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International Journal of Molecular... Dec 2023Ferroptosis is a newly discovered form of regulated cell death. The main feature of ferroptosis is excessive membrane lipid peroxidation caused by iron-mediated chemical... (Review)
Review
Ferroptosis is a newly discovered form of regulated cell death. The main feature of ferroptosis is excessive membrane lipid peroxidation caused by iron-mediated chemical and enzymatic reactions. In normal cells, harmful lipid peroxides are neutralized by glutathione peroxidase 4 (GPX4). When GPX4 is inhibited, ferroptosis occurs. In mammalian cells, ferroptosis serves as a tumor suppression mechanism. Not surprisingly, in recent years, ferroptosis induction has gained attention as a potential anticancer strategy, alone or in combination with other conventional therapies. However, sensitivity to ferroptosis inducers depends on the metabolic state of the cell. Endometrial cancer (EC) is the sixth most common cancer in the world, with more than 66,000 new cases diagnosed every year. Out of all gynecological cancers, carcinogenesis of EC is mostly dependent on metabolic abnormalities. Changes in the uptake and catabolism of iron, lipids, glucose, and glutamine affect the redox capacity of EC cells and, consequently, their sensitivity to ferroptosis-inducing agents. In addition to this, in EC cells, ferroptosis-related genes are usually mutated and overexpressed, which makes ferroptosis a promising target for EC prediction, diagnosis, and therapy. However, for a successful application of ferroptosis, the connection between metabolic rewiring and ferroptosis in EC needs to be deciphered, which is the focus of this review.
Topics: Animals; Female; Humans; Ferroptosis; Endometrial Neoplasms; Biological Transport; Regulated Cell Death; Iron; Phospholipid Hydroperoxide Glutathione Peroxidase; Mammals
PubMed: 38203246
DOI: 10.3390/ijms25010075 -
Redox Biology Oct 2023Peroxisomes are metabolically active organelles that are known for exerting oxidative metabolism, but the precise mechanism remains unclear in diabetic nephropathy (DN)....
Peroxisomes are metabolically active organelles that are known for exerting oxidative metabolism, but the precise mechanism remains unclear in diabetic nephropathy (DN). Here, we used proteomics to uncover a correlation between the antioxidant protein disulfide-bond A oxidoreductase-like protein (DsbA-L) and peroxisomal function. In vivo, renal tubular injury, oxidative stress, and cell apoptosis in high-fat diet plus streptozotocin (STZ)-induced diabetic mice were significantly increased, and these changes were accompanied by a "ghost" peroxisomal phenotype, which was further aggravated in DsbA-L-deficient diabetic mice. In vitro, the overexpression of DsbA-L in peroxisomes could improve peroxisomal phenotype and function, reduce oxidative stress and cell apoptosis induced by high glucose (HG, 30 mM) and palmitic acid (PA, 250 μM), but this effect was reversed by 3-Amino-1,2,4-triazole (3-AT, a catalase inhibitor). Mechanistically, DsbA-L regulated the activity of catalase by binding to it, thereby reducing peroxisomal leakage and proteasomal degradation of peroxisomal matrix proteins induced by HG and PA. Additionally, the expression of DsbA-L in renal tubules of patients with DN significantly decreased and was positively correlated with peroxisomal function. Taken together, these results highlight an important role of DsbA-L in ameliorating tubular injury in DN by improving peroxisomal function.
Topics: Animals; Mice; Catalase; Diabetic Nephropathies; Peroxisomes; Diabetes Mellitus, Experimental; Oxidative Stress
PubMed: 37597421
DOI: 10.1016/j.redox.2023.102855 -
Molecular Metabolism Oct 2023Peroxiredoxin 1 (PRDX1) is a peroxidase and guards against oxidative stress by scavenging intracellular peroxides, whereas it also has been shown to stimulate...
OBJECTIVE
Peroxiredoxin 1 (PRDX1) is a peroxidase and guards against oxidative stress by scavenging intracellular peroxides, whereas it also has been shown to stimulate inflammatory response by functioning as a chaperone protein. The potential in vivo link between PRDX1's peroxidase activity and its pro-inflammatory activity remains elusive.
METHODS
We generated peroxidase-dead PRDX1 variant mice by mutating its peroxidatic cysteine at 52 (Cys52) to serine, here referred to as PRDX1. Trx-TrxR-NADPH coupled activity assay was applied to evaluate the peroxidase activity of global PRDX in PRDX1 variant mice. PRDX1 mice and their wild-type littermates were subjected to western diet or methionine and choline deficient diet feeding. NASH phenotypes were assessed through different analyses including physiological measurements, immunohistochemical staining, and quantitative PCR (qPCR). RNA sequencing, qPCR and western blotting were used to reveal and validate any changes in the signaling pathways responsible for the altered NASH phenotypes observed between WT and PRDX1 variant mice.
RESULTS
PRDX1 variant mice showed impaired global PRDX peroxidase activity and reduced susceptibility to diet-induced NASH and liver fibrosis. Mechanistically, PRDX1 Cys52Ser variant suppressed NF-κB signaling and STAT1 signaling pathways that are known to promote inflammation and NASH.
CONCLUSION
The peroxidatic Cys52 of PRDX1 is required for its pro-inflammatory activity in vivo. This study further suggests that PRDX1 may play dual but opposing roles in NASH.
Topics: Animals; Mice; Non-alcoholic Fatty Liver Disease; Peroxiredoxins; NF-kappa B; Inflammation; Liver Cirrhosis
PubMed: 37562742
DOI: 10.1016/j.molmet.2023.101789 -
Kidney International Mar 2024
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Peroxidase
PubMed: 38388102
DOI: 10.1016/j.kint.2023.10.008 -
International Journal of Molecular... Nov 2023Selenium (Se) is a metalloid that is recognized as one of the vital trace elements in our body and plays multiple biological roles, largely mediated by proteins... (Review)
Review
Selenium (Se) is a metalloid that is recognized as one of the vital trace elements in our body and plays multiple biological roles, largely mediated by proteins containing selenium-selenoproteins. Selenoproteins mainly have oxidoreductase functions but are also involved in many different molecular signaling pathways, physiological roles, and complex pathogenic processes (including, for example, teratogenesis, neurodegenerative, immuno-inflammatory, and obesity development). All of the selenoproteins contain one selenocysteine (Sec) residue, with only one notable exception, the selenoprotein P (SELENOP), which has 10 Sec residues. Although these mechanisms have been studied intensely and in detail, the characteristics and functions of many selenoproteins remain unknown. This review is dedicated to the recent data describing the identity and the functions of several selenoproteins that are less known than glutathione peroxidases (Gpxs), iodothyronine deiodinases (DIO), thioredoxin reductases (TRxRs), and methionine sulfoxide reductases (Msrs) and which are named after alphabetical letters (i.e., F, H, I, K, M, N, O, P, R, S, T, V, W). These "alphabet" selenoproteins are involved in a wide range of physiological and pathogenetic processes such as antioxidant defense, anti-inflammation, anti-apoptosis, regulation of immune response, regulation of oxidative stress, endoplasmic reticulum (ER) stress, immune and inflammatory response, and toxin antagonism. In selenium deficiency, the "alphabet" selenoproteins are affected hierarchically, both with respect to the particular selenoprotein and the tissue of expression, as the brain or endocrine glands are hardly affected by Se deficiency due to their equipment with LRP2 or LRP8.
Topics: Selenium; Selenoproteins; Glutathione Peroxidase; Selenoprotein P; Antioxidants
PubMed: 37958974
DOI: 10.3390/ijms242115992 -
Proceedings of the National Academy of... Nov 2023Recognition that common human amyloidoses are prion diseases makes the use of the prion model systems to screen for possible anti-prion components of increasing...
Recognition that common human amyloidoses are prion diseases makes the use of the prion model systems to screen for possible anti-prion components of increasing importance. [PSI+] and [URE3] are amyloid-based prions of Sup35p and Ure2p, respectively. Yeast has at least six anti-prion systems that together cure nearly all [PSI+] and [URE3] prions arising in their absence. We made a promoted bank of 14,913 human open reading frames in a yeast shuttle plasmid and isolated 20 genes whose expression cures [PSI+] or [URE3]. PRPF19 is an E3 ubiquitin ligase that cures [URE3] if its U-box is intact. DNAJA1 is a J protein that cures [PSI+] unless its interaction with Hsp70s is defective. Human Bag5 efficiently cures [URE3] and [PSI+]. Bag family proteins share a 110 to 130 residue "BAG domain"; Bag 1, 2, 3, 4, and 6 each have one BAG domain while Bag5 has five BAG domains. Two BAG domains are necessary for curing [PSI+], but one can suffice to cure [URE3]. Although most Bag proteins affect autophagy in mammalian cells, mutations blocking autophagy in yeast do not affect Bag5 curing of [PSI+] or [URE3]. Curing by Bag proteins depends on their interaction with Hsp70s, impairing their role, with Hsp104 and Sis1, in the amyloid filament cleavage necessary for prion propagation. Since Bag5 curing is reduced by overproduction of Sis1, we propose that Bag5 cures prions by blocking Sis1 access to Hsp70s in its role with Hsp104 in filament cleavage.
Topics: Animals; Humans; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Prions; HSP70 Heat-Shock Proteins; Mutation; Amyloid; Glutathione Peroxidase; Fungal Proteins; Mammals; RNA Splicing Factors; Nuclear Proteins; DNA Repair Enzymes
PubMed: 37903258
DOI: 10.1073/pnas.2314781120 -
Proceedings of the National Academy of... Sep 2023Accumulating evidence has demonstrated the presence of intertissue-communication regulating systemic aging, but the underlying molecular network has not been fully...
Accumulating evidence has demonstrated the presence of intertissue-communication regulating systemic aging, but the underlying molecular network has not been fully explored. We and others previously showed that two basic helix-loop-helix transcription factors, MML-1 and HLH-30, are required for lifespan extension in several longevity paradigms, including germlineless . However, it is unknown what tissues these factors target to promote longevity. Here, using tissue-specific knockdown experiments, we found that MML-1 and its heterodimer partners MXL-2 and HLH-30 act primarily in neurons to extend longevity in germlineless animals. Interestingly, however, the downstream cascades of MML-1 in neurons were distinct from those of HLH-30. Neuronal RNA interference (RNAi)-based transcriptome analysis revealed that the glutamate transporter GLT-5 is a downstream target of MML-1 but not HLH-30. Furthermore, the MML-1-GTL-5 axis in neurons is critical to prevent an age-dependent collapse of proteostasis and increased oxidative stress through autophagy and peroxidase MLT-7, respectively, in long-lived animals. Collectively, our study revealed that systemic aging is regulated by a molecular network involving neuronal MML-1 function in both neural and peripheral tissues.
Topics: Animals; Aging; Amino Acid Transport System X-AG; Autophagy; Caenorhabditis elegans; Neurons; Peroxidases; Caenorhabditis elegans Proteins
PubMed: 37722055
DOI: 10.1073/pnas.2221553120 -
JACC. Heart Failure Jul 2023Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF).
OBJECTIVES
This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers.
METHODS
Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database.
RESULTS
TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients.
CONCLUSIONS
Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.
Topics: Humans; Antigens, Neoplasm; Biomarkers; Cell Adhesion Molecules; Heart Failure; Peroxidase; Proteomics; Quality of Life; Stroke Volume
PubMed: 37140510
DOI: 10.1016/j.jchf.2023.03.002 -
Nutrients Jul 2023The available evidence on selenium supplementation in the treatment of autoimmune thyroiditis (AIT) was inconclusive. This research serves to assess the effects of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The available evidence on selenium supplementation in the treatment of autoimmune thyroiditis (AIT) was inconclusive. This research serves to assess the effects of selenium supplementation in the treatment of AIT.
METHODS
Online databases including PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to 10 June 2022. The AMSTAR-2 tool was used to assess the methodological quality of included studies. The information on the randomized controlled trials of the included studies was extracted and synthesized. The GRADE system was used to assess the certainty of evidence.
RESULTS
A total of 6 systematic reviews with 75 RCTs were included. Only one study was rated as high quality. The meta-analysis showed that in the levothyroxine (LT4)-treated population, thyroid peroxidase antibody (TPO-Ab) levels decreased significantly in the selenium group at 3 months (SMD = -0.53, 95% CI: [-0.89, -0.17], < 0.05, very low certainty) and 6 months (SMD = -1.95, 95% CI: [-3.17, -0.74], < 0.05, very low certainty) and that thyroglobulin antibody (Tg-Ab) levels were not decreased. In the non-LT4-treated population, TPO-Ab levels decreased significantly in the selenium group at 3 and 6 months and did not decrease at 12 months. Tg-Ab levels decreased significantly in the selenium group at 3 and 6 months and did not decrease at 12 months. The adverse effects reported in the selenium group were not significantly different from those in the control group, and the certainty of evidence was low.
CONCLUSION
Although selenium supplementation might reduce TPO-Ab levels at 3 and 6 months and Tg-Ab levels at 3 and 6 months in the non-LT4-treated population, this was based on a low certainty of evidence.
Topics: Humans; Thyroiditis, Autoimmune; Selenium; Iodide Peroxidase; Systematic Reviews as Topic; Hashimoto Disease; Thyroxine; Dietary Supplements
PubMed: 37513612
DOI: 10.3390/nu15143194 -
Redox Biology Nov 2023Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in...
Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in inflammation and immune defense. MPO also binds to several proteins, lipids, and DNA to alter their function. MPO is present at the feto-maternal interface during pregnancy, where neutrophils are abundant. In this study, we determined the effect of MPO on JEG-3 human choriocarcinoma cells as a model of extravillous trophoblasts (EVTs) during early pregnancy. We found that MPO was internalized by JEG-3 cells and localized to the cytoplasm and nuclei. MPO internalization and activity enhanced JEG-3 cell migration and invasion, whereas this effect was impaired by pre-treating cells with heparin, to block cellular uptake, and MPO-activity inhibitor 4-ABAH. This study identifies a novel mechanism for the effect of MPO on EVT function during normal pregnancy and suggests a potential role of MPO in abnormal pregnancies.
Topics: Female; Humans; Pregnancy; Cell Line, Tumor; Choriocarcinoma; Peroxidase; Proteins; Trophoblasts
PubMed: 37776707
DOI: 10.1016/j.redox.2023.102885