thioredoxin
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An excessive increase in reactive oxygen species (ROS) levels is one of the main causes of mitochondrial dysfunction. However, when ROS levels are maintained in balance with antioxidant mechanisms, ROS fulfill the role of signaling molecules and modulate various physiological processes. Recent advances in mitochondrial bioenergetics research have revealed a significant interplay between mitochondrial peroxiredoxins (PRDXs) and monoamine oxidase-A (MAO-A) in regulating ROS levels. Both proteins are associated with hydrogen peroxide (H2O2), MAO-A as a producer and PRDXs as the primary antioxidant scavengers of H2O2. This review focuses on the currently available knowledge on the function of these proteins and their interaction, highlighting their importance in regulating oxidative damage, apoptosis, and metabolic adaptation in the heart. PRDXs not only scavenge excess H2O2, but also act as regulatory proteins, play an active role in redox signaling, and maintain mitochondrial membrane integrity. Overexpression of MAO-A is associated with increased oxidative damage, leading to mitochondrial dysfunction and subsequent progression of cardiovascular diseases (CVD), including ischemia/reperfusion injury and heart failure. Considering the central role of oxidative damage in the pathogenesis of many CVD, targeting PRDXs activation and MAO-A inhibition may offer new therapeutic strategies aimed at improving cardiac function under conditions of pathological load related to oxidative damage. Keywords: Mitochondria, Peroxiredoxin, Monoamine oxidase-A, Reactive oxygen species, Cardioprotective signaling.
- MeSH
- lidé MeSH
- monoaminoxidasa * metabolismus MeSH
- oxidační stres MeSH
- peroxiredoxiny * metabolismus MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- signální transdukce * MeSH
- srdeční mitochondrie metabolismus enzymologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The most vital factors that hostile health human are toxic heavy metals (THMs). Heavy metals are harmful environmental contaminants that can decrease the likelihood of a healthy pregnancy and afterwards impede a healthy birth. Both paternal and maternal toxic metal exposure could influence pregnancy, So the rates of pregnancy failure are constantly rising. The current study's goal is to explore the effect of Pеrоxirеdоxin 3 antioxidant, as well as some toxic metals (TMs) such as arsenic, cadmium and mercury in missed abortion patients and compared with healthy pregnant and non˗pregnant women without a history of abortion in order to evaluate the degree of this effect on this pathological situation. Additionally, it will demonstrate the connection between these biochemical variables and gestational age. Pеrоxirеdоxin 3 (Prx3), Arsenic (As), Cadmium (Cd), and Mercury (Hg) as a (THMs) were estimated in 40 healthy non˗pregnant (HNP) women, 40 healthy prеgnаnts (HP) with no abortion history, and 20 women with missed abortion (MA). All woman participants are of reproductive age, with the maternal gestational age in the HP and MA groups being ≤ 20 weeks. Maternal gestational age was used to categorize MA and HP women into two groups (1st & 2nd trimester).Regarding to the findings of recent research, Prx3 levels declined noticeably in MA patients compared to HP and HNP groups, on other hand the difference of toxic metals which represented in this study as: (As, Cd, and Hg) elevated statistically significantly in MA patients compared to HP and HNP groups. Within the first and second trimesters of pregnancy, the difference of Prx3 levels showed statistically significant reduction between the MA and HP groups. A statistical significance elevation was found between the two comparable gestational age of both groups in regard to blood serum (As, Cd, and Hg) levels. Lastly, the impact of gestational period within MA cases was revealed, serum (Cd) and (Hg) showing a significant variation between the first and second trimester of pregnancy, whereas Prx3 and (As) were unaffected by pregnancy advances within the MA group.
Cysteine is one of the least abundant but most conserved amino acid residues in proteins, playing a role in their structure, metal binding, catalysis, and redox chemistry. Thiols present in cysteines can be modified by post-translational modifications like sulfenylation, acylation, or glutathionylation, regulating protein activity and function and serving as signals. Their modification depends on their position in the structure, surrounding amino acids, solvent accessibility, pH, etc. The most studied modifications are the redox modifications by reactive oxygen, nitrogen, and sulfur species, leading to reversible changes that serve as cell signals or irreversible changes indicating oxidative stress and cell damage. Selected antioxidants undergoing reversible oxidative modifications like peroxiredoxin-thioredoxin system are involved in a redox-relay signaling that can propagate to target proteins. Cysteine thiols can also be modified by acyl moieties' addition (derived from lipid metabolism), resulting in protein functional modification or changes in protein anchoring in the membrane. In this review, we update the current knowledge on cysteine modifications and their consequences in pancreatic β-cells. Because β-cells exhibit well-balanced redox homeostasis, the redox modifications of cysteines here serve primarily for signaling purposes. Similarly, lipid metabolism provides regulatory intermediates that have been shown to be necessary in addition to redox modifications for proper β-cell function and, in particular, for efficient insulin secretion. On the contrary, the excess of reactive oxygen, nitrogen, and sulfur species and the imbalance of lipids under pathological conditions cause irreversible changes and contribute to oxidative stress leading to cell failure and the development of type 2 diabetes.
Protracted opioid withdrawal is considered to be a traumatic event with many adverse effects. However, little attention is paid to its consequences on the protein expression in the rat brain. A better understanding of the changes at the molecular level is essential for designing future innovative drug therapies. Our previous proteomic data indicated that long-term morphine withdrawal is associated with altered proteins functionally involved in energy metabolism, cytoskeletal changes, oxidative stress, apoptosis, or signal transduction. In this study, we selected peroxiredoxin II (PRX II) as a marker of oxidative stress, 14-3-3 proteins as adaptors, and creatine kinase-B (CK-B) as a marker of energy metabolism to detect their amounts in the brain cortex and hippocampus isolated from rats after 3-month (3 MW) and 6-month morphine withdrawal (6 MW). Methodically, our work was based on immunoblotting accompanied by 2D resolution of PRX II and 14-3-3 proteins. Our results demonstrate significant upregulation of PRX II in the rat brain cortex (3-fold) and hippocampus (1.3-fold) after 3-month morphine abstinence, which returned to the baseline six months since the drug was withdrawn. Interestingly, the level of 14-3-3 proteins was downregulated in both brain areas in 3 MW samples and remained decreased only in the brain cortex of 6 MW. Our findings suggest that the rat brain cortex and hippocampus exhibit the oxidative stress-induced vulnerability represented by compensatory upregulation of PRX II after three months of morphine withdrawal.
- MeSH
- abstinenční syndrom * metabolismus MeSH
- hipokampus metabolismus MeSH
- krysa rodu rattus MeSH
- morfin metabolismus MeSH
- mozek metabolismus MeSH
- peroxiredoxiny metabolismus farmakologie MeSH
- proteiny 14-3-3 metabolismus MeSH
- proteomika MeSH
- upregulace MeSH
- závislost na morfiu * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The pаthоphysiolоgy of recurrent spontaneous abortion (RSA) has been linked to oxidative stress (OS), which is defined as an imbalance between the formation of oxidants and the antioxidant defense system. The goal of this study was to assess the state of OS in recurrent spontaneous abortion by assessing some of its indicators in order to identify women who are at risk of abortion and enhance their reproductive health. Peroxiredoxin 3 (Prx3), progesterone (P4), glutathione (GSH), uric acid (UA), pеrоxynitritе (ONOO-), and mаlоndialdеhyde (MDA) were measured in 40 healthy non-pregnant (HNP) women, 40 healthy pregnant (HP) women without abortion history, and 21 women with recurrent spontaneous abortion (Have at least ≥ 3 consecutive abortion). All subjects are of reproductive age, with the mother gestational age in the HP and RSA groups being ≤ 20 weeks. According to maternal gestational age, RSA and HP women were separated into two categories (1st & 2nd trimester). According to the findings of this study, Prx3 and GSH levels declined considerably in RSA patients compared to HP and HNP patients, but ONOO- and MDA levels increased statistically significantly in RSA patients compared to HP and HNP groups. However, P4 of RSA was found to be significantly lower in the HP group and much higher in the HNP group. The difference in uric acid levels between the RSA and HP groups was statistically significant, but the difference between the RSA and HNP groups was not.Within the first and second trimesters of pregnancy, the difference between the RSA and HP groups showed statistically significant changes in oxidative stress-related biomarkers, with the exception of uric acid, which showed a non-significant difference between the two groups within the second trimester.Finally, the effect of gestational age within RSA was revealed, with serum Prx3 and P4 showing a significant difference between the first and second stages of pregnancy, whereas other oxidative stress indicators were unaffected by pregnancy length within the RSA group.
- MeSH
- antioxidancia analýza MeSH
- biochemická analýza krve metody MeSH
- habituální potrat * krev MeSH
- lidé MeSH
- oxidační stres MeSH
- oxidancia krev MeSH
- peroxiredoxin III * krev MeSH
- statistika jako téma MeSH
- těhotenství krev MeSH
- Check Tag
- lidé MeSH
- těhotenství krev MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinická studie MeSH
- Geografické názvy
- Irák MeSH
T-2 toxin is a worldwide problem for feed and food safety, leading to livestock and human health risks. The objective of this study was to explore the mechanism of T-2 toxin-induced small intestine injury in broilers by integrating the advanced microbiomic, metabolomic and transcriptomic technologies. Four groups of 1-day-old male broilers (n = 4 cages/group, 6 birds/cage) were fed a control diet and control diet supplemented with T-2 toxin at 1.0, 3.0, and 6.0 mg/kg, respectively, for 2 weeks. Compared with the control, dietary T-2 toxin reduced feed intake, body weight gain, feed conversion ratio, and the apparent metabolic rates and induced histopathological lesions in the small intestine to varying degrees by different doses. Furthermore, the T-2 toxin decreased the activities of glutathione peroxidase, thioredoxin reductase and total antioxidant capacity but increased the concentrations of protein carbonyl and malondialdehyde in the duodenum in a dose-dependent manner. Moreover, the integrated microbiomic, metabolomic and transcriptomic analysis results revealed that the microbes, metabolites, and transcripts were primarily involved in the regulation of nucleotide and glycerophospholipid metabolism, redox homeostasis, inflammation, and apoptosis were related to the T-2 toxin-induced intestinal damage. In summary, the present study systematically elucidated the intestinal toxic mechanisms of T-2 toxin, which provides novel ideas to develop a detoxification strategy for T-2 toxin in animals.
- MeSH
- antioxidancia metabolismus MeSH
- apoptóza MeSH
- dieta MeSH
- homeostáza MeSH
- krmivo pro zvířata analýza MeSH
- kur domácí * metabolismus MeSH
- lidé MeSH
- oxidace-redukce MeSH
- potravní doplňky MeSH
- T-2 toxin * toxicita MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme, a unique member of the peroxiredoxin family, with an important role in antioxidant defense. Moreover, it has also been linked with the biosynthesis of anti-inflammatory and anti-diabetic lipids called fatty acid esters of hydroxy fatty acids (FAHFAs) and many diseases, including cancer, inflammation, and metabolic disorders. Here, we performed metabolomic and lipidomic profiling of subcutaneous adipose tissue from mouse models with genetically modified Prdx6. Deletion of Prdx6 resulted in reduced levels of FAHFAs containing 13-hydroxylinoleic acid (13-HLA). Mutation of Prdx6 C47S impaired the glutathione peroxidase activity and reduced FAHFA levels, while D140A mutation, responsible for phospholipase A2 activity, showed only minor effects. Targeted analysis of oxidized phospholipids and triacylglycerols in adipocytes highlighted a correlation between FAHFA and hydroxy fatty acid production by Prdx6 or glutathione peroxidase 4. FAHFA regioisomer abundance was negatively affected by the Prdx6 deletion, and this effect was more pronounced in longer and more unsaturated FAHFAs. The predicted protein model of Prdx6 suggested that the monomer-dimer transition mechanism might be involved in the repair of longer-chain peroxidized phospholipids bound over two monomers and that the role of Prdx6 in FAHFA synthesis might be restricted to branching positions further from carbon 9. In conclusion, our work linked the peroxidase activity of Prdx6 with the levels of FAHFAs in adipose tissue.
- MeSH
- antioxidancia MeSH
- fosfolipidy MeSH
- mastné kyseliny MeSH
- metabolomika * MeSH
- myši MeSH
- peroxiredoxin VI * genetika MeSH
- peroxiredoxiny MeSH
- tukové buňky MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Atopická dermatitida je nejčastější chronické onemocnění kůže. Etiopatogeneze tohoto onemocnění však ještě jednoznačně stanovena není. I vzhledem k polymorfním fenotypům se pravděpodobně jedná o kombinaci více činitelů. Jedním z faktorů, které by mohly ovlivňovat průběh atopické dermatitidy, je i interakce imunitního systému s lipofilními kvasinkami z rodu Malassezia, které jsou běžně součástí kožní mikroflóry. Několik aktuálních prací odhalilo senzibilizaci vůči těmto kvasinkám u pacientů s atopickou dermatitidou zejména v oblasti hlavy a krku. Míra senzibilizace následně koreluje se závažností průběhu onemocnění atopickou dermatitidou. Přesná etiopatogeneze této korelace není známa, ale předpokládá se několik možných mechanismů. Přes porušenou kožní bariéru pronikají ve větší míře antigeny malassezie. V zásaditějším prostředí atopické kůže se navíc zvyšuje jejich produkce. I na samotný průnik malassezie reaguje imunitní systém zánětlivou odpovědí. Rovněž byla popsána autoreaktivita T lymfocytů proti mykotickým enzymům, které jsou vysoce homologní s lidskými enzymy. Jedná se zejména mangan-dependentní superoxid dismutázu a thioredoxin. Všechny tyto mechanismy mohou potencovat zánětlivou kožní reakci.
Atopic dermatitis is the most common chronic inflammatory dermatosis. However, the etiopatogenesis of the disease is not yet clearly established. Even with polymorphic phenotypes, this is likely to be a combination of multiple agents. One factor that could influence the course of atopic dermatitis is the immune system's interaction with lipophilic yeasts of the genus Malassezia, which are commonly part of the skin microflora. Several recent papers have revealed sensitisation to these yeasts in atopic dermatitis patients especially in the head and neck area. The rate of sensitisation is subsequently correlated with the severity of the progression of atopic dermatitis disease. The exact etiopatogenesis of this corre-lation is unknown, but several possible mechanisms are assumed. Malassezia antigens penetrate more widely through the broken skin barrier. Moreover, in the more alkaline environment of atopic skin, their production increases. Even to the penetration of Malassezia itself, the immune system responds with an inflammatory response. The autoreactivity of T-lymphocytes against fungal enzymes that are highly homologous with human enzymes has also been described. This is particularly the case with omangan-dependent superoxiddismuthase and thioredoxin. All of these mechanisms can potentiate the inflammatory skin response.
- MeSH
- antifungální látky terapeutické užití MeSH
- atopická dermatitida * imunologie mikrobiologie patofyziologie MeSH
- imunoglobulin E izolace a purifikace MeSH
- imunologické testy MeSH
- interakce hostitele a patogenu imunologie MeSH
- lidé MeSH
- Malassezia imunologie izolace a purifikace patogenita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase 5, which mediates various stress signals including oxidative stress. The catalytic activity of ASK1 is tightly controlled by oligomerization and binding of several cofactors. Among these cofactors, thioredoxin stands out as the most important ASK1 inhibitor, but only the reduced form of thioredoxin inhibits ASK1 by direct binding to its N-terminal domain. In addition, oxidation-driven thioredoxin dissociation is the key event in oxidative stress-mediated ASK1 activation. However, the structural mechanism of ASK1 regulation by thioredoxin remains unknown. Here, we report the characterization of the ASK1 domain responsible for thioredoxin binding and its complex using NMR spectroscopy and chemical cross-linking, thus providing the molecular basis for ASK1: thioredoxin complex dissociation under oxidative stress conditions. Our data reveal that the N-terminal domain of ASK1 adopts a fold resembling the thioredoxin structure while retaining substantial conformational plasticity at the thioredoxin-binding interface. Although oxidative stress induces relatively moderate structural changes in thioredoxin, the formation of intramolecular disulfide bridges leads to a considerable conformational rearrangement of the thioredoxin-binding interface on ASK1. Moreover, the cysteine residue at position 250 of ASK1 is the key element of this molecular switch. Finally, our results show that the redox-active site of thioredoxin is directly involved in ASK1 binding that is modulated by oxidative stress, thereby identifying a key target for the structure-based drug design.
- MeSH
- apoptóza * MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- MAP kinasa-kinasa-kinasa 5 antagonisté a inhibitory metabolismus MeSH
- molekulární modely MeSH
- oxidace-redukce MeSH
- oxidační stres * MeSH
- thioredoxiny chemie metabolismus MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
