<p>Oxidative biochemistry centered about 35 years ago on the one-electron reduction of H<sub>2</sub>O<sub>2</sub> by Fe<sup>2+</sup>, the Fenton reaction, to yield HO<sup>·</sup> and a Fe(III)-complex. The discovery that NO<sup>·</sup> is formed <i>in vivo</i> and that it reacts with O<sub>2</sub><sup>·</sup><sup>−</sup> at a diffusion-controlled rate led to ONOO<sup>−</sup> as an additional oxidant. The rate constant of the Fenton reaction is 53 M<sup>−1</sup>s<sup>−1</sup> up to about pH 4, but above it the rate constant increases linearly with pH.  This acceleration of the Fenton reaction led to the hypothesis that above pH 5 formation of FeO<sup>2+</sup> predominates.  Thermodynamically, this species is comparable to HO<sup>·</sup> as an oxidant.  HCO<sub>3</sub><sup>−</sup> accelerates the reaction even more, and convincing evidence has been presented that the complex of Fe<sup>2+</sup> with CO<sub>3</sub><sup>2−</sup> reacts with H<sub>2</sub>O<sub>2</sub> to form CO<sub>3</sub><sup>·</sup><sup>−</sup> and a Fe(III)-complex, conceivably <i>via</i> FeO<sup>2+</sup> as an intermediate. The rapid reaction of ONOO<sup>−</sup> with CO<sub>2</sub> (<i>k</i> > 10<sup>7</sup> M<sup>−1</sup>s<sup>−1</sup>) leads to ONOOCO<sub>2</sub><sup>−</sup> that, depending on the CO<sub>2</sub> concentration, yields varying amounts of NO<sub>2</sub><sup>·</sup> and CO<sub>3</sub><sup>·</sup><sup>−</sup>.  These two oxidizing radicals together nitrate aromatic residues. Compared to 35 years ago, oxidative biochemistry is no longer concerned with the indiscriminate oxidations and additions of HO<sup>·</sup>, but with the more selective reactions of CO<sub>3</sub><sup>·</sup><sup>−</sup> and NO<sub>2</sub><sup>·</sup>.</p>

<p>A high proliferation rate and the malignancy of cancer cells are favoured by redox and metabolic plasticity, which is determined by the co-evolution of cancer cells with their host microenvironment. The tight functional connections between the mammary glands' epithelium and adipose tissue (AT) allow breast cancer cells to subjugate the AT and form a protumorigenic cancer-associated adipose tissue (CAAT). Our findings in luminal invasive ductal carcinomas in premenopausal women confirmed key cancer cell strategies - the Warburg effect, increased mitochondrial metabolism and redox adaptability, which are associated with a specific shift in the metabolic and redox phenotype of CAAT. Notably, the upregulated master redox-sensitive transcription factor Nrf2 appears to be responsible for the cancer cell-induced redox and metabolic shift of CAAT. We also investigated the role of Nrf2 in the metabolic co-evolution of cancer cells and CAAT during disease progression. Our results in the orthotopic breast cancer mouse model and in the co-culture of breast cancer cells with adipocytes confirmed the different spatiotemporal redox and metabolic properties of cancer cells and CAAT, established with respect to the Nrf2-coupled/uncoupled tumour microenvironment. The uncovered metabolic and redox strategies adopted by breast cancer cells according to CAAT properties and at different disease stages have helped to better understand the biology of the aggressive disease and to identify breast cancer vulnerabilities that could become therapeutic targets.</p> <p><i>This research was supported by the Science Fund of the Republic of Serbia, #7750238, Exploring new avenues in breast cancer research: Redox and metabolic reprogramming of cancer and associated adipose tissue - REFRAME.</i></p>

<p>Nitrite is the typical byproduct of nitric oxide (<sup>•</sup>NO) autooxidation in biological systems. However, certain circumstances favor its reduction “back” to the signaling free radical, providing a non-enzymatic route for the synthesis of <sup>•</sup>NO. In pathophysiological conditions such as ischemia/reperfusion (I/R), where low oxygen availability limits nitric oxide synthase activity, nitrite reduction to <sup>•</sup>NO may allow protective modulation of mitochondrial oxidative metabolism and thus reduce the impact of I/R on brain tissue. In the current study, we used high-resolution respirometry to evaluate the effects of nitrite in an in vitro model I/R using hippocampal slices. We found that reoxygenation was accompanied by an increase in oxygen flux, a phenomenon that has been coined “oxidative burst”. The amplitude of this “oxidative burst” was decreased by nitrite in a concentration-dependent manner. These results support the notion that nitrite mediates a decrease in the hyper-reduction of the electron transport system during ischemia, decreasing the accelerated oxygen consumption that characterizes the reoxygenation phase of I/R that has been associated with an increase in oxidant production. Additionally, a pilot in vivo study in which animals received a nitrate-rich diet as a strategy to increase circulating and tissue levels of nitrite also revealed that the “oxidative burst” was decreased in the nitrate-treated animals. These results may provide mechanistic support to the observation of a protective effect of nitrite in situations of brain ischemia.</p>

<p>According to global epidemiology, non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting about a quarter of the adult population worldwide. NAFLD is characterised by the accumulation of triglycerides in hepatocytes (steatosis), which can progress to non-alcoholic steatohepatitis, a more severe form of NAFLD. Oxidative stress is closely linked to the disease progression due to the activation of inflammatory pathways. The aim of this study was to identify markers of redox status that could predict the risk of developing steatosis. The study included 179 participants who underwent ultrasound examination at University Medical Centers Zemun and Zvezdara. Participants were divided into two groups: 119 patients with steatosis and 60 apparently healthy controls (control group, CG). Biochemical markers as well as markers of redox status: total oxidant status (TOS) and total antioxidant status (TAS) were determined in serum spectrophotometrically on biochemical analysers. Univariate and multivariate binary logistic regression analyses were used to test the predictions of TOS and TAS for NAFLD. Patients had higher body mass index (P<0.001), glucose (P<0.001), uric acid (P<0.001), TOS (P=0.007), and TAS (P<0.001) levels compared to CG. Univariate binary regression analysis revealed significant predictive capability of TOS and TAS for NAFLD demonstrated by the following ORs: 1.104 (1.020-1.195) (P=0.014) and 1.003 (1.001-1.004) (P<0.001), respectively. After applying multivariate binary logistic regression analyses (adjustments were made for sex and BMI), TOS and TAS kept independent significant predictive capability for NAFLD, as demonstrated by the following ORs: 1.098 (1.009-1.195) (P=0.030) and 1.002 (1.000-1.003) (P=0.026), respectively. TOS and TAS are positively associated with the risk of developing NAFLD, independent of sex and BMI. Both markers are elevated, probably because increased oxidative activity requires a stronger antioxidant defence response, which should be confirmed by a follow-up study including more participants.</p>

<p>Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this ‘interdependence’ behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that complete disruption of each of the OXPHOS complexes resulted in a perturbation in energy deficiency sensing pathways, including the integrated stress response (ISR) pathway. The secondary decrease of complex I (cI) level was triggered by both complex IV and complex V deficiency, and it was independent of ISR signaling. On the other hand, we identified the unifying mechanism behind cI downregulation in the downregulation of mitochondrial ribosomal proteins and, thus, mitochondrial translation. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.<i></i><i></i></p>