Abstract 238: S-nitrosoglutathione Reductase (GSNOR) Plays a Critical Role in Placental Vascularization Working Through the VEGF-NO Pathway

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Shathiyah Kulandavelu ◽  
Michael A Bellio ◽  
Julia Fritsch ◽  
Wayne Balkan ◽  
Joshua M Hare
Keyword(s):  
Nitrosative Stress ◽  
Critical Role ◽  
Late Pregnancy ◽  
Protein S ◽  
Capillary Density ◽  
Fetal Mortality ◽  
Mortality And Morbidity ◽  
Working Through ◽  
Concentric Hypertrophy ◽  
Enos Protein

Introduction: Preeclampsia (PE), a leading cause of maternal and fetal mortality and morbidity, is characterized by increased levels of reactive oxygen species (ROS) and S-nitrosylated protein, and decreased levels of the antioxidant, ascorbate (Asc), which is required for the release of nitric oxide (NO) from nitrosylated proteins. Mice lacking S-nitrosoglutathione reductase (GSNOR –/– ), a denitrosylase that regulates protein S-nitrosylation, exhibit a PE-like phenotype including maternal hypertension, cardiac concentric hypertrophy and impaired placental vascularization. We hypothesized that impaired placental vascularization, one of the primary causes of preeclampsia is mediated by alteration in S-nitrosylation of the VEGF-NO pathway, and ascorbate treatment rescues this pathologic phenotype. Methods: Pregnant GSNOR –/– and control (WT) mice (n=5-7) were studied at late pregnancy (day 17.5). Ascorbate was provided in drinking water beginning at day 0.5. Fetoplacental capillary density was determined from isolectin staining and reactive nitrosative stress determined from nitrotyrosine staining in placental sections. S-nitrosylation of VEGF was determined using SNO-Rac and eNOS levels by Western blot analysis. Results: Fetoplacental capillary density was reduced 19% in GSNOR –/– fetuses compared to WT (P<0.001). GSNOR –/– placentas exhibited higher nitrotyrosine staining than WT placentas, indicating the presence of nitrosative stress. These increases were associated with reduced level of eNOS protein (P<0.05) and decreased S-nitrosylation of VEGF (P<0.05) in the GSNOR –/– placentas as compared to WT. Ascorbate treatment decreased nitrotyrosine staining, and increased fetoplacental capillary density ~10% (P<0.001), eNOS protein levels (P<0.05) and S-nitrosylation of VEGF (P<0.05) in the GSNOR –/– placentas as compared to WT. Conclusion: These findings suggest that GSNOR plays an essential role in promoting placental vascularization in part working through the VEGF-NO pathway. Ascorbate treatment rescued the nitrosative stress and improved placental vascularization, suggesting that it can be used therapeutically to treat or prevent preeclampsia.

Abstract 66: Ascorbate Prevents Hypertension, Proteinuria and Concentric Hypertrophy by Balancing the Nitroso-redox System in a Model of Preeclampsia, the S-nitrosoglutathione Reductase (gsnor) Deficient Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Shathiyah Kulandavelu ◽  
Raul A Dulce ◽  
Rosemeire K Takeuchi ◽  
Wayne Balkan ◽  
Joshua M Hare
Keyword(s):  
Nitrosative Stress ◽  
Fluorescent Dyes ◽  
Protein S ◽  
Redox System ◽  
Fetal Mortality ◽  
Mortality And Morbidity ◽  
Redox Imbalance ◽  
Concentric Hypertrophy ◽  
Maternal Hypertension ◽  
And Control

Introduction: Preeclampsia (PE), a leading cause of maternal and fetal mortality and morbidity, is characterized by increased levels of reactive oxygen species (ROS) and S-nitrosylated protein, and decreased levels of the antioxidant, ascorbate (Asc). Mice lacking S-nitrosoglutathione reductase (GSNOR –/– ), a denitrosylase that regulates protein S-nitrosylation, exhibit a PE-like phenotype including maternal hypertension, proteinuria, cardiac concentric hypertrophy and impaired placental vascularization. We hypothesize that the PE-like phenotype is mediated by nitroso-redox imbalance and nitrosative stress and can be rescued with ascorbate treatment. Methods: Pregnant GSNOR –/– and control (WT) mice (n=5-7) were provided drinking water ± Asc beginning at day 0.5 of gestation (E0.5). We determined blood pressure using a Millar catheter, relative wall thickness (RWT) by echocardiography, and placental vascularization by isolectin staining. Cardiomyocytes (CM) were isolated at late stage pregnancy (E17.5) and fluorescent dyes used to determine levels of ROS (2’7’-dichlorofluorescein), nitric oxide (NO, diaminofluorescin) and peroxynitrite (dihydrorhodamine 123). Results: Isolated CMs from pregnant GSNOR –/– hearts, exhibited elevated levels of ROS (2.48±0.39 vs. 1.58±0.18 ΔF/F 0 ), free NO (6.65±0.43 vs. 5.59±0.26 ΔF/F 0 ) and peroxynitrite (0.75±0.04 vs. 0.39±0.03 ΔF/F 0 ) compared to WT. These increases were prevented with Asc treatment (P<0.01), which completely rescued the PE phenotype in GSNOR –/– mothers, including hypertension (105±2 mmHg vs. 95± mmHg in Asc-treated, P<0.05), proteinuria (P<0.05) and RWT (0.56±0.04 vs. 0.45±0.03 in Asc-treated (P<0.05). Placental vascularization was also significantly improved with Asc treatment in GSNOR –/– mothers. Asc had no significant effect in WT mice. Conclusion: Our findings indicate that nitroso-redox imbalance and nitrosative stress contributes to PE in mice. Asc treatment balanced the nitroso-redox system and rescued the pathological phenotypes in GSNOR –/– mice, suggesting that it can be used therapeutically to treat or prevent preeclampsia.

scholarly journals S-nitrosoglutathione reductase deficiency causes aberrant placental S-nitrosylation and preeclampsia

2020 ◽  
Author(s):  
Shathiyah Kulandavelu ◽  
Raul A Dulce ◽  
Christopher I Murray ◽  
Michael A Bellio ◽  
Julia Fritsch ◽  
...  
Keyword(s):  
Nitrosative Stress ◽  
Protein S ◽  
Fetal Mortality ◽  
Oxygen Species ◽  
Fetal Growth Retardation ◽  
Amino Acid Residues ◽  
Mortality And Morbidity ◽  
Therapeutic Implications ◽  
Concentric Hypertrophy ◽  
The Difference

ABSTRACTPreeclampsia (PE), a leading cause of maternal and fetal mortality and morbidity, is characterized by an increase in S-nitrosylated (SNO) proteins and reactive oxygen species (ROS), suggesting a pathophysiologic role for dysregulation in nitrosylation and nitrosative stress. Here we show that mice lacking S-nitrosoglutathione reductase (GSNOR−/−), a denitrosylase regulating protein S-nitrosylation, exhibit a PE phenotype, including hypertension, proteinuria, renal pathology, cardiac concentric hypertrophy, decreased placental vascularization, and fetal growth retardation. ROS, nitric oxide (NO) and peroxynitrite levels are elevated. Importantly, mass spectrometry reveals elevated placental SNO-amino acid residues in GSNOR−/−mice. Ascorbate reverses the phenotype except for fetal weight, reduces the difference in the S-nitrosoproteome, and identifies a unique set of SNO-proteins in GSNOR−/−mice. Importantly, the human preeclamptic placenta exhibits decreased GSNOR activity and increased nitrosative stress. Therefore, deficiency of GSNOR creates dysregulation of placental S-nitrosylation and preeclampsia in mice, which can be rescued by ascorbate. Coupled with similar findings in human placentas, these findings offer valuable insights and therapeutic implications for PE.

Interleukin-6 and Malondialdehyde in Women with Preterm Birth

2019 ◽  
Vol 15 (2) ◽  
pp. 207-212
Author(s):  
Vinita Verma ◽  
Hina Oza ◽  
Riddhi Thaker ◽  
Sunil Kumar
Keyword(s):  
Oxidative Stress ◽  
Preterm Birth ◽  
Interleukin 6 ◽  
Critical Role ◽  
Serum Levels ◽  
Maternal Serum ◽  
Full Term ◽  
Mortality And Morbidity ◽  
Term Birth ◽  
Weak Negative Correlation

Background: Preterm Birth (PTB) is one of the main causes of neonatal death and infant mortality and morbidity. The pro-inflammatory cytokine interleukin-6 (IL-6) is a major proinflammatory mediator of the host response to infection and malondialdehyde (MDA) is a marker of oxidative stress. Objective : To evaluate potential associations between IL-6 and MDA levels in women with preterm birth. Method: A total of 150 women (66 with full-term and 84 with PTB) were enrolled in this case-control study. Predesigned performas were filled through questionnaire interviews to collect data on personal, demographic, occupational, lifestyle and reproductive history. Blood samples were collected within 36 hours of delivery. Serum concentrations of IL-6 and MDA were determined in mothers with full-term and preterm birth. Results: The mean age was marginally higher; whereas BMI was slightly lower in cases (PTB) as compared to controls (full-term) subjects. Serum IL-6 and MDA levels were significantly higher in subjects with PTB than full-term birth. The data were further analyzed with respect to underweight, normal and overweight/obese BMI. In all the BMI categories, the levels of IL-6 and MDA were higher in PTB cases. Among the PTB categories, the levels of IL-6 and MDA were highest in moderate to late preterm birth. A significant positive correlation was found between IL-6 and MDA levels. There was a weak negative correlation between either IL-6 or MDA and the number of gestational weeks. Conclusion : Elevated maternal serum levels of Interleukin-6 and Malondialdehyde in preterm as compared to full-term birth might suggest that inflammation and oxidative stress play a critical role in PTB.

scholarly journals Perinatal Findings in Pregnancy Induced Hypertension: A Study in a Tertiary Teaching Hospital in Dhaka City

2017 ◽  
Vol 2 (1) ◽  
pp. 10-13
Author(s):  
Zobaida Sultana Susan ◽  
Surayea Bulbul ◽  
Jannat Ara Ferdows ◽  
Abu Nayeem
Keyword(s):  
Cross Sectional Study ◽  
Fetal Mortality ◽  
Pregnancy Induced Hypertension ◽  
College Hospital ◽  
Cross Sectional ◽  
Mortality And Morbidity ◽  
Tertiary Teaching ◽  
Induced Hypertension ◽  
Questionnaire Result ◽  
In Pregnancy

Background: Hypertensive disorders are common complication occurring during pregnancy which are responsible for maternal and fetal mortality and morbidity. Objective: The purpose of the present study was to determine the perinatal outcome in pregnancy induced hypertension. Methodology: This study was designed as cross-sectional study and was conducted from April 2013 to September 2013 for a period of six (06) moths. Patients admitted in the Department of Obstetrics and Gynaecology at Shaheed SuhrawardyMedical College Hospital, Dhaka. Data were collected by interview, physical examintions (blood pressure, pulse rate, oedema, heart and lungs auscultation) and lab investigations using a structural questionnaire. Result: Majority of the women belonged to age group 21-25 year. Maximum were (56%) primigravida. The mean gestational age was 34.6 weeks with the range from 28 to 40 weeks. Hyperurecaemia was frequent among patients with pregnancy induced hypertension. Intrauterine growth retardation (IUGR) was secondary to pregnancy induced hypertension which was associated with significantly increased perinatalmortality. Conclusion: In this study, prematurity is frequent in pregnancy induced hypertension and convulsion in nonresponsive patients is associated with significantly increased perinatal mortality.Journal of National Institute of Neurosciences Bangladesh, January 2016;2(1): 10-13

scholarly journals Zinc deficiency may play a crucial role in dialysis-associated bacterial infections

2020 ◽  
Vol 11 (1) ◽  
pp. e9-e9
Author(s):  
Zahra Lotfi ◽  
Abbas Ali Zeraati ◽  
Elaheh Dashti ◽  
Tina Zeraati ◽  
Maryam Arghiany ◽  
...  
Keyword(s):  
Zinc Deficiency ◽  
Bacterial Infections ◽  
Critical Role ◽  
Serum Zinc ◽  
Zinc Level ◽  
Healthy Individuals ◽  
Mortality And Morbidity ◽  
Increased Risk ◽  
The Mean

Introduction: Systemic bacterial infections are a common cause of mortality and morbidity in hemodialysis patients. Zinc has a critical role in several immune system functions. Patients who have enough amounts of zinc are able to better face infections caused by various pathogens in comparison to those with zinc insufficiency Objective We sought to assess the role of zinc deficiency in dialysis-associated bacterial infections. Patients and Methods: Eighty-Three adult patients with end-stage renal disease (ESRD) on hemodialysis including 43 patients with bacterial infectious complications and 40 non-infected patients as well as 41 healthy individuals were enrolled. Clinical data, laboratory values including serum zinc level and imaging findings were collected. SPSS was utilized to analyze the data with a significance cutoff set at P < 0.05. Results: Out of 124 participants, 80 (64.51%) were males and 44 (35.49%) were females. The mean age of infected hemodialysis group, non-infected hemodialysis group, and healthy controls were 50.8 ± 16.25, 49.1 ± 18.1, and 56.3 ± 18.2 years, respectively. Catheter site infection (37.3%) and urinary tract infection (30.2%) were the most common infections. The mean serum zinc concentration was significantly lower in the infected patients, compared to non-infected patients and healthy individuals (P < 0.001). Conclusion: The ESRD patients on hemodialysis have lower serum zinc levels which are associated with increased risk of bacterial infection. The role of screening for zinc deficiency and use of supplemental zinc in these patients need to be studied.

scholarly journals Venous Thromboembolic Disease and Bone Marrow Transplant: A Remarkable Cause of Mortality and Morbidity — Potentially Preventable

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5070-5070
Author(s):  
Marta Rivas Luque ◽  
Estefanía Morente Constantin ◽  
Pablo Romero Garcia ◽  
Maria Almudena Garcia-Ruiz ◽  
Manuel Jurado
Keyword(s):  
Medical History ◽  
Conflicts Of Interest ◽  
Protein S ◽  
Marrow Transplant ◽  
Morbidity And Mortality ◽  
Hematopoietic Stem ◽  
Mortality And Morbidity ◽  
Vein Thrombosis ◽  
Venous Thromboembolic ◽  
Hemorrhagic Risk

Abstract Thrombotic events are frequent in patients undergoing HSCT, being an important cause of morbidity and mortality. The highest incidence occurs three months after the transplant. There are several risk factors, which add to those already known for VTE: neoplasia, central venous catheters, immobilization, chemotherapy, infections, GVHD. In the series described, the frequencies are variable, between 0.5 and 23.5%, with an overall incidence of 5%. In patients with GVHD, this incidence increases, with up to 35% of events. METHODS A retrospective observational study that includes patients transplanted in our Unit between 2014 and 2017 has been conducted, with the objective of analyzing the incidence of VTE peri-TPH. Likewise, we have analyzed if it is associated to catheter, presence of CVRF, if there was a known medical history of thrombophilia, number of platelets at time of thrombosis, the heparin used and whether anticoagulation was maintained indefinitely or not. RESULTS Out of the 235 patients included in our series, 130 underwent an autologous transplant and 105 an allogeneic transplant. 18 thrombotic events occurred (9 men and 9 women, aged between 18 and 65 years), which means 7.5% (14 occurred between days 0-100, 12 in patients undergoing autologous hematopoietic stem cell transplantation). Three of them had thromboembolism and the rest deep vein thrombosis, 4 of which with catheter. The platelet count at the time of the event ranges from 21 to 409,000 / mm3. Regarding the heparin used, 2 were treated with Tinzaparin and the rest with Bemiparin. Only 1 of the patients presented prior VTE. Among the patients, there were some with CVRF and others without relevant medical history. Just in one patient, a family thrombophilia study had been performed prior to his hematological diagnosis, resulting in a deficit of protein S. In 8 of the patients, anticoagulation was maintained indefinitely with LMWH in the post-transplant period. CONCLUSIONS Our incidence approaches the literature, albeit the series of published cases are heterogeneous and with variable differences. Although the incidence of thrombosis in these patients is a cause of marked morbidity and mortality, the risk of bleeding also increases, therefore routine prophylaxis is not recommended in all patients. We must undergo an exhaustive analysis of the data to identify individually which patients may be candidates for prophylaxis, with the aim of reducing the incidence without raising the hemorrhagic risk of our patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting Inflammasome Activation in COVID-19: Delivery of RNA Interference-Based Therapeutic Molecules

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1823
Author(s):  
Lealem Gedefaw ◽  
Sami Ullah ◽  
Thomas M. H. Lee ◽  
Shea Ping Yip ◽  
Chien-Ling Huang
Keyword(s):  
Rna Interference ◽  
Effective Treatment ◽  
Critical Role ◽  
Treatment Strategies ◽  
Drug Efficacy ◽  
Immune Dysregulation ◽  
Inflammasome Activation ◽  
Mortality And Morbidity ◽  
Therapeutic Molecules ◽  
Non Coding Rnas

Mortality and morbidity associated with COVID-19 continue to be significantly high worldwide, owing to the absence of effective treatment strategies. The emergence of different variants of SARS-CoV-2 is also a considerable source of concern and has led to challenges in the development of better prevention and treatment strategies, including vaccines. Immune dysregulation due to pro-inflammatory mediators has worsened the situation in COVID-19 patients. Inflammasomes play a critical role in modulating pro-inflammatory cytokines in the pathogenesis of COVID-19 and their activation is associated with poor clinical outcomes. Numerous preclinical and clinical trials for COVID-19 treatment using different approaches are currently underway. Targeting different inflammasomes to reduce the cytokine storm, and its associated complications, in COVID-19 patients is a new area of research. Non-coding RNAs, targeting inflammasome activation, may serve as an effective treatment strategy. However, the efficacy of these therapeutic agents is highly dependent on the delivery system. MicroRNAs and long non-coding RNAs, in conjunction with an efficient delivery vehicle, present a potential strategy for regulating NLRP3 activity through various RNA interference (RNAi) mechanisms. In this regard, the use of nanomaterials and other vehicle types for the delivery of RNAi-based therapeutic molecules for COVID-19 may serve as a novel approach for enhancing drug efficacy. The present review briefly summarizes immune dysregulation and its consequences, the roles of different non-coding RNAs in regulating the NLRP3 inflammasome, distinct types of vectors for their delivery, and potential therapeutic targets of microRNA for treatment of COVID-19.

Diagnosis and Treatment of States of Shock

2017 ◽  
Author(s):  
Ahmed Reda Taha
Keyword(s):  
Arterial Pressure ◽  
Cardiogenic Shock ◽  
Hypovolemic Shock ◽  
Tissue Perfusion ◽  
Capillary Density ◽  
Clinical Syndrome ◽  
Clinical Indication ◽  
Hemodynamic Parameters ◽  
Metabolic Markers ◽  
Mortality And Morbidity

Shock remains a diagnosis of significant mortality and morbidity. The current definition defines shock as an acute clinical syndrome that results from inadequate tissue perfusion, which is significantly different from the previous definition of hypotension. Clinical manifestation varies broadly, and is based on the underlying etiology, degree of organ perfusion, and previous organ dysfunction. This review covers the classification, pathogenesis and organ response, evaluation, and management of shock. Figures show the balance between oxygen delivery and oxygen consumption, perfused capillary density, the Krogh Cylinder Model demonstrating the Anoxic-Hypercapnic Lethal Corner, the relation between systolic blood pressure, mean arterial pressure, and diastolic arterial pressure, glycolysis, and the approach to the patient with shock. Tables list clinical and metabolic markers of perfusion alteration to the organs, hemodynamic parameters in different types of shock, normal hemodynamic parameters, problems associated with the use of pulmonary artery catheter, clinical presentation of hypovolemic shock according to severity, causes of cardiogenic shock and cardiogenic pulmonary edema, and receptor activity of different vaspressors and clinical indication. This review contains 6 figures, 7 tables, and 55 references. Key Words: Shock; Hypovolemic shock; Cardiogenic shock; Neurogenic shock; Vasogenic shock; Septic shock; Obstructive shock

Abstract 484: Nitrosative Stress Enhances S-nitrosation Of Peroxiredoxins In The Heart

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Michael Reinartz ◽  
Zhaoping Ding ◽  
Axel Gödecke ◽  
Jürgen Schrader
Keyword(s):  
Nitric Oxide ◽  
Nitrosative Stress ◽  
Protein S ◽  
List Type ◽  
Basal Expression ◽  
Protein Thiols ◽  
Wide Range ◽  
Well Data ◽  
Oxide Synthase ◽  
Biotin Switch

Nitric oxide (NO) is produced by different isoforms of NO-synthases and operates as a mediator of important cell signaling pathways. To explore thiol-based protein modifications in a situation of nitrosative stress, two transgenic mouse models recently generated in our laboratory were used: Cardiac specific overexpression of inducible nitric oxide synthase (iNOS) (tg-iNOS + ) and tg-iNOS + with concomitant myoglobin-deficiency (tg-iNOS + /myo −/− ). Protein S-nitrosation, an important redox-based posttranslational modification, revealed no differences between WT and tg-iNOS + hearts as measured by the biotin-switch assay and 2-D PAGE. Even in the absence of myoglobin - an efficient endogenous NO-oxidase - the protein S-nitrosation pattern for nearly all the detected proteins (>40) remained unchanged in the tg-iNOS + /myo −/− hearts, with the exception of three proteins. Tandem mass spectrometry uncovered these proteins as peroxiredoxins (Prx II, III, VI), which are known to possess peroxidase activity, whereby hydrogen peroxide, peroxynitrite and a wide range of organic hydroperoxides are reduced and detoxified. To prove whether the higher abundance of the Prxs was due to enhanced S-nitrosation or due to changes in their basal expression levels, immunoblotting with specific antibodies was applied and revealed upregulation of Prx VI in tg-iNOS + /myo −/− hearts. The other proteins found to be S-nitrosated were identified as well. Data mining indicated a significant overlap of these proteins with proteins becoming glutathiolated. Protein glutathiolation detected by immunoblotting was enhanced in the tg-iNOS + hearts and even more so in the tg-iNOS + /myo −/− hearts. We conclude that protein glutathiolation in our transgenic model of nitrosative stress is important to protect protein thiols from irreversible oxidation. The upregulation of antioxidant proteins like Prx VI appears to be an additional mechanism to antagonize an excess of reactive oxygen/nitrogen species. Enhanced S-nitrosation of the Prxs may serve a new function in the signalling cascade coping with nitrosative stress.

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