Explore the vast range of titles available.

Oxidative stress (OS) is generated by the imbalance between reactive oxygen species (ROS) and antioxidant enzyme activities, such as catalases, superoxide dismutases, and glutathione peroxidases. In the Y. lipolytica genome, three genes encoding catalases (CAT1, CAT2, and CAT3) have been identified; all three genes are transcriptionally active in cells grown under OS conditions. This study aimed to analyze whether the CAT1 and CAT2 genes exhibit a compensatory function that allows maintaining the functionality of the antioxidant response in Y. lipolytica cells lacking the CAT3 gene. The construction of the mutant strain (Ylcat3-Δ) was performed using Double-Joint PCR. OS was induced by the addition of H2O2 [5 mM], ROS production was quantified by fluorescence using 2′,7′-dichlorofluorescein diacetate (DCFH-DA), and gene expression was analyzed by semi-quantitative RT-PCR in both parental (P01a) and mutant (Ylcat3-Δ) strains exposed or not to oxidative conditions. ROS production was lower in P01a cells than in Ylcat3-Δ cells when exposed to H2O2 [5 mM]. Also, under OS conditions, CAT1 gene expression levels decreased in both strains, whereas CAT2 gene expression increased in both types of cells. Under OS, both parental and Ylcat3-Δ strains showed similar growth rate, sensitivity to oxidative conditions and gene expression patterns, and it can be concluded that CAT3 gene deletion does not alter the transcriptional activity of CAT1 and CAT2 genes, suggesting that the compensatory function among the CAT genes of Y. lipolytica may not be limited to the presence/absence of CAT3 gene.

This article reviews the current knowledge on the mechanisms of adaptive response to low doses of ionizing radiation or chemical exposure. A better knowledge of these mechanisms is needed to improve our understanding of health risks at low levels of environmental or occupational exposure and their involvement in cancer or non-cancer diseases. This response is orchestrated through a multifaceted cellular program involving the concerted action of diverse stress response pathways. These evolutionary highly conserved defense mechanisms determine the cellular response to chemical and physical aggression. They include DNA damage repair (p53, ATM, PARP pathways), antioxidant response (Nrf2 pathway), immune/inflammatory response (NF-κB pathway), cell survival/death pathway (apoptosis), endoplasmic response to stress (UPR response), and other cytoprotective processes including autophagy, cell cycle regulation, and the unfolded protein response. The coordinated action of these processes induced by low-dose radiation or chemicals produces biological effects that are currently estimated with the linear non-threshold model. These effects are controversial. They are difficult to detect because of their low magnitude, the scarcity of events in humans, and the difficulty of corroborating associations over the long term. Improving our understanding of these biological consequences should help humans and their environment by enabling better risk estimates, the revision of radiation protection standards, and possible therapeutic advances.

Lactoferrin (LF) is an 80 kDa glycoprotein that contains approximately 700 amino acids and is a member of the transferrin family. The essential properties of LF, including antimicrobial, antiviral, anticancer, anti-inflammatory, antioxidant, and probiotic effects, have been studied for decades. The iron chelation activity of LF is significantly associated with its antimicrobial, anti-inflammatory, and antioxidant properties. Owing to its probiotic and prebiotic activity, LF also facilitates the growth of beneficial microorganisms and iron-defense immediate-effect properties on pathogens. Additionally, the ability to regulate cell signaling pathways and immune responses makes LF a prominent modulatory protein. These diverse characteristics of LF have gained interest in its therapeutic potential. Studies have suggested that LF could serve as an alternative source to antibiotics in severe infections and illnesses. LF has also gained interest in the food industry for its potential as an additive to fortify products such as yogurt, infant formula, and meat derivatives while also improving the shelf life of foods and providing antimicrobial and antioxidant activity. Prior to using LF in the food industry, the safety and toxicity of food processing are necessary to be investigated. These safety investigations are crucial for addressing potential harm or side effects and ensuring a healthy lifestyle. This review discusses the attributes and safety of LF, particularly its exploitation in the food industry.

Testicular dysfunction, a major contributory factor to infertility, has received a lot of attention over the recent years. Several studies have linked abnormal sperm function and morphology with an enhanced generation of reactive oxygen species (ROS) and oxidative stress. The nuclear factor erythroid-derived 2 (Nrf2) is a transcriptional response to cellular stresses (intrinsic or extrinsic) that regulates the oxidative status, mitochondrial dysfunction, inflammation, and proteostasis. In this review, the therapeutic role of Nrf2 was explored. To do so, scientific data were retrieved from databases such as Elsevier, Wiley, Web of Science, Springer, PubMed, Taylor and Francis, and Google Scholar using search terms such as “Nrf2” and “testis,” “sperm,” “testicular function,” and “testosterone.” It has been noted that Nrf2 influences the physiology and pathology of testicular dysfunction, especially in the spermatogenic process, by regulating cellular resistance to oxidative stress, inflammation, and environmental toxicants. However, numerous compounds serve as activators and inhibitors of testicular Nrf2. Nrf2 activators might play a therapeutic role in the prevention and treatment of testicular dysfunction, while molecules that inhibit Nrf2 might induce dysfunction in testis components. Nrf2 activators protect cells against oxidative damage and activate Nrf2/KEAP1 signaling which promotes its movement to the nucleus, and increased Nrf2 function and expression, along with their downstream antioxidant gene. Nrf2 inhibitors facilitate oxidative stress via interfering with the Nrf2 signal pathway. The Nrf2 activation could serve as a promising therapeutic target for testicular dysfunction. This review explored the effect of Nrf2 on testicular function while highlighting potential activators and inhibitors of Nrf2.

‘Reactive oxygen species’ (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as ‘oxidative distress’. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as ‘oxidative eustress’. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·−), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).Reactive oxygen species (ROS) were originally associated with cellular damage and disease. However, ROS, notably hydrogen peroxide, at low physiological levels also engage in physiological signalling, supporting cellular responses and adaptation to changing environments and stress. Accordingly, controlling specific ROS-mediated signalling pathways offers new perspectives for a more refined redox medicine.

Sepsis is a potentially fatal condition characterized by organ dysfunction caused by an imbalanced immune response to infection. Although an increased inflammatory response significantly contributes to the pathogenesis of sepsis, several molecular mechanisms underlying the progression of sepsis are associated with increased cellular reactive oxygen species (ROS) generation and exhausted antioxidant pathways. This review article provides a comprehensive overview of the involvement of ROS in the pathophysiology of sepsis and the potential application of antioxidants with antimicrobial properties as an adjunct to primary therapies (fluid and antibiotic therapies) against sepsis. This article delves into the advantages and disadvantages associated with the utilization of antioxidants in the therapeutic approach to sepsis, which has been explored in a variety of animal models and clinical trials. While the application of antioxidants has been suggested as a potential therapy to suppress the immune response in cases where an intensified inflammatory reaction occurs, the use of multiple antioxidant agents can be beneficial as they can act additively or synergistically on different pathways, thereby enhancing the antioxidant defense. Furthermore, the utilization of immunoadjuvant therapy, specifically in septic patients displaying immunosuppressive tendencies, represents a promising advancement in sepsis therapy.

Polyphenol-rich fruits represent promising natural candidates for mitigating oxidative stress. We determined in dose–response manner the intracellular antioxidant activities of P. cerasus (tart cherry) extract in HepG2 cells using three different cellular assays targeting specific mechanisms of action: (1) the AOP1 assay, to assess intracellular ROS scavenging activity; (2) the CAA assay, to estimate ROS scavenging activity at the cell membrane; and (3), the HepG2-ARE-luc assay, to evaluate Antioxidant Response Element (ARE) pathway modulation. Tart cherry extract exhibited a high and concentration-dependent intracellular ROS scavenging activity with the AOP1 assay (EC50 of 72.02 µg/mL), whereas antioxidant efficacy measured via the CAA assay was much lower (EC50 of 6.975 mg/mL). Notably, P. cerasus extract did not activate the ARE-driven luciferase gene expression. Instead, the extract induced a clear dose-dependent repression of ARE-driven transcriptional activity, with a reduction in luciferase gene expression ranging from 20 to 70% across the sample tested concentrations (0.38–98 µg/mL). These findings suggest that, at concentrations where it functions as a potent intracellular ROS scavenger, P. cerasus extract exerts a negative regulation of the ARE pathway. Further investigations are warranted to elucidate the compounds underlying these effects.

PurposePolycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is typically accompanied by a defective oxidative defense system. Here, we investigated the effect of astaxanthin (AST) as a powerful antioxidant on the oxidative stress (OS) response and assisted reproductive technology (ART) outcomes in PCOS patients.MethodsIn this double-blind, randomized, placebo-controlled trial, PCOS patients were randomly assigned into two groups. The intervention group received 8 mg AST, and the control group received the placebo daily for 40 days. The primary outcomes were the serum and follicular fluid (FF) levels of the OS biomarkers and the expression levels of the specific genes and proteins in the oxidative stress response pathway. The secondary outcomes were considered ART outcomes.ResultsAccording to our findings, a 40-day course of AST supplementation led to significantly higher levels of serum CAT and TAC in the AST group compared to the placebo group. However, there were no significant intergroup differences in the serum MDA and SOD levels, as well as the FF levels of OS markers. The expression of Nrf2, HO-1, and NQ-1 was significantly increased in the granulosa cells (GCs) of the AST group. Moreover, the MII oocyte and high-quality embryo rate were significantly increased in the AST group compared to the placebo group. We found no significant intergroup difference in the chemical and clinical pregnancy rates.ConclusionAST treatment has been shown to increase both serum TAC levels and activation of the Nrf2 axis in PCOS patients’ GCs.Trial RegistrationClincialTrials.gov Identifier: NCT03991286.

Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes 1 , 2 , and regulate cellular functions such as metabolism 3 – 5 and transcription 6 . An important ‘sensor’ protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF2 7 , 8 , which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1–NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases. Inhibition of the glycolytic enzyme PGK1 using a small molecular probe reveals a molecular link between glycolysis and the KEAP1–NRF2 signalling cascade.

Antimicrobial efficacy, which is central to many aspects of medicine, is being rapidly eroded by bacterial resistance. Since new resistance can be induced by antimicrobial action, highly lethal agents that rapidly reduce bacterial burden during infection should help restrict the emergence of resistance. To improve lethal activity, recent work has focused on toxic reactive oxygen species (ROS) as part of the bactericidal activity of diverse antimicrobials. We report that when Escherichia coli was subjected to antimicrobial stress and the stressor was subsequently removed, both ROS accumulation and cell death continued to occur. Blocking ROS accumulation by exogenous mitigating agents slowed or inhibited poststressor death. Similar results were obtained with a temperature-sensitive mutational inhibition of DNA replication. Thus, bacteria exposed to lethal stressors may not die during treatment, as has long been thought; instead, death can occur after plating on drug-free agar due to poststress ROS-mediated toxicity. Examples are described in which (i) primary stress-mediated damage was insufficient to kill bacteria due to repair; (ii) ROS over-came repair (i.e., protection from anti-ROS agents was reduced by repair deficiencies); and (iii) killing was reduced by anti-oxidative stress genes acting before stress exposure. Enzymatic suppression of poststress ROS-mediated lethality by exogenous catalase supports a causal rather than a coincidental role for ROS in stress-mediated lethality, thereby countering challenges to ROS involvement in anti-microbial killing. We conclude that for a variety of stressors, lethal action derives, at least in part, from stimulation of a self-amplifying accumulation of ROS that overwhelms the repair of primary damage.