste and process water. Ozone is easily generated and is eco-sustainable as it tends to disappear in a short time, leaving no residues of ozone. However, its oxidation potential can lead to the peroxidation of cheese polyunsaturated fatty acids. In this review we intend to investigate the use of ozone in the dairy sector, selecting the studies that have been most relevant over the last years.

Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells.

Ferroptosis is an iron-dependent cell death-driven by excessive peroxidation of polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.

Redox Signaling in Doxorubicin-Induced Ferroptosis

Doxorubicin is among the most widely used anticancer drugs; however, its clinical use is associated with cardiomyopathy and heart failure. Studies show ferroptosis as a pivotal form of cell death underlying doxorubicin cardiomyopathy. Recently, multiple redox signaling pathways have been discovered to underly doxorubicin-induced ferroptosis. This Cutting-Edge Research Highlights discusses these latest advances, focusing on pathways involving Nrf2/HO-1, GPx4, and Alas1/heme synthesis. (First online: February 19, 2023) REFERENCES Zhu H, Sarkar S, Scott L, Danelisen I, Trush MA, Jia Z, et al. Doxorubicin Redox biology: redox cycling, topoisomerase inhibition, and oxidative stress. React Oxyg Species (Apex) 2016; 1(3):189–98. doi: https://dx.doi.org/10.20455/ros.2016.835 Higgins AY, O'Halloran TD, Chang JD. Chemotherapy-induced cardiomyopathy. Heart Fail Rev 2015; 20(6):721–30. doi: https://dx.doi.org/10.1007/s10741-015-9502-y Page RL, 2nd, O'Bryant CL, Cheng D, Dow TJ, Ky B, Stein CM, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation 2016; 134(6):e32–69. doi: https://dx.doi.org/10.1161/CIR.0000000000000426 Fang X, Wang H, Han D, Xie E, Yang X, Wei J, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA 2019; 116(7):2672–80. doi: https://dx.doi.org/10.1073/pnas.1821022116 Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5):1060–72. doi: https://dx.doi.org/10.1016/j.cell.2012.03.042 Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 2016; 113(34):E4966–75. doi: https://dx.doi.org/10.1073/pnas.1603244113 Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017; 13(1):81–90. doi: https://dx.doi.org/10.1038/nchembio.2238 Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014; 124(2):617–30. doi: https://dx.doi.org/10.1172/JCI72931 Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 2020; 5(9). doi: https://dx.doi.org/10.1172/jci.insight.132747 Abe K, Ikeda M, Ide T, Tadokoro T, Miyamoto HD, Furusawa S, et al. Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis. Sci Signal 2022; 15(758):eabn8017. doi: https://dx.doi.org/10.1126/scisignal.abn8017

Modeling and optimization of malondialdehyde (MDA) absorbance behavior through response surface methodology (RSM) and artificial intelligence network (AIN): An endeavor to estimate lipid peroxidation by determination of MDA

AbstractOxidative stress (OS) associated with reactive oxygen species (ROS) attacks many biomolecules, leading to cell death, lipid peroxidation (LP), and physiological mechanism damage in the human body because of its reaction with nucleotides, membrane lipids, and proteins. Malondialdehyde (MDA) is one of the end products of polyunsaturated fatty acids peroxidation. The elevated level of MDA is widely known as a biomarker for the indirect measurement of OS during LP. Although several derivatizations' approaches and successful commercial kits are available, their analytical validity and reliability in clinical studies require further attention to obtain robust quantitation and high‐quality data. Also, re‐evaluation and development of new analytical methods with high sensitivity and selectivity in response to free MDA and total MDA, DNA and protein adducts are not well‐characterized. Here, response surface methodology (RSM) and artificial neural network (ANN) were proposed to model, predict, and optimize MDA detection. This paper introduced a novel, simple, and fast modeling method using a new reagent (para methoxy aniline or PMA) for the first time to convert MDA to an adduct which could be detectable by UV‐Vis spectroscopy. Based on the interactions between MDA and PMA at times and temperatures, RSM and artificial intelligence network (AIN) were then applied to forecast the absorbance rate of MDA‐PMA. The optimum mode for the highest absorbance rate of MDA‐PMA is at the temperature of 74.99°C with a PMA concentration of 499.87 μM and MDA concentration of 49.98 μM. The best structure with five hidden layers, including 5,5,5,9,4 neurons with the transfer function logsig for each layer, was selected for the MLP‐ANN model. The maximum error rate of the MLP‐ANN model was 2.08%.Our new approach is an improvement over existing assay kits, overcoming limitations such as time, temperature, and reliability with a bright future to target increased MDA level in human samples.

A correlation biomarker between BMI and lipid peroxidation in type 2 diabetes mellitus with and without other complications

Objectives: Body mass index (BMI) is a traditional measurement practice that divides a person’s weight by their height to find out whether they have a healthy range of weight. The objective of this study is to understand the relation between BMI and prevalence of diabetes mellitus, hypertension, and dyslipidemia. Material and Methods: BMI distribution among these patients was compared with and without hypertension and dyslipidemia. The improper of secretion of insulin leads to changes in metabolism of lipids, proteins, and carbohydrates also characterized hyperglycemia generally considered as diabetes mellitus (DM). Results: The excessive formation of free radicals induces oxidative stress, and the antioxidant defense system becomes weaken and hence arises diabetic disorder and overproduction of malondialdehyde (MDA). In cells, the polyunsaturated fatty acid peroxidation is considered as the final product and marker of oxidative stress. Conclusion: In this study, significantly increased BMI is observed in diabetic victims in comparison with control group. A significant positive correlation was noticed between glycated hemoglobin, cholesterol, and MDA. In conclusion, for the prevention and management of vascular complication in type 2 diabetes mellitus, maintaining normal levels of MDA and body weight are very important. Further large-scale studies are required to confirm it.

A protein-lipid complex that detoxifies free fatty acids.

Fatty acids (FAs) are well known to serve as substrates for reactions that provide cells with membranes and energy. In contrast to these metabolic reactions, the physiological importance of FAs themselves known as free FAs (FFAs) in cells remains obscure. Since accumulation of FFAs in cells is toxic, cells must develop mechanisms to detoxify FFAs. One such mechanism is to sequester free polyunsaturated FAs (PUFAs) into a droplet-like structure assembled by Fas-Associated Factor 1 (FAF1), a cytosolic protein. This sequestration limits access of PUFAs to Fe2+ , thereby preventing Fe2+ -catalyzed PUFA peroxidation. Consequently, assembly of the FAF1-FFA complex is critical to protect cells from ferroptosis, a cell death pathway triggered by PUFA peroxidation. The observations that free PUFAs in cytosol are not randomly diffused but rather sequestered into a membraneless complex should open new directions to explore signaling pathways by which FFAs regulate cellular physiology.

Characterization of the action of the lipid oxidation product 4-hydroxyhexenal on Lactiplantibacillus plantarum, the dominant bacterium in dry-cured fish

(E)-4-Hydroxyhexenal (HHE) is receiving widespread attention as a representative reactive carbonyl species (RCS) derived from n-3 polyunsaturated fatty acids peroxidation due to its health hazard. However, few studies have addressed the potential effects of lipid oxidation products on microbial growth in food products. Therefore, this study attempted to elucidate the action of HHE on Lactiplantibacillus plantarum (L. plantarum), the dominant bacteria in dry-cured fish. The results showed that the minimum inhibitory concentration (MIC) of HHE was 250 μg/mL. Time-kill curves confirmed the strong inhibitory activity of HHE. Lactate dehydrogenase (LDH) assay indicated that HHE disrupted the integrity of cell wall. Scanning electron microscopy (SEM) and flow cytometry analysis revealed that HHE induced changes in cell morphology, compromised cell membrane permeability, and thus disrupted intracellular homeostasis. Based on untargeted metabolomic analysis, HHE disrupted multiple metabolic pathways in L. plantarum involving amino acid metabolism, lipid metabolism, protein biosynthesis, nucleic acid metabolism and energy metabolism. This research provide new insights into the HHE inhibition mechanism and theoretical support for studying the effects of lipid oxidation products on microorganisms in food matrix.

A ferroptosis-inducing biomimetic nanocomposite for the treatment of drug-resistant prostate cancer.

Second-generation androgen receptor (AR) inhibitors such as enzalutamide are the first-line treatments for castration-resistant prostate cancer (CRPC). Resistance to enzalutamide will greatly increase the difficulty of prostate cancer treatment and reduce the survival time of patients. However, drug-resistant cancer cells seem to be more sensitive to ferroptosis. Therefore, we constructed a biomimetic tumor-targeting magnetic lipid nanoparticle (t-ML) to codeliver dihomo-γ-linolenic acid (DGLA) and 2,4-dienoyl-CoA reductase 1 (DECR1) siRNA (t-ML@DGLA/siDECR1). DGLA is a dietary polyunsaturated fatty acid (PUFA), while DECR1 is overexpressed in prostate cancer and can inhibit the generation of PUFAs. The combination of DGLA and siDECR1 can efficiently induce ferroptosis by peroxidation of PUFAs, which has been verified both in vitro and in vivo. With the assistance of an external magnet, t-ML showed good tumor targeting ability and biocompatibility, and t-ML@DGLA/siDECR1 exhibited significant ferroptosis induction and tumor suppression capabilities. Moreover, in a nude mouse model of prostate cancer fed on a high-fat diet (HFD), there was no distant organ metastasis when the tumor-bearing mice were treated with t-ML@DGLA/siDECR1 and an external magnet, with upregulated PUFAs and downregulated monounsaturated fatty acids (MUFAs). Hence, this study has broadened the way of treating drug-resistant prostate cancer based on ferroptosis induction.

Malondialdehyde-Induced Post-translational Modifications in Hemoglobin of Smokers by NanoLC-NSI/MS/MS Analysis.

Malondialdehyde (MDA) is the most abundant α,β-unsaturated aldehyde generated from endogenous peroxidation of polyunsaturated fatty acids and is present in cigarette smoke. Post-translational modifications of blood hemoglobin can serve as biomarkers for exposure to chemicals. In this study, two types of MDA-induced modifications, the N-propenal and the dihydropyridine (DHP), were identified at multiple sites in human hemoglobin digest by the high-resolution mass spectrometry. The N-propenal and the DHP types of modification led to the increase of 54.0106 and 134.0368 amu, respectively, at the N-terminal and lysine residues. Among the 21 MDA-modified peptides, 14 with dose-response to MDA concentrations were simultaneously quantified in study subjects by the nanoflow liquid chromatography nanoelectrospray ionization tandem mass spectrometry under selected reaction monitoring (nanoLC-NSI-MS/MS-SRM) without prior enrichment. The results showed that the modifications of the N-propenal-type at α-Lys-11, α-Lys-16, α-Lys-61, β-Lys-8, and β-Lys-17, as well as the DHP-type at the α-N-terminal valine, are significantly higher in hemoglobin isolated from the blood of smokers than in nonsmoking individuals. This is the first report to identify and quantify multiple sites of MDA-induced modifications in human hemoglobin from peripheral blood. Our results suggest that the MDA-derived modifications on hemoglobin might represent valuable biomarkers for MDA-induced protein damage.