Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 137

Publication Record

Connections

Microvascular disease confers additional risk to COVID-19 infection.
Bale BF, Doneen AL, Vigerust DJ
(2020) Med Hypotheses 144: 109999
MeSH Terms: Adult, Aging, COVID-19, Cardiovascular Diseases, Child, Diabetes Mellitus, Disease Susceptibility, Humans, Hydrogen Peroxide, Hypertension, Hypochlorous Acid, Immunity, Innate, Lung, Microcirculation, Microvessels, Neutrophils, Pandemics, Peroxidase, Risk Factors, United States
Show Abstract · Added June 25, 2020
The majority of fatalities thus far in the COVID-19 pandemic have been attributed to pneumonia. As expected, the fatality rate reported in China is higher in people with chronic pulmonary disease (6.3%) and those who have cancer (5.6%). According to the American College of Cardiology Clinical Bulletin "COVID-19 Clinical Guidance for the CV Care Team", there is a significantly higher fatality rate in people who are elderly (8.0% 70-79 years; 14.8% ≥80 years), diabetic (7.3%), hypertensive (6.0%), or have known cardiovascular disease (CVD) (10.5%). We propose a biological reason for the higher mortality risk in these populations that is apparent. We further present a set of pathophysiological reasons for the heightened danger that could lead to therapies for enhanced management and prevention.
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension.
Dikalov S, Itani H, Richmond B, Vergeade A, Rahman SMJ, Boutaud O, Blackwell T, Massion PP, Harrison DG, Dikalova A
(2019) Am J Physiol Heart Circ Physiol 316: H639-H646
MeSH Terms: Angiotensin II, Animals, Blood Pressure, Calcium Channels, Endothelium, Vascular, Hydrogen Peroxide, Hypertension, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Heart, Oxidative Stress, Superoxide Dismutase, TRPV Cation Channels, Tobacco Smoking, Vasoconstrictor Agents
Show Abstract · Added March 26, 2019
Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial HO in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg·day), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial HO in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Prophylactic Treatment With Simvastatin Modulates the Immune Response and Increases Animal Survival Following Lethal Sepsis Infection.
Braga Filho JAF, Abreu AG, Rios CEP, Trovão LO, Silva DLF, Cysne DN, Nascimento JR, Fortes TS, Silva LA, Guerra RNM, Maciel MCG, Serezani CH, Nascimento FRF
(2018) Front Immunol 9: 2137
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Hydrogen Peroxide, Male, Mice, Sepsis, Simvastatin
Show Abstract · Added March 18, 2020
Chronic use of statins may have anti-inflammatory action, promoting immunomodulation and survival in patients with sepsis. This study aimed to analyze the effects of pretreatment with simvastatin in lethal sepsis induced by cecal ligation and puncture (CLP). Male mice received prophylactic treatment with simvastatin or pyrogen-free water orally in a single daily dose for 30 days. After this period, the CLP was performed. Naïve and Sham groups were performed as non-infected controls. Animal survival was monitored for 60 h after the CLP. Half of mice were euthanized after 12 h to analyze colony-forming units (CFUs); hematological parameters; production of IL-10, IL-12, IL-6, TNF-α, IFN-γ, and MCP-1; cell counts on peritoneum, bronchoalveolar lavage (BAL), bone marrow, spleen, and mesenteric lymph node; immunephenotyping of T cells and antigen presenting cells and production of hydrogen peroxide (HO). Simvastatin induced an increase in survival and a decrease in the CFU count on peritoneum and on BAL cells number, especially lymphocytes. There was an increase in the platelets and lymphocytes number in the Simvastatin group when compared to the CLP group. Simvastatin induced a greater activation and proliferation of CD4+ T cells, as well as an increase in IL-6 and MCP-1 production, in chemotaxis to the peritoneum and in HO secretion at this site. These data suggest that simvastatin has an impact on the survival of animals, as well as immunomodulatory effects in sepsis induced by CLP in mice.
0 Communities
1 Members
0 Resources
MeSH Terms
OxyR Regulates the Transcriptional Response to Hydrogen Peroxide.
Juttukonda LJ, Green ER, Lonergan ZR, Heffern MC, Chang CJ, Skaar EP
(2019) Infect Immun 87:
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Anti-Infective Agents, Local, Gene Expression Regulation, Bacterial, Hydrogen Peroxide, Mice, Oxidants, Repressor Proteins, Stress, Physiological
Show Abstract · Added April 7, 2019
is a Gram-negative opportunistic pathogen that causes diverse infections, including pneumonia, bacteremia, and wound infections. Due to multiple intrinsic and acquired antimicrobial-resistance mechanisms, isolates are commonly multidrug resistant, and infections are notoriously difficult to treat. The World Health Organization recently highlighted carbapenem-resistant as a "critical priority" for the development of new antimicrobials because of the risk to human health posed by this organism. Therefore, it is important to discover the mechanisms used by to survive stresses encountered during infection in order to identify new drug targets. In this study, by use of imaging, we identified hydrogen peroxide (HO) as a stressor produced in the lung during infection and defined OxyR as a transcriptional regulator of the HO stress response. Upon exposure to HO, differentially transcribes several hundred genes. However, the transcriptional upregulation of genes predicted to detoxify hydrogen peroxide is abolished in an strain in which the transcriptional regulator is genetically inactivated. Moreover, inactivation of in both antimicrobial-susceptible and multidrug-resistant strains impairs growth in the presence of HO OxyR is a direct regulator of and , which encode the major HO-degrading enzymes in , as confirmed through measurement of promoter binding by recombinant OxyR in electromobility shift assays. Finally, an mutant is less fit than wild-type during infection of the murine lung. This work reveals a mechanism used by this important human pathogen to survive HO stress encountered during infection.
Copyright © 2018 American Society for Microbiology.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide.
Loperena R, Van Beusecum JP, Itani HA, Engel N, Laroumanie F, Xiao L, Elijovich F, Laffer CL, Gnecco JS, Noonan J, Maffia P, Jasiewicz-Honkisz B, Czesnikiewicz-Guzik M, Mikolajczyk T, Sliwa T, Dikalov S, Weyand CM, Guzik TJ, Harrison DG
(2018) Cardiovasc Res 114: 1547-1563
MeSH Terms: Aged, Angiotensin II, Animals, Blood Pressure, Case-Control Studies, Cell Communication, Cell Differentiation, Cells, Cultured, Coculture Techniques, Disease Models, Animal, Endothelial Cells, Female, Humans, Hydrogen Peroxide, Hypertension, Interleukin-6, Male, Mechanotransduction, Cellular, Mice, Inbred C57BL, Middle Aged, Monocytes, Nitric Oxide, Phenotype, STAT3 Transcription Factor, Stress, Mechanical
Show Abstract · Added March 26, 2019
Aims - Monocytes play an important role in hypertension. Circulating monocytes in humans exist as classical, intermediate, and non-classical forms. Monocyte differentiation can be influenced by the endothelium, which in turn is activated in hypertension by mechanical stretch. We sought to examine the role of increased endothelial stretch and hypertension on monocyte phenotype and function.
Methods and results - Human monocytes were cultured with confluent human aortic endothelial cells undergoing either 5% or 10% cyclical stretch. We also characterized circulating monocytes in normotensive and hypertensive humans. In addition, we quantified accumulation of activated monocytes and monocyte-derived cells in aortas and kidneys of mice with Angiotensin II-induced hypertension. Increased endothelial stretch enhanced monocyte conversion to CD14++CD16+ intermediate monocytes and monocytes bearing the CD209 marker and markedly stimulated monocyte mRNA expression of interleukin (IL)-6, IL-1β, IL-23, chemokine (C-C motif) ligand 4, and tumour necrosis factor α. STAT3 in monocytes was activated by increased endothelial stretch. Inhibition of STAT3, neutralization of IL-6 and scavenging of hydrogen peroxide prevented formation of intermediate monocytes in response to increased endothelial stretch. We also found evidence that nitric oxide (NO) inhibits formation of intermediate monocytes and STAT3 activation. In vivo studies demonstrated that humans with hypertension have increased intermediate and non-classical monocytes and that intermediate monocytes demonstrate evidence of STAT3 activation. Mice with experimental hypertension exhibit increased aortic and renal infiltration of monocytes, dendritic cells, and macrophages with activated STAT3.
Conclusions - These findings provide insight into how monocytes are activated by the vascular endothelium during hypertension. This is likely in part due to a loss of NO signalling and increased release of IL-6 and hydrogen peroxide by the dysfunctional endothelium and a parallel increase in STAT activation in adjacent monocytes. Interventions to enhance bioavailable NO, reduce IL-6 or hydrogen peroxide production or to inhibit STAT3 may have anti-inflammatory roles in hypertension and related conditions.
0 Communities
1 Members
0 Resources
25 MeSH Terms
Sulfenylation of Human Liver and Kidney Microsomal Cytochromes P450 and Other Drug-Metabolizing Enzymes as a Response to Redox Alteration.
Albertolle ME, Phan TTN, Pozzi A, Guengerich FP
(2018) Mol Cell Proteomics 17: 889-900
MeSH Terms: Animals, Biocatalysis, Cysteine, Cytochrome P-450 Enzyme System, Humans, Hydrogen Peroxide, Kidney, Mice, Transgenic, Microsomes, Liver, Oxidation-Reduction, Pharmaceutical Preparations, Recombinant Proteins, Staining and Labeling, Sulfenic Acids, Sulfhydryl Compounds
Show Abstract · Added March 14, 2018
The lumen of the endoplasmic reticulum (ER) provides an oxidizing environment to aid in the formation of disulfide bonds, which is tightly regulated by both antioxidant proteins and small molecules. On the cytoplasmic side of the ER, cytochrome P450 (P450) proteins have been identified as a superfamily of enzymes that are important in the formation of endogenous chemicals as well as in the detoxication of xenobiotics. Our previous report described oxidative inhibition of P450 Family 4 enzymes via oxidation of the heme-thiolate cysteine to a sulfenic acid (-SOH) (Albertolle, M. E. (2017) 292, 11230-11242). Further proteomic analyses of murine kidney and liver microsomes led to the finding that a number of other drug-metabolizing enzymes located in the ER are also redox-regulated in this manner. We expanded our analysis of sulfenylated enzymes to human liver and kidney microsomes. Evaluation of the sulfenylation, catalytic activity, and spectral properties of P450s 1A2, 2C8, 2D6, and 3A4 led to the identification of two classes of redox sensitivity in P450 enzymes: heme-thiolate-sensitive and thiol-insensitive. These findings provide evidence for a mammalian P450 regulatory mechanism, which may also be relevant to other drug-metabolizing enzymes. (Data are available via ProteomeXchange with identifier PXD007913.).
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
1 Members
0 Resources
15 MeSH Terms
Heme-thiolate sulfenylation of human cytochrome P450 4A11 functions as a redox switch for catalytic inhibition.
Albertolle ME, Kim D, Nagy LD, Yun CH, Pozzi A, Savas Ü, Johnson EF, Guengerich FP
(2017) J Biol Chem 292: 11230-11242
MeSH Terms: Animals, Catalysis, Cytochrome P-450 CYP4A, Dithiothreitol, Heme, Humans, Hydrogen Peroxide, Hydroxyeicosatetraenoic Acids, Kidney, Liver, Mice, Mice, Transgenic, Oxidation-Reduction, Rats
Show Abstract · Added March 14, 2018
Cytochrome P450 (P450, CYP) 4A11 is a human fatty acid ω-hydroxylase that catalyzes the oxidation of arachidonic acid to the eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE), which plays important roles in regulating blood pressure regulation. Variants of P450 4A11 have been associated with high blood pressure and resistance to anti-hypertensive drugs, and 20-HETE has both pro- and antihypertensive properties relating to increased vasoconstriction and natriuresis, respectively. These physiological activities are likely influenced by the redox environment, but the mechanisms are unclear. Here, we found that reducing agents ( dithiothreitol and tris(2-carboxyethyl)phosphine) strongly enhanced the catalytic activity of P450 4A11, but not of 10 other human P450s tested. Conversely, added HO attenuated P450 4A11 catalytic activity. Catalytic roles of five of the potentially eight implicated Cys residues of P450 4A11 were eliminated by site-directed mutagenesis. Using an isotope-coded dimedone/iododimedone-labeling strategy and mass spectrometry of peptides, we demonstrated that the heme-thiolate cysteine (Cys-457) is selectively sulfenylated in an HO concentration-dependent manner. This sulfenylation could be reversed by reducing agents, including dithiothreitol and dithionite. Of note, we observed heme ligand cysteine sulfenylation of P450 4A11 e in kidneys and livers derived from transgenic mice. We also detected sulfenylation of murine P450 4a12 and 4b1 heme peptides in kidneys. To our knowledge, reversible oxidation of the heme thiolate has not previously been observed in P450s and may have relevance for 20-HETE-mediated functions.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Reactive Oxygen Species Shielding Hydrogel for the Delivery of Adherent and Nonadherent Therapeutic Cell Types.
Dollinger BR, Gupta MK, Martin JR, Duvall CL
(2017) Tissue Eng Part A 23: 1120-1131
MeSH Terms: Animals, Cell Adhesion, Cell Count, Cell Death, Cytoprotection, Humans, Hydrogels, Hydrogen Peroxide, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Mice, Polymers, Reactive Oxygen Species, Rheology
Show Abstract · Added March 14, 2018
Cell therapies suffer from poor survival post-transplant due to placement into hostile implant sites characterized by host immune response and innate production of high levels of reactive oxygen species (ROS). We hypothesized that cellular encapsulation within an injectable, antioxidant hydrogel would improve viability of cells exposed to high oxidative stress. To test this hypothesis, we applied a dual thermo- and ROS-responsive hydrogel comprising the ABC triblock polymer poly[(propylene sulfide)-block-(N,N-dimethyl acrylamide)-block-(N-isopropylacrylamide)] (PPS-b-PDMA-b-PNIPAAM, PDN). The PPS chemistry reacts irreversibly with ROS such as hydrogen peroxide (HO), imparting inherent antioxidant properties to the system. Here, PDN hydrogels were successfully integrated with type 1 collagen to form ROS-protective, composite hydrogels amenable to spreading and growth of adherent cell types such as mesenchymal stem cells (MSCs). It was also shown that, using a control hydrogel substituting nonreactive polycaprolactone in place of PPS, the ROS-reactive PPS chemistry is directly responsible for PDN hydrogel cytoprotection of both MSCs and insulin-producing β-cell pseudo-islets against HO toxicity. In sum, these results establish the potential of cytoprotective, thermogelling PDN biomaterials for injectable delivery of cell therapies.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection.
Salina AC, Souza TP, Serezani CH, Medeiros AI
(2017) Innate Immun 23: 219-227
MeSH Terms: Animals, Apoptosis, Bacteriolysis, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Dinoprostone, Female, Homeostasis, Humans, Hydrogen Peroxide, Jurkat Cells, Macrophages, Alveolar, Phagocytosis, Pneumococcal Infections, Rats, Rats, Wistar, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Streptococcus pneumoniae
Show Abstract · Added May 4, 2017
Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of HO production. Our data suggest that the PGE produced by AMs during efferocytosis inhibits HO production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.
0 Communities
1 Members
0 Resources
20 MeSH Terms
The PAS Domain-Containing Protein HeuR Regulates Heme Uptake in Campylobacter jejuni.
Johnson JG, Gaddy JA, DiRita VJ
(2016) mBio 7:
MeSH Terms: Animals, Bacterial Proteins, Campylobacter jejuni, Catalase, Chickens, Gastrointestinal Tract, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Heme, Humans, Hydrogen Peroxide, Iron, Mutation
Show Abstract · Added April 26, 2017
Campylobacter jejuni is a leading cause of bacterially derived gastroenteritis. A previous mutant screen demonstrated that the heme uptake system (Chu) is required for full colonization of the chicken gastrointestinal tract. Subsequent work identified a PAS domain-containing regulator, termed HeuR, as being required for chicken colonization. Here we confirm that both the heme uptake system and HeuR are required for full chicken gastrointestinal tract colonization, with the heuR mutant being particularly affected during competition with wild-type C. jejuni Transcriptomic analysis identified the chu genes-and those encoding other iron uptake systems-as regulatory targets of HeuR. Purified HeuR bound the chuZA promoter region in electrophoretic mobility shift assays. Consistent with a role for HeuR in chu expression, heuR mutants were unable to efficiently use heme as a source of iron under iron-limiting conditions, and mutants exhibited decreased levels of cell-associated iron by mass spectrometry. Finally, we demonstrate that an heuR mutant of C. jejuni is resistant to hydrogen peroxide and that this resistance correlates to elevated levels of catalase activity. These results indicate that HeuR directly and positively regulates iron acquisition from heme and negatively impacts catalase activity by an as yet unidentified mechanism in C. jejuni IMPORTANCE: Annually, Campylobacter jejuni causes millions of gastrointestinal infections in the United States, due primarily to its ability to reside within the gastrointestinal tracts of poultry, where it can be released during processing and contaminate meat. In the developing world, humans are often infected by consuming contaminated water or by direct contact with livestock. Following consumption of contaminated food or water, humans develop disease that is characterized by mild to severe diarrhea. There is a need to understand both colonization of chickens, to make food safer, and colonization of humans, to better understand disease. Here we demonstrate that to efficiently colonize a host, C. jejuni requires iron from heme, which is regulated by the protein HeuR. Understanding how HeuR functions, we can develop ways to inhibit its function and reduce iron acquisition during colonization, potentially reducing C. jejuni in the avian host, which would make food safer, or limiting human colonization.
Copyright © 2016 Johnson et al.
0 Communities
1 Members
0 Resources
13 MeSH Terms