scholarly journals ALLOPURINOL BLOCKS THE FORMATION AND PROGRESSION OF AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME ACTING AS SCAVENGER OF REACTIVE OXYGEN SPECIES

2021 ◽  
Author(s):  
Isaac Rodriguez-Rovira ◽  
Cristina Arce ◽  
Karo de Rycke ◽  
Belen Perez ◽  
Aitor Carretereo ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Uric Acid ◽  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Nuclear Translocation ◽  
Elastic Fiber ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Redox Stress ◽  
Nitric Oxide Signaling

The pathogenesis and progression of aortic aneurysm in Marfan syndrome (MFS) involves dysregulated TGF-β and nitric oxide signaling, altered hemodynamics, and biomechanical forces. Increasing evidence indicates that redox stress participates in MFS aortopathy development, though its contribution is not well established. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS mice and in patient aortic samples. Here we address the contribution of xanthine dehydrogenase (XDH) which catabolizes purines into uric acid plus ROS. XDH mRNA and protein expression levels are increased in the aorta of young but not older MFS mice (Fbn1C1041G/+). The protein and enzymatic activity of the oxidase form (XO) is increased with respect to the dehydrogenase. In patients, XO protein levels were increased in the dilated and the adjacent non-dilated zone of aortic aneurysm. The palliative administration of the XDH inhibitor allopurinol attenuated the progression of the aortic root aneurysm in MFS mice. Allopurinol was also protective when administrated before the appearance of aneurysm onset. MFS-induced elastic fiber fragmentation, fibrotic remodeling, nuclear translocation of pNRF2, and increased 3-nitrotyrosine levels in the aortic tunica media, as well as endothelial dysfunction, were all prevented by allopurinol. Mechanistically, allopurinol mediates these effects by inhibiting H2O2 overproduction, with no apparent relevance for uric acid, whose plasma levels remained constant with age. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and supports a clinical trial for allopurinol in the pharmacological treatment of MFS aortopathy.

scholarly journals Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation

2019 ◽  
Vol 23 (10) ◽  
pp. 7000-7009 ◽  
Author(s):  
Fabian Emrich ◽  
Kiril Penov ◽  
Mamoru Arakawa ◽  
Nathan Dhablania ◽  
Grayson Burdon ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Marfan Syndrome ◽  
Reactive Oxygen Species Production ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Aneurysm Formation ◽  
Species Production

Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP

2006 ◽  
Vol 290 (5) ◽  
pp. F1169-F1176 ◽  
Author(s):  
Xiaoming Zhou ◽  
Joan D. Ferraris ◽  
Maurice B. Burg
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Reactive Oxygen ◽  
Hek293 Cells ◽  
Organic Osmolytes ◽  
Ros Production ◽  
Oxygen Species ◽  
Hypertonic Stress ◽  
Mitochondrial Ros

Hypertonicity activates the transcription factor tonicity-responsive enhancer/osmotic response element binding protein (TonEBP/OREBP), resulting in increased expression of genes involved in osmoprotective accumulation of organic osmolytes, including glycine betaine, and in increased expression of osmoprotective heat shock proteins. Our previous studies showed that high NaCl increases reactive oxygen species (ROS), which contribute to activation of TonEBP/OREBP. Mitochondria are a major source of ROS. The purpose of the present study was to examine whether mitochondria produce the ROS that contribute to activation of TonEBP/OREBP. We inhibited mitochondrial ROS production in HEK293 cells with rotenone and myxothiazol, which inhibit mitochondrial complexes I and III, respectively. Rotenone (250 nM) and myxothiazol (12 nM) reduce high NaCl-induced ROS over 40%, whereas apocynin (100 μM), an inhibitor of NADPH oxidase, and allopurinol (100 μM), an inhibitor of xanthine oxidase, have no significant effect. Rotenone and myxothiazol reduce high NaCl-induced increases in TonEBP/OREBP transcriptional activity (ORE/TonE reporter assay) and BGT1 (betaine transporter) mRNA abundance ranging from 53 to 69%. They inhibit high NaCl-induced TonEBP/OREBP transactivating activity, but not its nuclear translocation. Release of ATP into the medium on hypertonic stress has been proposed to be a signal that triggers cellular osmotic responses. However, we do not detect release of ATP into the medium or inhibition of high NaCl-induced ORE/TonE reporter activity by an ATPase, apyrase (20 U/ml), indicating that high NaCl-induced activation of TonEBP/OREBP is not mediated by release of ATP. We conclude that high NaCl increases mitochondrial ROS production, which contributes to the activation of TonEBP/OREBP by increasing its transactivating activity.

scholarly journals A Monitoring of Allantoin, Uric Acid, and Malondialdehyde Levels in Plasma and Erythrocytes After Ten Minutes of Running Activity

2014 ◽  
pp. 753-762
Author(s):  
R. KANĎÁR ◽  
X. ŠTRAMOVÁ ◽  
P. DRÁBKOVÁ ◽  
J. KŘENKOVÁ
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Uric Acid ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Intense Exercise ◽  
Suitable Candidate ◽  
Running Activity ◽  
Plasma Malondialdehyde

Uric acid is the final product of human purine metabolism. It was pointed out that this compound acts as an antioxidant and is able to react with reactive oxygen species forming allantoin. Therefore, the measurement of allantoin levels may be used for the determination of oxidative stress in humans. The aim of the study was to clarify the antioxidant effect of uric acid during intense exercise. Whole blood samples were obtained from a group of healthy subjects. Allantoin, uric acid, and malondialdehyde levels in plasma and erythrocytes were measured using a HPLC with UV/Vis detection. Statistical significant differences in allantoin and uric acid levels during short-term intense exercise were found. Immediately after intense exercise, the plasma allantoin levels increased on the average of 200 % in comparison to baseline. Plasma uric acid levels increased slowly, at an average of 20 %. On the other hand, there were no significant changes in plasma malondialdehyde. The results suggest that uric acid, important antioxidant, is probably oxidized by reactive oxygen species to allantoin. Therefore allantoin may be suitable candidate for a marker of acute oxidative stress.

Regulation of IGF binding protein-1 in Hep G2 cells by cytokines and reactive oxygen species

1999 ◽  
Vol 276 (3) ◽  
pp. G719-G727 ◽  
Author(s):  
Charles H. Lang ◽  
Gerald J. Nystrom ◽  
Robert A. Frost
Keyword(s):  
Reactive Oxygen Species ◽  
Nuclear Translocation ◽  
Binding Protein ◽  
Reactive Oxygen ◽  
Free Radical Scavengers ◽  
Oxygen Species ◽  
Hep G2 ◽  
Hep G2 Cells ◽  
Tnf Α ◽  
G2 Cells

The liver is a major site of synthesis for insulin-like growth factor binding protein (IGFBP)-1. Because IGFBP-1 inhibits many anabolic actions of IGF-I, increases in IGFBP-1 may be partly responsible for the decrease in lean body mass observed in catabolic/inflammatory conditions. This study aimed to determine in Hep G2 cells 1) the sensitivity of IGFBP-1 synthesis to treatment with interleukin (IL)-1, tumor necrosis factor-α (TNF-α), and IL-6, 2) the ability of reactive oxygen species (ROS) to enhance IGFBP-1 production, and 3) the role of ROS in mediating cytokine-induced increases in IGFBP-1. Hep G2 cells responded to IL-1β, TNF-α, and IL-6 with maximal 8- to 10-fold increases in IGFBP-1 production. Although the maximal responsiveness of cells treated with TNF-α and IL-6 was 20–30% less than that with IL-1β, cells demonstrated a similar sensitivity to all cytokines (half-maximal responsive dose of ∼10 ng/ml). A low concentration (3 ng/ml) of all three cytokines had an additive effect on IGFBP-1 production. Cytokines also increased IGFBP-1 mRNA. The half-life of IGFBP-1 mRNA was ∼4 h and not altered by IL-1β. Incubation with ROS, including H2O2and nitric oxide (NO) donors, resulted in a relatively smaller increase in IGFBP-1. However, preincubating Hep G2 cells with various free radical scavengers and NO synthase and eicosanoid inhibitors failed to prevent or attenuate cytokine-induced increases in IGFBP-1. Finally, preincubating cells with pyrrolidinedithiocarbamate (PDTC) but not SN50 (inhibitors of nuclear factor-κB activation and nuclear translocation, respectively) attenuated increases in IGFBP-1 induced by IL-1. These results indicate that 1) proinflammatory cytokines directly enhance IGFBP-1 synthesis by stimulating transcription without altering mRNA stability, 2) addition of exogenous ROS also stimulates IGFBP-1 production but to a smaller extent than cytokines, and 3) the cytokine-induced increase in IGFBP-1 production is not mediated by endogenous production of ROS or eicosanoids but appears to at least partially involve a PDTC-sensitive pathway.

scholarly journals Respiratory Syncytial Virus Infection Induces a Reactive Oxygen Species-MSK1-Phospho-Ser-276 RelA Pathway Required for Cytokine Expression

2009 ◽  
Vol 83 (20) ◽  
pp. 10605-10615 ◽  
Author(s):  
Mohammad Jamaluddin ◽  
Bing Tian ◽  
Istvan Boldogh ◽  
Roberto P. Garofalo ◽  
Allan R. Brasier
Keyword(s):  
Gene Expression ◽  
Reactive Oxygen Species ◽  
Respiratory Syncytial Virus ◽  
Inflammatory Response ◽  
Target Gene ◽  
Nuclear Translocation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Target Gene Expression ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a human pathogen that induces airway inflammation, at least in part, by modulating gene expression programs in airway epithelial cells. The presence of RSV replication is detected by the intracellular retinoic acid-inducible gene I (RIG-I) RNA helicase that forms a productive signaling complex with the mitochondrion-anchored MAVS protein, resulting in nuclear translocation of the NF-κB transcription factor. Although nuclear translocation is a prerequisite for activation of the innate inflammatory response, recent studies show that separate pathways governing RelA activation are also required for target gene expression. In this study, we examine the mechanism of RelA phosphorylation and its requirement for RSV-induced gene expression. RSV infection produced a time-dependent RelA phosphorylation on serine (Ser) residues Ser-276 and Ser-536 in parallel with enhanced reactive oxygen species (ROS) stress. Inhibition of RSV-induced ROS inhibited formation of phospho-Ser-276 RelA without affecting phospho-Ser-536 RelA formation. RSV potently induced activation of cytoplasmic mitogen- and stress-related kinase 1 (MSK1) in an ROS-dependent manner. Inhibition of MSK1 using H89 and small interfering RNA knockdown both reduced RSV-induced phospho-Ser-276 RelA formation and expression of a subset of NF-κB-dependent genes. Direct examination of the role of phospho-Ser-276 in target gene expression by expression of a RelA Ser-276-to-Ala site mutation in RelA−/− mouse embryonic fibroblasts showed that the mutation was unable to mediate RSV-induced NF-κB-dependent gene expression. We conclude that RSV induces RelA activation in the innate inflammatory response via a pathway separate from that controlling RelA cytoplasmic release, mediated by ROS signaling to cytoplasmic MSK1 activation and RelA Ser-276 phosphorylation.

scholarly journals HUBUNGAN KADAR ASAM URAT DENGAN KEJADIAN GAGAL JANTUNG AKUT PADA PASIEN HIPERTENSI

e-CliniC ◽  
2015 ◽  
Vol 3 (1) ◽  
Author(s):  
Rezuanto Pualillin ◽  
Starry H. Rampengan ◽  
Frans Wantania
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Reactive Oxygen Species ◽  
Uric Acid ◽  
Acute Heart Failure ◽  
Heart Muscle ◽  
Odds Ratio ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Probability Sampling

Abstract: Long period of hypertension causes enlargement of the heart muscle, which leads to heart failure. Increased uric acid will causes endothelial dysfunction nas a result of the over production of reactive oxygen species (ROS), decrease the amount of nitric oxide (NO), increased rennin production, and the occurrence of inflammatory reactions. This speeds up the deterioration of the heart muscle, causing acute phase of heart failure. This study aimed to determine the relationship between uric acid levels and the incidence of acute heart failure in hypertensive patients in the emergency department and hypertension clinic of Prof. Dr R.D Kandou Hospital in Manado. This was an analytical observation by using the cross-sectional design. By using a non-probability sampling method we found 40 people as samples who had been diagnosed with heart failure due to hypertension. There were 15 samples that had experienced acute heart failure and 25 samples did not. Logistic Regression Test results stated that there was no significant effect of uric acid level with the incidence of acute heart failure (p = 0.188), with the value of the odds ratio of 1.198. Conclusion: There was no correlation between the levels of uric acid with the incidence of acute heart failure in patients with hypertension.Keywords: uricacid, hypertension, acute heart failureAbstrak: Hipertensi yang lama menyebabkan terjadinya pembesaran otot jantung sehingga berdampak pada terjadinya gagal jantung. Peningkatan asam urat juga menyebabkan disfungsi endotel akibat produksi reactive oxygen species (ROS) yang berlebihan, penurunan jumlah nitric oxide(NO), produksi renin meningkat, dan terjadinya reaksi inflamasi. Hal ini mempercepat perburukan otot jantung sehingga terjadi fase akut gagal jantung. Untuk mengetahui hubunganantara kadar asam urat dengan kejadian gagal jantung akut pada pasien hipertensidi instalasi rawat daruratdan poliklinik hipertensi RSUP Prof. Dr. R.D Kandou Manado. Jenis Penelitian ini adalah observasi analitik dengan menggunakan rancangan penelitian potong lintang. Dengan menggunakan metode non-probability sampling didapatkan 40 orang sebagai sampel yang telah didiagnosis menderita gagal jantung akibat hipertensi dimana 15 sampel yang mengalami episode akut dan 25 sampel yang tidak mengalami gagal jantung akut. Hasil Uji Regresi Logistik menyatakan bahwa tidak ada pengaruh yang signifikan antara kadar asam urat dengan kejadian gagal jantung akut (p=0,188), dengan nilai odds ratio sebesar 1,198. Simpulan: Tidak terdapat hubungan antara kadar asam urat dengan kejadian gagal jantung akut pada pasien hipertensi.Abstract: Long period of hypertension causes enlargement of the heart muscle, which leads to heart failure. Increased uric acid will causes endothelial dysfunction nas a result of the over production of reactive oxygen species (ROS), decrease the amount of nitric oxide (NO), increased rennin production, and the occurrence of inflammatory reactions. This speeds up the deterioration of the heart muscle, causing acute phase of heart failure. This study aimed to determine the relationship between uric acid levels and the incidence of acute heart failure in hypertensive patients in the emergency department and hypertension clinic of Prof. Dr R.D Kandou Hospital in Manado. This was an analytical observation by using the cross-sectional design. By using a non-probability sampling method we found 40 people as samples who had been diagnosed with heart failure due to hypertension. There were 15 samples that had experienced acute heart failure and 25 samples did not. Logistic Regression Test results stated that there was no significant effect of uric acid level with the incidence of acute heart failure (p = 0.188), with the value of the odds ratio of 1.198. Conclusion: There was no correlation between the levels of uric acid with the incidence of acute heart failure in patients with hypertension.Keywords: uricacid, hypertension, acute heart failureAbstrak: Hipertensi yang lama menyebabkan terjadinya pembesaran otot jantung sehingga berdampak pada terjadinya gagal jantung. Peningkatan asam urat juga menyebabkan disfungsi endotel akibat produksi reactive oxygen species (ROS) yang berlebihan, penurunan jumlah nitric oxide(NO), produksi renin meningkat, dan terjadinya reaksi inflamasi. Hal ini mempercepat perburukan otot jantung sehingga terjadi fase akut gagal jantung. Untuk mengetahui hubunganantara kadar asam urat dengan kejadian gagal jantung akut pada pasien hipertensidi instalasi rawat daruratdan poliklinik hipertensi RSUP Prof. Dr. R.D Kandou Manado. Jenis Penelitian ini adalah observasi analitik dengan menggunakan rancangan penelitian potong lintang. Dengan menggunakan metode non-probability sampling didapatkan 40 orang sebagai sampel yang telah didiagnosis menderita gagal jantung akibat hipertensi dimana 15 sampel yang mengalami episode akut dan 25 sampel yang tidak mengalami gagal jantung akut. Hasil Uji Regresi Logistik menyatakan bahwa tidak ada pengaruh yang signifikan antara kadar asam urat dengan kejadian gagal jantung akut (p=0,188), dengan nilai odds ratio sebesar 1,198. Simpulan: Tidak terdapat hubungan antara kadar asam urat dengan kejadian gagal jantung akut pada pasien hipertensi.Kata kunci: asam urat, hipertensi, gagal jantung akut: asam urat, hipertensi, gagal jantung akut

scholarly journals Reactive oxygen species induced by uric acid promote NRK‑52E cell apoptosis through the NEK7‑NLRP3 signaling pathway

2021 ◽  
Vol 24 (4) ◽  
Author(s):  
Dongdong Li ◽  
Luobing Wang ◽  
Jiaoying Ou ◽  
Chuanxu Wang ◽  
Jiabao Zhou ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Uric Acid ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Reactive Oxygen ◽  
Oxygen Species
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