Free Radical Research最新文献

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, the incidence of which increases with age. However, since there is no fundamental treatment or methods for early diagnosis, new methods of treatment and diagnosis are urgently needed. We focused on post-translational modifications of DJ-1, which is encoded by the familial PD-causative gene PARK7 in red blood cells (RBCs). DJ-1 has three cysteines (Cys46, Cys53, and Cys106), with Cys106 being preferentially oxidized. We previously reported that sulfinated/sulfonated Cys106 DJ-1 (oxDJ-1) is increased in the RBCs of PD patients. In this study, we analyzed RBC-derived DJ-1 from PD patients and control subjects by 2-dimensional electrophoresis. We found that the ratio of the spot of DJ-1 with a more acidic isoelectric point than oxDJ-1 was increased more significantly than that of oxDJ-1 in RBCs from patients at the early stage of unmedicated PD and decreased with the progression of PD stage and treatment. Furthermore, we revealed that this acidic spot of DJ-1 increased upon exposure to H₂O₂. However, when either Cys53 or Cys106 of DJ-1 was replaced with serine, there was no significant increase in the acidic spot caused by H₂O₂. In this study, we propose a new biomarker for early diagnosis of PD using both the ratios of oxDJ-1 to total DJ-1 and the acidic spot of DJ-1 to total DJ-1.

Peroxisomes are essential organelles that help mitigate the oxidative damage caused by reactive oxygen species (ROS) through their antioxidant systems. They perform functions such as α-oxidation, β-oxidation, and the synthesis of cholesterol and ether phospholipids. During the breakdown of specific metabolites, peroxisomes generate ROS as byproducts, which can either be neutralized or contribute to oxidative stress. The relationship between peroxisomal metabolism and ROS-related disorders, including neurodegenerative diseases and cancers, has been studied for decades; however, the exact mechanisms remain unclear. Our review will provide recent insights into the peroxisomal redox system and its association with oxidative stress-related diseases.

Alterations in amino acid metabolism have emerged as a critical component in cancer biology, influencing various aspects of tumor initiation, progression, and metastasis. This review explores how amino acids, beyond their role as protein building blocks, are essential for redox balance, cell proliferation, metastasis, signaling/epigenetic regulation, and tumor microenvironment modulation in cancer. We particularly focus on the intricate relationship between amino acid metabolism and nuclear factor erythroid 2-related factor 2 (NRF2) signaling, a master regulator of oxidative stress response that frequently hyperactivated in cancer. Increasing evidence indicates that NRF2 is a key player in amino acid metabolism, orchestrating metabolism of cysteine, glutamine, and serine/glycine to promote cancer cell survival and growth. This comprehensive analysis provides insights into potential therapeutic strategies targeting the NRF2-amino acid metabolism axis, offering new avenues for cancer treatment that address multiple aspects of tumor biology.

Background: Post-hepatectomy liver failure (PHLF) is a fatal complication of hepatectomy. However, the mechanism of hepatocyte injury in PHLF remains elusive.

Methods: PHLF was induced by extended 86% hepatectomy (eHx) in mice. Lipidomics was performed to investigate the eHx-induced lipid alteration in the residual liver. Ferroptosis was assessed to screen the hepatocyte injury induced by eHx. The therapeutic effects of ferrostatin-1 (Fer-1) on PHLF were evaluated.

Results: PHLF was induced by eHx with elevation in markers of hepatocyte injury and mortality in mice within 48 h after surgery. eHx-induced hepatocyte injury was manifested by hepatocyte enlargement and hepatocyte death with glycogen depletion and lipid accumulation. Lipidomics revealed that eHx induced the accumulation of ferroptosis-favored polyunsaturated lipids. Ferroptosis was found to mediate the eHx-induced hepatocyte death in the residual liver during the development of PHLF. Fer-1 could attenuate the eHx-induced ferroptotic hepatocyte death and PHLF in mice.

Conclusions: Ferroptosis partly mediates the eHx-induced hepatocyte injury during the development of PHLF. Accumulation of polyunsaturated lipids in hepatocytes may promote eHx-induced ferroptosis, and targeting lipid peroxidation is a potential therapeutic strategy for PHLF.

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.

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.

Despite limited number of studies, oxysterols are known to contribute to the progression of nonalcoholic steatohepatitis (NASH) by affecting lipid/cholesterol metabolism and elevating proinflammatory and profibrotic processes. Accordingly, we used a high cholesterol-mediated in vivo NASH model and aimed to determine alterations in fatty acid content and oxysterol levels together with their effects on cholesterol/lipid metabolism during the progression of the disease. We further investigated the beneficial role of α-tocopherol. To this end, in our hypercholesterolemic rabbit model, we determined fatty acid profile by GC-MS while 25-, 27-, 4β-, 7α, and 24(S)-Hydroxycholesterol levels by means of LC-MS/MS. Additionally, lipid (SREBP-1c, PPARα, PPARγ) and cholesterol metabolism-related proteins (LXRα, SREBP2 and ABCA1) were determined by immunoblotting. In conclusion, the present findings provide a complete analysis of the hepatic alterations in lipid and oxysterol profiles mediated by a high-cholesterol diet. In addition, this study explains the protective effect of α-tocopherol on lipogenesis and oxysterol production in hypercholesterolemia-induced NASH. We believe that present study will guide to novel theories in the progression and therapeutic targeting of fatty liver diseases.

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.

Diabetic foot wounds associated with oxidative stress are treated with hyperbaric oxygen (HBO), but that may also induce the stress itself; therefore, we studied the effect of HBO treatments on the oxidant-antioxidant balance in the venous blood of patients with diabetic foot syndrome. In addition, blood counts were also examined. 14 male patients (24-74 years), at risk of lower limb amputation were treated with 30 HBO procedures (60 min of the inhalation of pure oxygen at a pressure of 2.5 atm per day, 5 days a week). The control group consisted of 29 healthy male volunteers aged 25-69 years. No members of the group had been subjected to HBO therapy previously (ClinicalTrials.gov, no. NCT06401941). The analyzed redox parameters did not change during the experiment in the patients (p > 0.05). The concentration of thiobarbituric acid reactive substances (TBARS) in the plasma was higher in the patients before the first and after the thirtieth HBO treatments when compared to the control group. In contrast, the TBARS concentration in erythrocytes was lower in the patients after the first treatment vs. the controls. Moreover, the higher activity of catalase in the patients' erythrocytes was noted before the therapy and after the first and last treatments compared to the controls. HBO therapy increased the percentage of monocytes and platelet volume, but it decreased the volume of platelets in the patients' blood. HBO therapy does not affect the oxidant-antioxidant balance disturbed in diabetic foot patients.

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.