PPARα alleviates iron overload-induced ferroptosis in mouse liver.

Ferroptosis is an iron-dependent form of non-apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly understood. Here, we show that PPARα suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPARα directly induces Gpx4 expression by binding to a PPRE element within intron 3. PPARα knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high-iron diet than wild-type mice. Ferrous iron (Fe2+ ) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine-based "turn-on" fluorescent probe(probe1) is suitable for the in vivo detection of Fe2+ . Probe1 displays high selectivity towards Fe2+ , and exhibits a stable response for Fe2+ with a concentration of 20 µM in tissue. Our data thus show that PPARα activation alleviates iron overload-induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPARα may be a promising therapeutic target for drug discovery in ferroptosis-related tissue injuries. Moreover, we identified a fluorescent probe that specifically labels ferrous ions and can be used to monitor Fe2+ in vivo.

Influence of pH on the Kinetics and Mechanism of Photoreductive Dissolution of Amorphous Iron Oxyhydroxide in the Presence of Natural Organic Matter: Implications to Iron Bioavailability in Surface Waters.

In this study, we investigate the influence of pH on the kinetics and mechanism of photoreductive dissolution of amorphous iron oxyhydroxide (AFO) in view of the recognition that the light-mediated dissolution of iron oxides controls Fe availability in many natural waters. Our results show that both ligand-to-metal charge transfer (LMCT) and photogenerated superoxide (O2•-) play an important role in AFO photoreductive dissolution in the presence of the chosen surrogate of natural organic matter, Suwannee river fulvic acid (SRFA). The pH dependence of LMCT-mediated AFO photoreductive dissolution is mainly controlled by the influence of pH on AFO solubility. A decrease in pH increases the concentration of the dissolved and more photolabile Fe(III)-SRFA complex present in equilibrium with AFO, a complex in which Fe(III) is readily reduced by LMCT. The pH dependence of superoxide-mediated Fe(III) reduction (SMIR) is also controlled by the influence of pH on AFO solubility with an increase in the dissolved inorganic Fe(III) concentration with the decrease in pH resulting in an increased rate of SMIR. No influence of pH was observed on the steady-state O2•- concentration generated on SRFA irradiation as well as the O2•- decay rate in the presence of SRFA, suggesting that the concentration and lifetime of O2•- are not important factors in controlling the pH dependence of O2•--mediated AFO dissolution. Overall, the results of this study show that the impact of acidification of natural waters on Fe availability will be much more pronounced when Fe is present as iron oxyhydroxide compared to that observed when organically bound Fe dominates with this effect because of the strong dependency of iron oxyhydroxide solubility on pH. The increased rate and extent of dissolution of iron oxyhydroxides on the acidification of natural waters will also have implications to the fate of other contaminants (such as heavy metals and organic compounds) that may be present on the iron oxyhydroxide surface.

Effect of Chloride and Suwannee River Fulvic Acid on Cu Speciation: Implications to Cu Redox Transformations in Simulated Natural Waters.

Copper is a critical trace nutrient and, at higher concentrations, a toxicant in natural waters, with the relative rates of transformation between the Cu(I) and Cu(II) oxidation states being key to its speciation, bioavailability, and toxicity. While the influence of chloride (Cl-) and natural organic matter on Cu speciation and associated redox transformations has been studied separately, their combined influence on Cu speciation and Cu redox transformations has not been examined. As such, in this study, we investigate the impact of Cl- and Suwannee River fulvic acid (SRFA) on Cu(II) reduction and Cu(I) oxidation kinetics at pH 8.2. SRFA plays a dual role in providing Cu(II) reducing moieties as well as Cu ligating sites. Our results indicate that the SRFA-bound Cu(II) is less reactive than the inorganic Cu(II), and the SRFA-bound Cu(I) being much more rapidly oxidized than the inorganic Cu(I). The presence of Cl- weakens Cu(II) binding by SRFA, thereby increasing the reactivity of Cu(II). Similarly, weakening of Cu(I) binding by SRFA and concomitant binding of Cu(I) by Cl- stabilizes Cu(I). Our results further show that continuous formation of hydrogen peroxide occurs in the presence of Cu(II), SRFA, and Cl- in air-saturated solution with the presence of H2O2 enhancing the dynamic nature of the system.

Is Superoxide-Mediated Fe(III) Reduction Important in Sunlit Surface Waters?

Two major pathways are reported to account for photochemical reduction of Fe(III) in sunlit surface waters, namely, ligand-to-metal charge transfer (LMCT) and superoxide-mediated iron reduction (SMIR). In this study, we investigate the impact of Fe(III) speciation (organically complexed (Fe(III)L versus iron oxyhydroxide (AFO)) on Fe(III) reducibility by photogenerated superoxide (O2•-) and LMCT. To simulate conditions typical of fresh, estuarine, and coastal waters, we have used Suwannee River Fulvic Acid (SRFA) as a representative of the natural organic matter likely to associate with Fe(III). Our results show that the photolabile Fe(III)SRFA complex is reduced rapidly by LMCT, while O2•- does not play a role in reduction of these entities. In contrast, the relatively less photolabile AFO is reduced by both O2•- and LMCT. The reduction of AFO by O2•- occurs following the dissolution of AFO, and hence, the contribution of O2•- to reductive dissolution of AFO is dependent on conditions such as the age of the AFO and initial AFO concentration affecting the rate of dissolution of AFO. Our results further show that while colloidal Fe(III) (in this work, particles >0.025 µm) is reduced by O2•-, there is no involvement of O2•- in dissolved Fe(III) reduction. Overall, our results show that superoxide-mediated iron reduction will be important only in natural waters containing limited concentrations of Fe binding ligands.

Interspecies electron transfer and microbial interactions in a novel Fe(II)-mediated anammox coupled mixotrophic denitrification system.

This study effectively coupled anammox and mixotrophic denitrification at a high nitrogen load rate of 6.84 g N/L/d with 40 mg/L Fe(II). Fe(II) enhanced the activity of nitrate reductase, nitrite reductase, and hydrazine dehydrogenase enzymes, facilitating accelerated ATP synthesis. Through electrochemical experiments, interspecies electron transfer processes in coupled system were explored. Fe(II) promoted flavin mononucleotide secretion, enhancing electron-donating and electron-accepting capacity by 2.8 and 1.3 times, respectively. Fe(II) triggered the enrichment of autotrophic denitrifying bacteria (Azospira and Hydrogenophaga), transitioning from single organic nutrient to mixotrophic denitrification. Meanwhile, Fe(II) increased Candidatus_Kuenenia abundance from 35.2 % to 49.0 %, establishing the competitive advantage of anammox bacteria over completed denitrifying bacteria (Comamonas). The synergistic interactions between anammox and various denitrification pathways achieved a nitrogen removal rate of 5.88 g N/L/d, with anammox contribution rate of 88.3 %. This study provides insights into broadening the application of partial denitrification /anammox and electron transfer in multi-bacterial coupling systems.

pH-dependent bisphenol A transformation and iodine disinfection byproduct generation by peracetic acid: Kinetic and mechanistic explorations.

Peracetic acid (PAA) is regarded as an environmentally friendly oxidant because of its low formation of toxic byproducts. However, this study revealed the potential risk of generating disinfection byproducts (DBPs) when treating iodine-containing wastewater with PAA. The transformation efficiency of bisphenol A (BPA), a commonly detected phenolic contaminant and a surrogate for phenolic moieties in dissolved organic matter, by PAA increased rapidly in the presence of I-, which was primarily attributed to the formation of active iodine (HOI/I2) in the system. Kinetic model simulations demonstrated that the second-order rate constant between PAA and HOI was 54.0 M-1 s-1 at pH 7.0, which was lower than the generation rate of HOI via the reaction between PAA and I-. Therefore, HOI can combine with BPA to produce iodine disinfection byproducts (I-DBPs). The transformation of BPA and the generation of I-DBPs in the I-/PAA system were highly pH-dependent. Specifically, acidic conditions were more favorable for BPA degradation because of the higher reaction rates of BPA and HOI. More iodinated aromatic products were detected after 5 min of the reaction under acidic and neutral conditions, resulting in higher toxicity towards E. coli. After 12 h of the reaction, more adsorbable organic iodine (AOI) was generated at alkaline conditions because HOI was not able to efficiency transform to IO3-. The presence of H2O2 in the PAA solution played a role in the reaction with HOI, particularly under alkaline conditions. This study significantly advances the understanding of the role of I- in BPA oxidation by PAA and provides a warning to further evaluate the potential environmental risk during the treatment of iodine-bearing wastewater with PAA.

Effects of pH, chloride, and bicarbonate on Cu(I) oxidation kinetics at circumneutral pH.

The oxidation kinetics of nanomolar concentrations of Cu(I) in NaCl solutions have been investigated over the pH range 6.5-8.0. The overall apparent oxidation rate constant was strongly affected by chloride, moderately by bicarbonate, and to a lesser extent by pH. In the absence of bicarbonate, an equilibrium-based speciation model indicated that Cu(+) and CuClOH(-) were the most kinetically reactive species, while the contribution of other Cu(I) species to the overall oxidation rate was minor. A kinetic model based on recognized key redox reactions for these two species further indicated that oxidation of Cu(I) by oxygen and superoxide were important reactions at all pH values and chloride concentrations considered, but back reduction of Cu(II) by superoxide only became important at relatively low chloride concentrations. Bicarbonate concentrations from 2 to 5 mM substantially accelerated Cu(I) oxidation. Kinetic analysis over a range of bicarbonate concentrations revealed that this was due to formation of CuCO(3)(-), which reacts relatively rapidly with oxygen, and not due to inhibition of the back reduction of Cu(II) by formation of Cu(II)-carbonate complexes. We conclude that the simultaneous oxygenation of Cu(+), CuClOH(-), and CuCO(3)(-) is the rate-limiting step in the overall oxidation of Cu(I) under these conditions.

Mechanistic insights into the catalytic ozonation process using iron oxide-impregnated activated carbon.

In the present study, radiolabelled formate was used as a probe compound in order to gain mechanistic insight into the catalytic ozonation process using a commercially available iron oxide-impregnated activated carbon catalyst. We simultaneously analysed the adsorptive and oxidative removal of formate in order to determine the contribution of the catalyst to adsorption and oxidant generation processes respectively. Our results show that the presence of the catalyst enhanced ozone decay as well as the rate and extent of formate oxidation at pH 3.0 compared to that observed in the presence of ozone alone as a result of oxidant generation via O3-Fe oxide interaction. A reduction in rate and extent of formate oxidation on addition of t-butanol and Cl- (known hydroxyl radical (•OH) scavengers under acidic conditions) provides evidence that the oxidant generated during catalytic ozonation at pH 3.0 is •OH. Moreover, the oxidation of formate during catalytic ozonation mostly occurs at the solid-liquid interface and/or in bulk solution with adsorption playing no role in the overall oxidation process with this finding supported by the exceptionally high oxidation efficiency compared to the extent of adsorption observed when no O3 was added. While catalytic ozonation was effective in formate oxidation at pH 3.0, the presence of the catalyst did not lead to an increase in either the rate or extent of formate oxidation at pH 7.3 and 8.5 suggesting that only protonated iron oxide surface sites generate strong oxidant(s) on interaction with O3. Based on our understanding of the processes operating during the ozonation and catalytic ozonation processes, a mathematical model has been developed that adequately describes the experimental results obtained here. Overall, this study shows that systematic measurement of ozone decay, removal of the parent compound as well as formation of the oxidized products under well controlled conditions are required for unequivocal elucidation of the mechanism of catalytic ozonation.

Oxidant Generation Resulting from the Interaction of Copper with Menadione (Vitamin K3)-a Model for Metal-mediated Oxidant Generation in Living Systems.

The oxidation of hydroquinones is of interest both due to the generation of reactive oxygen species (ROS) and to the implications to trace metal redox state. Menadione (MNQ), a typical toxicant quinone used extensively for studying the mechanisms underlying oxidative stress, is known to be an effective source of exogenous ROS. In this study, the kinetics and mechanism of the oxidation of menadiol (MNH2Q, the reduced form of MNQ) in the absence and presence of copper (Cu) over the pH range 6.0-7.5 was examined. The autoxidation rate increased with increasing pH and concentration of O2 and also slightly increased with increasing concentration of MNH2Q and MNQ with Cu shown to play a significant role in catalysing the oxidation of MNH2Q. A kinetic model showed that the mono-deprotonated menadiol, MNHQ-, accounted for the pH dependence of the autoxidation rate. In this proposed mechanism, both MNH2Q and MNHQ- species were oxidized quickly by Cu(II), generating menadione semiquinone (MNSQ•-) and superoxide (O2•-) and the reduced form of Cu, Cu(I). Oxygen not only facilitated the catalytic role of Cu(II) by rapidly regenerating Cu(II) but also effectively removed MSNQ•-, generating the important chain-propagating species O2•-. The model demonstrated that Cu(I) was a significant sink of O2•- resulting in the generation of H2O2 with subsequent generation of highly oxidative intermediates including Cu(III). These results provide considerable insight into the clinical significance of the biological activation and detoxification of MNQ with the kinetic model developed of use in identifying key processes in the generation of harmful oxidants in living systems.