SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: Free radical research

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Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.

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The p22phox is a critical component of vascular NADPH oxidases and is encoded by the CYBA gene. It was shown that functionally relevant polymorphisms of the CYBA gene - 930A>G, -852C>G , -675A>T , -536C>T, 214C>T (previously described as 242C>T), *24A>G (previously described as 640A>G), and *49A>G modulate generation of reactive oxygen species (ROS).

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TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target protein that plays critical roles in glycolysis and redox balance. Accumulating evidence shows that TIGAR is highly expressed in cancer. TIGAR redirects glycolysis and promotes carcinoma growth by providing metabolic intermediates and reductive power derived from pentose phosphate pathway (PPP). The expression of TIGAR in cancer is positively associated with chemotherapy resistance, suggesting that TIGAR could be a novel therapeutic target. In this review, we briefly presented the function of TIGAR in metabolic homeostasis in normal and cancer cells. Finally, we discussed the future directions of TIGAR research in cancer.

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The reaction between superoxide (O2·-) and organic chemicals is of interest in many scientific disciplines including biology and synthetic chemistry, as well as for the evaluation of chemical fate in the environment. Due to limited data and lack of congeneric modeling, the involvement of superoxide in many complex processes cannot be adequately evaluated. In this study, we developed new Quantitative Structure-Property Relationship (QSPR) models for the prediction of the aqueous-phase rate constant for the reaction between superoxide and a wide variety of organic chemicals reacting via one-electron oxidation, reduction and hydrogen-transfer. It is shown that the relative importance of these pathways is related to frontier molecular orbital (FMO) interaction and to pH. The class-specific QSPRs developed have good statistics (0.84 ≤ R2 ≤ 0.92). For noncongeneric chemicals it is demonstrated that the reactivity towards superoxide can be described by applying explicit descriptions for competition kinetics and speciation. Therefore, the relationships developed in this study are useful as a starting point to evaluate more complex molecules having eg multiple reactive functional groups, labile H bonds, or delocalized cationic charges. However, additional kinetic data and more rigorous computation are needed to evaluate such molecules.

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Cancer stem cells (CSCs) constitute a subpopulation of transformed cells that possess intrinsic ability to undergo selfrenewal and differentiation, which drive tumour resistance and cancer recurrence. It has been reported that CSCs possess enhanced protection against oxidative stress induced by reactive oxygen species compared with nonstem-like cancer cells. In the present work, we investigated the role of heme oxygenase-1 (HO-1), a representative antioxidant enzyme, on the stemness and selfrenewal of human breast CSCs. We found that pharmacologic or genetic inhibition of HO-1 attenuated the sphere formation, whereas HO-1 inducers enhanced the number and the size of tumourspheres in breast CSCs. Carbon monoxide (CO) is endogenously generated as a consequence of degradation of heme by HO-1. The proportion of populations of CD44+/CD24- cells retaining CSC properties was increased in MDA-MB-231 cells treated with a CO-releasing molecule (CORM-2). Following CORM-2 treatment, the expression of Notch-1 and related genes Jagged-1 and Hes1 was increased, which was accompanied by the mammosphere formation. Taken together, these findings suggest that HO-1-derived CO production stimulates the formation of mammospheres in breast cancer cells through activation of Notch-1 signalling.

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Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterized from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that via an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress via different agents with antioxidant properties have not translated into sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far employed to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future.

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It has been reported that heme oxygenase-1 (Hmox1) induction attenuates neointimal thickening. Here we further investigated the potential mechanisms regulating this important pathological process. We revealed that histone deacetylase 2 (HDAC2) was induced following Hmox1 induction under 1% oxygen treatment and this induction was attenuated after the treatment of siRNA against Hmox1. Interestingly, this HDAC2 induction was dependent on Hmox1 protein as well as its enzymatic activity, and was regulated by carbon monoxide released from heme degradation. Furthermore, histone deacetylase inhibitor, trichostatin A, successfully abrogated the inhibitory effects of vascular smooth muscle migration and proliferation by Hmox1 induction in vitro. In a rat carotid balloon injury model, similar results were observed by measuring neointimal thickening. As such, we concluded that Hmox1 inhibits neointimal hyperplasia via HDAC2 in rats.

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Reactive oxygen species (ROS) caused by ultraviolet A (UVA) can be reduced by treating with antioxidants and photoprotective reagents. Here we reported a real-time chemiluminescence (CL) imaging method which was simple, non-invasive and sensitive to evaluate UVA-induced ROS generation and the efficacy of sunscreens and antioxidants in vivo. The in vitro experiments indicated that l-ascorbic acid, live SPSC01 yeast, and its intracellular metabolites can suppress the intensity of CL signals in the presence of hydrogen peroxide, which proved the good antioxidant ability of them. Meanwhile, we used 8-amino-5-chloro-7-phenylpyrido[3,4-d] pyridazine-1,4(2H,3H) dione (L-012) as a high sensitive CL probe for in vivo imaging of ROS generated by UVA irradiation. The CL intensity was reduced after treated with l-ascorbic acid and SPSC01 yeast intracellular metabolites, consistent with the in vitro results. Additionally, the in vivo protective capability of two azobenzene compounds as sunscreens was confirmed further through the suppression of CL signals of UVA-induced ROS in mouse skin by this method.

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Epithelial-to-mesenchymal transition (EMT) is critical to the progression of several disease processes including carcinoma metastasis and organ fibrosis. Recent studies show that reactive oxygen species (ROS) and mitochondrial dysfunction have been associated with EMT. However, the role of mitochondria in the EMT process remains to be elucidated. Through the induction of EMT using TGF-β1, we demonstrated that mitochondrial functions were abnormal by increasing ROS production and reducing mitochondrial membrane potential, ATP content and mitochondrial complex protein expression. Resveratrol, a mitochondria protective agent, was found to prevent EMT by preserving mitochondrial functions during the process. However, the inhibitory effects of resveratrol on EMT were abolished in mitochondrial DNA-depleted cells. These findings suggest a critical role for mitochondria in EMT and implicate the protection of mitochondria as a potential target to prevent EMT to treat tumour metastasis or tissue fibrosis, and other diseases involving with mitochondria.

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Oxidative stress alters signalling pathways for survival and cell death favouring the adverse remodelling of postmyocardial remnant cardiomyocytes, promoting functional impairment. The administration of pterostilbene (PTS), a phytophenol with antioxidant potential, can promote cardioprotection and represents a therapeutic alternative in acute myocardial infarction (AMI). The present study aims to explore the effects of oral administration of PTS complexed with hydroxypropyl-β-cyclodextrin HPβCD (PTS:HPβCD complex) on the glutathione cycle, thiol protein activities and signalling pathways involving the protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β) proteins in the left ventricle (LV) of infarcted rats. Animals were submitted to acute myocardial infarction through surgical ligation of the descending anterior branch of the left coronary artery and received over 8 days, by gavage, PTS:HPβCD complex at dose of 100 mg kg-1 day-1 (AMI + PTS group) or vehicle (aqueous solution with HPβCD) divided into Sham-operated (SHAM) and infarcted (AMI) groups. The results showed that the PBS: HPβCD complex decreased lipid peroxidation, prevented the decrease in thioredoxin reductase (TRxR) activity, and increased the activity of glutathione-S-transferase (GST) and glutaredoxin (GRx). Additionally, the expression of nuclear factor-erythroid two (Nrf2) and p-GSK-3β was increased, whereas the p-GSK-3β/GSK-3β ratio was reduced in the LV of the infarcted animals. Overall, the PTS:HPβCD complex modulates activity of thiol-dependent enzymes and induces to the expression of antioxidant proteins, improving systolic function and mitigating the adverse cardiac remodelling post infarction.