Oxidative stress and the impact of prenatal chronic hypoxia on ryanodine receptor generated calcium responses in fetal pulmonary arterial myocytes (1089.11)

Pulmonary arterial hypertension of newborns (PAHN) constitutes a critical condition involving both severe cardiac remodeling and right ventricle dysfunction. One main cause of this condition is perinatal hypoxia and oxidative stress. Thus, it is a public health concern for populations living above 2500 m and in cases of intrauterine chronic hypoxia in lowlands. Still, pulmonary and cardiac impairments in PAHN lack effective treatments. Previously we have shown the beneficial effects of neonatal melatonin treatment on pulmonary circulation. However, the cardiac effects of this treatment are unknown. In this study, we assessed whether melatonin improves cardiac function and modulates right ventricle (RV) oxidative stress. Ten lambs were gestated, born, and raised at 3600 m. Lambs were divided in two groups. One received daily vehicle as control, and another received daily melatonin (1 mg·kg−1·d−1) for 21 days. Daily cardiovascular measurements were recorded and, at 29 days old, cardiac tissue was collected. Melatonin decreased pulmonary arterial pressure at the end of the experimental period. In addition, melatonin enhanced manganese superoxide dismutase and catalase (CAT) expression, while increasing CAT activity in RV. This was associated with a decrease in superoxide anion generation at the mitochondria and NADPH oxidases in RV. Finally, these effects were associated with a marked decrease of oxidative stress markers in RV. These findings support the cardioprotective effects of an oral administration of melatonin in newborns that suffer from developmental chronic hypoxia.

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Abstract 12873: Clonal Hematopoiesis With JAK2V617F Promotes Pulmonary Hypertension Through ALK1

Circulation ◽

10.1161/circ.142.suppl_3.12873 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yusuke KIMISHIMA ◽

Tomofumi Misaka ◽

Tetsuro Yokokawa ◽

Kento Wada ◽

Koki Ueda ◽

...

Keyword(s):

Bone Marrow ◽

Pulmonary Hypertension ◽

Right Ventricular ◽

Chronic Hypoxia ◽

Myeloproliferative Neoplasms ◽

Clonal Hematopoiesis ◽

Stat3 Phosphorylation ◽

Clinical Scenarios ◽

Pulmonary Arterial ◽

The Impact

Rationale: Pulmonary hypertension (PH) is associated with hematological disorders by unclear multifactorial mechanisms. JAK2 V617F is the most frequent driver mutation among the myeloproliferative neoplasms and is recently identified in clonal hematopoiesis. However, the impact of clonal hematopoiesis on PH remains unknown. Objectives: To elucidate the mechanistic relevance of hematopoietic JAK2V617F in the development of PH. Methods: We applied experimental mouse models, mimicking hematological clinical scenarios using Jak2 V617F-transgenic (JAK2 V617F ) mice and recipient mice transplanted with JAK2 V617F bone marrow cells (JAK2 V617F recipients), exposed to chronic hypoxia to induce PH. The presence of JAK2 V617F was also examined prospectively in PH patients. Measurements and Main Results: Increases in right ventricular systolic pressure and right ventricular hypertrophy accompanied by pulmonary arterial structural remodeling after exposure to chronic hypoxia were significantly exacerbated in both JAK2 V617F mice which showed a myeloproliferative neoplasm-phenotype and JAK2 V617F recipients which modeled clonal hematopoiesis compared to corresponding controls. JAK2V617F-expressing neutrophils were specifically accumulated in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines. RNA sequencing identified progressive upregulation of Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions in the enrichment of JAK-STAT-related molecules by JAK2V617F. JAK2V617F-mediated STAT3 phosphorylation upregulated ALK1-Smad1/5/8 signaling. Strikingly, ALK1 inhibition completely rescued the development of PH in JAK2 V617F mice. Furthermore, clonal hematopoiesis with JAK2 V617F was significantly more common in PH patients than in healthy subjects. Conclusions: Our study reveals clonal hematopoiesis with JAK2V617F as a crucial factor that causally leads to PH through ALK1.

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The Impact of Moderate Chronic Hypoxia and Hyperoxia on the Level of Apoptotic and Autophagic Proteins in Myocardial Tissue

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/5786742 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Alexandra Gyongyosi ◽

Laura Terraneo ◽

Paola Bianciardi ◽

Arpad Tosaki ◽

Istvan Lekli ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Hypoxia ◽

Hypoxia Inducible Factor ◽

Redox Balance ◽

Heart Tissue ◽

Protective Mechanism ◽

Protein Levels ◽

Hypoxia Inducible Factor 1 ◽

The Impact ◽

Hypoxic Group

The redox imbalance and the consequent oxidative stress have been implicated in many pathological conditions, including cardiovascular diseases. The lack or the excess of O2 supply can alter the redox balance. The aim of the present study was to understand the heart responses to prolonged hypoxia or hyperoxia and how such situations may activate survival mechanisms or trigger cell death. Seven-week-old Foxn1 mice were exposed to hypoxia (10% O2), normoxia (21% O2), or hyperoxia (30% O2) for 28 days, then the heart tissue was excised and analyzed. The alterations in redox balance, housekeeping protein levels, and autophagic and apoptotic process regulation were studied. The D-ROM test demonstrated an increased oxidative stress in the hypoxic group compared to the hyperoxic group. The level of hypoxia inducible factor-1 (HIF-1α) was increased by hypoxia while HIF-2α was not affected by treatments. Chronic hypoxia activated the biochemical markers of autophagy, and we observed elevated levels of Beclin-1 while LC3B-II and p62 were constant. Nevertheless, we measured significantly enhanced number of TUNEL-positive cells and higher Bax/Bcl2 ratio in hyperoxia with respect to hypoxia. Surprisingly, our results revealed alterations in the level of housekeeping proteins. The expression of α-tubulin, total-actin, and GAPDH was increased in the hypoxic group while decreased in the hyperoxic group. These findings suggest that autophagy is induced in the heart under hypoxia, which may serve as a protective mechanism in response to enhanced oxidative stress. While prolonged hypoxia-induced autophagy leads to reduced heart apoptosis, low autophagic level in hyperoxia failed to prevent the excessive DNA fragmentation.

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Assessment of Superoxide Dismutase and Catalase Evolution in Different Stages of an Experimental Endometriosis

Revista de Chimie ◽

10.37358/rc.17.6.5678 ◽

2017 ◽

Vol 68 (6) ◽

pp. 1381-1383

Author(s):

Allia Sindilar ◽

Carmen Lacramioara Zamfir ◽

Eusebiu Viorel Sindilar ◽

Alin Constantin Pinzariu ◽

Eduard Crauciuc ◽

...

Keyword(s):

Oxidative Stress ◽

Superoxide Dismutase ◽

Antioxidant Enzymes ◽

Reproductive Function ◽

Female Rats ◽

Oxygen Species ◽

Efficient Treatment ◽

Endometrial Cells ◽

Gynecological Disorder ◽

The Impact

Endometriosis is described as a gynecological disorder characterized by the presence of endometrial tissue outside the uterus; extensively explored because of its increasing incidency, with an indubitable diagnostic only after invasive surgery, with no efficient treatment, it has still many aspects to be elucidated. A growing body of facts sustain oxidative stress as a crucial factor between the numerous incriminated factors implicated in endometriosis ethiopathogeny. Reactive oxygen species(ROS) act to decline reproductive function. Our study intends to determine if an experimental model of endometriosis may be useful to assess the impact of oxidative stress on endometrial cells; we have used a murine model of 18 adult Wistar female rats. A fragment from their left uterine horn was implanted in the abdominal wall. After 4 weeks, a laparatomy was performed, 5 endometrial implants were removed, followed by biochemical tissue assay of superoxide dismutase(SOD) and catalase(CAT). At the end of the experiment, the rats were sacrificed, the implants were removed for histopathological exam and biochemical assay of antioxidant enzymes. The results revealed decreased levels of antioxidant enzymes, pointing on significant oxidative stress involvement.

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Evidences of Brain Plasticity and Motor Control Modulation after Hemodialysis Session by Helixone Membrane: BOLD-fMRI Study

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200902133343 ◽

2020 ◽

Vol 19 (6) ◽

pp. 466-477

Author(s):

Saïd Boujraf ◽

Rachida Belaïch ◽

Abdelkhalek Housni ◽

Badreeddine Alami ◽

Tariq Skalli ◽

...

Keyword(s):

Oxidative Stress ◽

Functional Activity ◽

Brain Plasticity ◽

Biological Assessment ◽

Bold Fmri ◽

Before And After ◽

Total Antioxidant ◽

Inflammatory State ◽

Functional Control ◽

The Impact

Objective: The aim of this paper is to demonstrate the impact of hemodialysis (HD) using synthetic Helixone membrane on brain functional control reorganization and plasticity in the cortical area generated while Oxidative Stress (OS) would be the main impacting agent. Methods: Indeed, 9 chronic HD patients underwent identical brain BOLD-fMRI assessment using the motor paradigm immediately before and after the same HD sessions. To assess the oxidative stress, the same patients underwent biological-assessment, including Malondialdehyde (MDA) and Total- Antioxidant-Activity (TAOA) reported in earlier papers. Results: BOLD-fMRI maps of motor areas obtained from HD-patients before and after HD sessions revealed a significant enhancement of activation volume of the studied motor cortex after HD reflecting brain plasticity. Results were correlated with OS assessed by the measurement of MDA and TAOA; this correlation was close to 1. Conclusion: Indeed, HD enhances the inflammatory state of brain tissues reflected by the increased OS. The functional brain reaction demonstrated a functional activity reorganization to overcome the inflammatory state and OS enhanced by HD process. This functional activity reorganization reveals brain plasticity induced by OS originated by HD.

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The Impact of L-Carnitine and Coenzyme Q10 as Protection Against Busulfan-Oxidative Stress in the Liver of Adult Rats

The Natural Products Journal ◽

10.2174/2210315509666190723131511 ◽

2020 ◽

Vol 10 (5) ◽

pp. 578-586

Author(s):

Areeg M. Abdelrazek ◽

Shimaa A. Haredy

Keyword(s):

Oxidative Stress ◽

Coenzyme Q10 ◽

Protective Role ◽

Albino Rats ◽

Distilled Water ◽

Negative Effects ◽

Adult Rats ◽

Stress Damage ◽

The Impact ◽

Liver Tissues

Background: Busulfan (Bu) is an anticancer drug with a variety of adverse effects for cancer patients. Oxidative stress has been considered as a common pathological mechanism and it has a key role in the initiation and progression of liver injury by Bu. Aim: The study aimed to evaluate the antioxidant impact of L-Carnitine and Coenzyme Q10 and their protective role against oxidative stress damage in liver tissues. Methods and Material: Thirty-six albino rats were divided equally into six groups. G1 (con), received I.P. injection of DMSO plus 1 ml of distilled water daily by oral gavages; G2 (Bu), received I.P. injection of Bu plus 1 ml of the distilled water daily; G3 (L-Car), received 1 ml of L-Car orally; G4 (Bu + L-Car) received I.P. injection of Bu plus 1 ml of L-Car, G5 (CoQ10) 1 ml of CoQ10 daily; and G6 (Bu + CoQ10) received I.P. injection of Bu plus 1 ml of CoQ10 daily. Results: The recent data showed that Bu induced significant (P<0.05) elevation in serum ALT, AST, liver GSSG, NO, MDA and 8-OHDG, while showing significant (P<0.05) decrease in liver GSH and ATP. On the other hand, L-Carnitine and Coenzyme Q10 ameliorated the negative effects prompted by Bu. Immunohistochemical expression of caspase-3 in liver tissues reported pathological alterations in Bu group while also showed significant recovery in L-Car more than CoQ10. Conclusion: L-Car, as well as CoQ10, can enhance the hepatotoxic effects of Bu by promoting energy production in oxidative phosphorylation process and by scavenging the free radicals.

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Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats

International Journal of Cardiology ◽

10.1016/j.ijcard.2019.07.078 ◽

2019 ◽

Vol 295 ◽

pp. 14-20 ◽

Cited By ~ 6

Author(s):

Dongzhi Wang ◽

Hailing Li ◽

E. Kenneth Weir ◽

Yawei Xu ◽

Dachun Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Right Heart Failure ◽

Dimethylarginine Dimethylaminohydrolase ◽

Right Heart ◽

Pulmonary Arterial

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Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽

10.3390/cancers13050986 ◽

2021 ◽

Vol 13 (5) ◽

pp. 986

Author(s):

Nada S. Aboelella ◽

Caitlin Brandle ◽

Timothy Kim ◽

Zhi-Chun Ding ◽

Gang Zhou

Keyword(s):

Oxidative Stress ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Redox Homeostasis ◽

Tumor Rejection ◽

Oxygen Species ◽

Antitumor Effects ◽

Key Drivers ◽

Cancer Immunotherapies ◽

The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

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Association of Genetic Polymorphisms in Oxidative Stress and Inflammation Pathways with Glaucoma Risk and Phenotype

Journal of Clinical Medicine ◽

10.3390/jcm10051148 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1148

Author(s):

Makedonka Atanasovska Velkovska ◽

Katja Goričar ◽

Tanja Blagus ◽

Vita Dolžan ◽

Barbara Cvenkel

Keyword(s):

Oxidative Stress ◽

Ocular Hypertension ◽

Gene Deletion ◽

Open Angle Glaucoma ◽

Protective Role ◽

Control Group ◽

Nucleotide Polymorphisms ◽

Gstm1 Gene ◽

Stress Genes ◽

The Impact

Oxidative stress and neuroinflammation are involved in the pathogenesis and progression of glaucoma. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in inflammation and oxidative stress genes on the risk of glaucoma, the patients’ clinical characteristics and the glaucoma phenotype. In total, 307 patients with primary open-angle glaucoma or ocular hypertension were enrolled. The control group included 339 healthy Slovenian blood donors. DNA was isolated from peripheral blood. Genotyping was performed for SOD2 rs4880, CAT rs1001179, GPX1 rs1050450, GSTP1 rs1695, GSTM1 gene deletion, GSTT1 gene deletion, IL1B rs1143623, IL1B rs16944, IL6 rs1800795 and TNF rs1800629. We found a nominally significant association of GSTM1 gene deletion with decreased risk of ocular hypertension and a protective role of IL1B rs16944 and IL6 rs1800629 in the risk of glaucoma. The CT and TT genotypes of GPX1 rs1050450 were significantly associated with advanced disease, lower intraocular pressure and a larger vertical cup–disc ratio. In conclusion, genetic variability in IL1B and IL6 may be associated with glaucoma risk, while GPX and TNF may be associated with the glaucoma phenotype. In the future, improved knowledge of these pathways has the potential for new strategies and personalised treatment of glaucoma.

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