Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

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Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.

https://link.springer.com/content/pdf/10.1097%2FWOX.0b013e3182439613.pdf

Oxidative Stress and Antioxidant Defense

Regulation of Ferroptotic Cancer Cell Death by GPX4

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

Publisher Summary This chapter presents a procedure for the preparation of glutathione peroxidase, which is regarded as a major protective system against endogenously and exogenously induced lipid peroxidation. Two types of methods are used for determining the activity of glutathione peroxidase. One involves a direct measurement of unconsumed glutathione (GSH) at fixed time periods by polarographic GSH analysis' (Method 1), or by the dithionitrobenzoic acid method (Method 2). The second approach takes advantage of the capability of glutathione reductase, with nicotinamide adenine dinucleotide phosphate (NADPH), to regenerate GSH from oxidized GSH. The decrease in NADPH is continuously measured spectrophotometrically, while the GSH concentration in the enzymatic cycle remains essentially constant (Method 3). A convenient source for the preparation of glutathione peroxidase is bovine blood including the following steps: hemolysate; organic solvent precipitation; phosphate precipitation; absorption to phenyl-sepharose; and washing on diethylaminoethyl (DEAE)–sephadex, S-300 sephacryl, and hydroxylapatite column.

[44] Glutathione peroxidase

Publisher Summary Research in food chemistry provided the basis of a new technique for the measurement of lipid peroxidation in living animals by quantitative gas chromatographic determination of exhaled saturated short-chain hydrocarbons. The mechanism is most likely to include the abstraction of a hydrogen of the unsaturated carbon closest to the methyl end; isomerization to a diene radical; the addition of oxygen to form a hydroperoxide; and β-scission to a hydroxyl and an alkoxy radical, the latter of which forms the corresponding alkane by hydrogen atom addition. This chapter presents two methods (method A and B) for the quantitative analysis of hydrocarbons from breath. Method A involves respiratory chamber and method B involves open-system-respiration chamber. The method of sample collection depends on the problem under investigation. It is convenient to work with a closed system, but the following reservations have to be made: (1) it is difficult to inject the animals during the experiment and (2) rodents metabolize hydrocarbons.

[2] Hydrocarbon exhalation

Publisher Summary This chapter describes an inflammatory liver disease model that includes a functioning circulation and a counter regulation of the peripheral system and is intimately connected to leukocyte function. The animals are sacrificed by cervical dislocation and the abdominal cavity is immediately opened. Thirty microliters of heparin in phosphate-buffered saline (PBS) is drawn into a 1 ml syringe equipped with a 0.7 × 30 mm needle. At least 50 μl of blood is withdrawn by heart puncture or by puncturing the inferior caval vein, transferred to an Eppendorf cup, and immediately centrifuged for 4 min at 5000 g. The enzyme determinations are carried out on an autoanalyzer. The experimental design of the three variants—that is, models for endotoxin-, leukotriene D4-, or tumor necrosis factor (TNF)-induced liver injury—is summarized in the chapter. Endotoxin administration leads to the synthesis and/or release of leukotriene D4. This leukocyte-derived mediator is known to be a strong vasoconstrictor and eventually leads to ischemic microcirculatory episodes. After termination of the action of this short-lived agonist, the reoxygenation of the affected areas may lead to superoxide-mediated triggering of tumor necrosis factor production, which is considered a major terminal event.

Albrecht Wendel

Papers

[44] Glutathione peroxidase

[2] Hydrocarbon exhalation

[74] Biochemical pharmacology of inflammatory liver injury in mice