Free Radical Research最新文献

Iron is necessary for life, but the simultaneous iron-catalyzed formation of reactive oxygen species (ROS) is involved in pathogenesis of many diseases. One of them is diabetes mellitus, a widespread disease with severe long-term complications, including neuropathy, retinopathy, and nephropathy. Much evidence points to methylglyoxal, a potent glycating agent, as the key mediator of diabetic complications. In diabetes, there is also a peculiar dysregulation of iron homeostasis, leading to an expansion of redox-active iron. This in vitro study focuses on the interaction of methylglyoxal with ferritin, which is the main cellular protein for iron storage. Methylglyoxal effectively liberates iron from horse spleen ferritin, as well as synthetic iron cores; in both cases, it is partially mediated by superoxide. The interaction of methylglyoxal with ferritin increases the production of hydrogen peroxide, much above the generation of peroxide by methylglyoxal alone, in an iron-dependent manner. Glycation with methylglyoxal results in structural changes in ferritin. All of these findings can be demonstrated with pathophysiologically relevant (submillimolar) methylglyoxal concentrations. However, the rate of iron release by ascorbate, the ferroxidase activity, or the diameter of gated pores even in intensely glycated ferritin is not altered. In conclusion, although the functional features of ferritin resist alterations due to glycation, the interaction of methylglyoxal with ferritin liberates iron and markedly increases ROS production, both of which could enhance oxidative stress in vivo. Our findings may have implications for the pathogenesis of long-term diabetic complications, as well as for the use of ferritin as a nanocarrier in chemotherapy.

Metformin is known for its antioxidant properties and ability to ameliorate metabolic dysfunction-associated fatty liver disease (MAFLD) and is the focus of this study. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is linked to MAFLD risk. This study investigated the effects of metformin on ferroptosis in free fatty acid (FFA)-treated Huh7 hepatoma cells and its association with MAFLD risk. Using Western blot, immunofluorescence, and ELISA, this study revealed that FFA treatment led to increased intracellular fat and iron accumulation, heightened Lp-PLA2 expression, reduced levels of the cysteine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), altered glutathione (GSH)/oxidized glutathione (GSSG) ratios, generation of reactive oxygen species (ROS), and initiation of lipid peroxidation, which ultimately resulted in cell ferroptosis. Importantly, metformin reversed FFA-induced iron accumulation, and this effect was attenuated by ferrostatin-1 but enhanced by erastin, RSL3, and si-GPX4. Additionally, metformin activated antioxidant and antiapoptotic mechanisms, which reduced lipid peroxidation and suppressed Lp-PLA2 expression in FFA-treated Huh7 cells. In conclusion, our findings indicate that metformin may protect against MAFLD by inhibiting iron accumulation and Lp-PLA2 expression through the ROS, ferroptosis, and apoptosis signaling pathways. This study highlights potential therapeutic strategies for managing MAFLD-related risks and emphasizes the diverse roles of metformin in maintaining hepatocyte balance.

The last three decades of redox biology research have been dominated by the term "oxidative stress" since it was first coined by Helmut Sies to represent a form of cellular redox modulation characterized by redox imbalance toward overproduction of oxidants. Almost every pathological condition, including cancer, has been linked with oxidative stress and so forth; targeting oxidative stress became the strategy for the new drug discovery with anticancer drugs aiming to selectively induce oxidative stress in cancerous cells while antioxidants aiming to prevent carcinogenesis as prophylactic agents. Time has now come to realize, how harmful the other side of the cellular redox spectrum, "reductive stress," characterized by redox imbalance toward the accumulation of reducing equivalents, maybe during carcinogenesis, and to tap its potential for the design of next-generation chemotherapeutic agents. Adjuvants-causing reductive stress may also work synergistically with radiation therapy under hypoxia to achieve better tumor control. Keeping this evolving field into account, the present review provides a current understating of the role of reductive stress in carcinogenesis, the status of reductive stress-based chemotherapeutic agents with particular emphasis on sulfhydryl and selenium-containing compounds and the gap areas that need to be addressed in future.

Free radicals are ubiquitous in biological systems, being responsible for pathogenesis of degenerative diseases and participating in vitally important biochemical processes, which are mediated by radical regulatory agents. The effects of the aliphatic amine substituents in the catechol-derived Mannich bases on their antioxidant and pro-oxidant activity were investigated. It has been found that the presence of catechol moiety in the structure of Mannich bases allows them to act as Cu(II) reductants, efficient Fe(II) chelators and potent DPPH radical scavengers. It has been found that the plausible mechanism of the DPPH radical scavenging proceeds via quinone formation, followed by their interaction with ethanol via the Michael addition reaction. In the neutrophil respiratory burst assay, several compounds have demonstrated a weak antioxidant activity at the micromolar level (0.1-10 µM), whereas at the millimolar level (0.1 mМ) a strong pro-oxidant effect has been observed. Additionally, at the highest used concentrations a pronounced cytotoxicity against dermal fibroblasts DF-2 and an immunosuppressive effect against T-lymphocytes have been observed for all the synthesized compounds. It has been demonstrated that the oxidation of catechols in the presence of low-molecular thiols results in the formation of covalent adducts, which provides an insight into their cytotoxicity and detoxification pathways.

Karyoptosis is a type of regulated cell death (RCD) characterized by explosive nuclear rupture caused by a loss of nuclear membrane integrity, resulting in the release of genomic DNA and other nuclear components into the cytosol and extracellular environment. The mechanism underlying karyoptosis involves a delicate balance between the following forces: the expansion force exerted by the tightly packed DNA in the nucleus, the resistance provided by the nuclear lamina at the inner nuclear membrane (INM), and the tensile force from the cytoskeleton that helps position the nucleus at the center of the cytoplasm, allowing it to remain maximally expanded. In addition, CREB3, a type II integral membrane protein with DNA-binding ability, tethers chromatin to the INM, providing a tightening force through chromatin interactions that prevent nuclear membrane rupture. UVB radiation can trigger this process, inducing CREB3-FL cleavage and producing CREB3-CF. Therefore, UVB acts as an intrinsic factor in the induction of karyoptosis. Importantly, biochemical analysis of RCD markers shows that karyoptosis is distinct from other forms of cell death, such as apoptosis, autophagy, necroptosis, and pyroptosis. This review explores the mechanisms involved in maintaining nuclear membrane integrity and the role of CREB3 in triggering karyoptosis and provides brief suggestions on the potential implications for targeting cancer cells.

Plasma-activated Ringer's lactate (PAL) solution prepared by irradiating an intravenous solution with a non-equilibrium atmospheric pressure plasma is a potential new cancer therapy having no side effects. However, the induction of autophagy to avoid cell death has been confirmed to occur following exposure to PAL solution. It is thought that the antitumor effect of PAL solution could be weakened by this process, which is meant to maintain homeostasis in cells and assists tumorigenesis. Thus, it would be helpful to devise PAL-based cancer therapies that inhibit autophagy. Unfortunately, it is not yet clear which substances in PAL solution promote autophagy. The present work examined the mechanism by which PAL solution induces autophagy when treating MCF-7 human breast cancer cells. Autophagy was found to be temporarily induced upon exposure to PAL solution, suggesting that this effect contributes to cell proliferation. Although autophagy is associated with reactive oxygen and nitrogen species and/or acidic environments, in this study, significant autophagy was observed using a PAL solution diluted 1/256x without these stressors. Acetate, glyoxylate and 2,3-dimethyltartrate in the PAL solution were determined to promote autophagy. Interestingly, 2,3-dimethyltartrate was found to either induce cell death or autophagy depending on the concentration.

A series of eight nitroxide compounds (four substituted piperidines, three pyrrolidines and one oxo-piperidine) are found to undergo electron transfer to 2'-deoxyribose-peroxyl and the guanyl radical. One-electron oxidation potentials of the nitroxides to oxoammonium cations (oxoammonium reduction potential), E^0', have been measured against a common redox indicator, chlorpromazine, and found to span the range 751 ± 15 mV to 973 ± 15 mV. Fast chemical reduction of the 2'-deoxyribose-peroxyl radical to the hydroperoxide, generated by ^•OH radical attack on 2-deoxyribose, dR, in oxygenated aqueous solution, is a redox-dependent reaction, with rate constants of 0.8-3.5 x 10⁷ M^-1 s^-1. The guanyl radicals, produced upon one-electron oxidation of 2'-deoxyguanosine monophosphate, dG, by the selenite radical, SeO₃^•-, react with the nitroxides in a redox-independent reaction with diffusion rate constants of 1-2 x 10⁸ M^-1 s^-1. These findings represent a possible antioxidant role for nitroxides in the fast chemical repair of DNA radicals, which is supported by an in vitro strand break study using a plasmid.

Non-Helicobacter pylori Helicobacter (NHPH) species are emerging as significant gastric pathogens. Despite their clinical importance, NHPH infections are less studied compared to Helicobacter pylori (H. pylori) due to their lower prevalence and diagnostic challenges. Zoonotic transmission, particularly from pigs, dogs, and cats, underscores the need for improved diagnostic methods and heightened clinical awareness. Gastric cancer (GC) remains a major global health issue, with H. pylori being a primary risk factor. The eradication of H. pylori reduces GC risk, but post-eradication surveillance is essential. Endoscopic findings, especially those from the Kyoto classification, and noninvasive biomarkers play crucial roles in early GC detection and risk assessment. The increasing antibiotic resistance in H. pylori necessitates new treatment strategies. Novel therapies, such as vonoprazan-based regimens, and alternatives like sitafloxacin and rifabutin, are being developed to improve eradication success rates. Understanding the fundamental mechanisms of gastric carcinogenesis, including the roles of oxidative stress and cancer stem cells, is key to advancing treatment. Targeting specific molecular pathways offers potential for more effective therapies.

A new approach to attenuating pathological inflammatory reactions by buffering the eicosanoid pathways with oxidation-resistant hexadeuterated arachidonic acid (D-ARA) is discussed. Enzymatic processing of ARA, released by phospholipase A2, by lipoxygenases, cyclooxygenases, and cytochromes yields a wide range of bioactive eicosanoids, including pro-inflammation, pro-angiogenesis and pro-thrombosis species that, when produced in excess, are an underlying cause of pathology. Conversely, some products of ARA oxidation possess pro-resolving properties. Non-enzymatic free radical oxidation of ARA generates another large group of products such as isoprostanes and their metabolites, associated with inflammation, ischemia-reperfusion stress, and atherosclerosis. A separate group comprises reactive carbonyl derivatives that irreversibly damage diverse biomolecules. Being resistant to both enzymatic and non-enzymatic oxidation pathways due to large kinetic isotope effects, D-ARA may play a role in mitigating inflammation-related disorders and conditions, including inflammaging.

Immense gains in understanding of mechanisms and effects of lipid oxidation have been achieved in the nearly 90 years over which lipid oxidation has been an active research focus. Even so, the substantial questions still being raised about lipid oxidation in this special issue show clearly that missing pieces remain and must be considered for full accounting of this important reaction in any system. In this context, epoxides are spotlighted as a critical overlooked product of lipid autoxidation - underestimated in analysis, underestimated in presence as a functionally active and competitive intermediate and product of lipid oxidation, and underestimated in potential contributions to impact of lipid oxidation on other molecules and cell functions. Logical reasons for ignoring or not finding epoxides are offered in historical development of lipid oxidation knowledge. Reactions generating lipid epoxides in autoxidation are reviewed, limitations in detecting and tracking epoxides are outlined to explain why epoxides may not be detected when they should be present, and justifications for increased research and analysis of epoxides are argued. The main goal is to provide a context for recognizing epoxides as critical products that must be accounted for in determining the state rather than extent of lipid oxidation and in tracking its consequences in oils, foods, personal care products, and tissues. A secondary goal is to stimulate new research using contemporary analyses to fill in the gaps of knowledge about epoxide formation, structure, and reactions in lipid autoxidation.