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Article ; Online: Endogenous generation of nitro-fatty acid hybrids having dual nitrate ester (RONO2) and nitroalkene (RNO2) substituents

Marco Fazzari / Steven R. Woodcock / Pascal Rowart / Karina Ricart / Jack R. Lancaster, Jr. / Rakesh Patel / Dario A. Vitturi / Bruce A. Freeman / Francisco J. Schopfer

Redox Biology, Vol 41, Iss , Pp 101913- (2021)

2021

Abstract: Organic nitrate esters, long-recognized therapies for cardiovascular disorders, have not been detected biologically. We characterize in rat stomach unsaturated fatty acid nitration reactions that proceed by generation of nitro-nitrate intermediates (NO2– ... ...

Abstract	Organic nitrate esters, long-recognized therapies for cardiovascular disorders, have not been detected biologically. We characterize in rat stomach unsaturated fatty acid nitration reactions that proceed by generation of nitro-nitrate intermediates (NO2–ONO2-FA) via oxygen and nitrite dependent reactions. NO2–ONO2-lipids represent ∼70% of all nitrated lipids in the stomach and they decay in vitro at neutral or basic pH by the loss of the nitrate ester group (-ONO2) from the carbon backbone upon deprotonation of the α-carbon (pKa ∼7), yielding nitrate, nitrite, nitrosative species, and an electrophilic fatty acid nitroalkene product (NO2-FA). Of note, NO2-FA are anti-inflammatory and tissue-protective signaling mediators, which are undergoing Phase II trials for the treatment of kidney and pulmonary diseases. The decay of NO2–ONO2-FA occurs during intestinal transit and absorption, leading to the formation of NO2-FA that were subsequently detected in circulating plasma triglycerides. These observations provide new insight into unsaturated fatty acid nitration mechanisms, identify nitro-nitrate ester-containing lipids as intermediates in the formation of both secondary nitrogen oxides and electrophilic fatty acid nitroalkenes, and expand the scope of endogenous products stemming from metabolic reactions of nitrogen oxides.
Keywords	Nitro-nitrate-fatty acid ; Nitro-conjugated linoleic acid ; Conjugated linoleic acid ; Fatty acid nitroalkene ; Nitrate ester ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	540 ; 571
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA.

Woodcock, Clayton B / Horton, John R / Zhou, Jujun / Bedford, Mark T / Blumenthal, Robert M / Zhang, Xing / Cheng, Xiaodong

Nucleic acids research

2020 Volume 48, Issue 18, Page(s) 10329–10341

Abstract: The recently characterized mammalian writer (methyltransferase) and eraser (demethylase) of the DNA N6-methyladenine (N6mA) methyl mark act on single-stranded (ss) and transiently-unpaired DNA. As YTH domain-containing proteins bind N6mA-containing RNA ... ...

Abstract	The recently characterized mammalian writer (methyltransferase) and eraser (demethylase) of the DNA N6-methyladenine (N6mA) methyl mark act on single-stranded (ss) and transiently-unpaired DNA. As YTH domain-containing proteins bind N6mA-containing RNA in mammalian cells, we investigated whether mammalian YTH domains are also methyl mark readers of N6mA DNA. Here, we show that the YTH domain of YTHDC1 (known to localize in the nucleus) binds ssDNA containing N6mA, with a 10 nM dissociation constant. This binding is stronger by a factor of 5 than in an RNA context, tested under the same conditions. However, the YTH domains of YTHDF2 and YTHDF1 (predominantly cytoplasmic) exhibited the opposite effect with ∼1.5-2× stronger binding to ssRNA containing N6mA than to the corresponding DNA. We determined two structures of the YTH domain of YTHDC1 in complex with N6mA-containing ssDNA, which illustrated that YTHDC1 binds the methylated adenine in a single-stranded region flanked by duplexed DNA. We discuss the hypothesis that the writer-reader-eraser of N6mA-containining ssDNA is associated with maintaining genome stability. Structural comparison of YTH and SRA domains (the latter a DNA 5-methylcytosine reader) revealed them to be diverse members of a larger family of DNA/RNA modification readers, apparently having originated from bacterial modification-dependent restriction enzymes.
MeSH term(s)	Adenine/chemistry ; DNA/chemistry ; DNA/genetics ; DNA/ultrastructure ; DNA, Single-Stranded/chemistry ; DNA, Single-Stranded/genetics ; Histone Demethylases/genetics ; Humans ; Methylation ; Methyltransferases/genetics ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/genetics ; Multiprotein Complexes/ultrastructure ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/ultrastructure ; Protein Conformation ; Protein Domains/genetics ; RNA Splicing Factors/chemistry ; RNA Splicing Factors/genetics ; RNA Splicing Factors/ultrastructure ; RNA-Binding Proteins/genetics
Chemical Substances	DNA, Single-Stranded ; Multiprotein Complexes ; Nerve Tissue Proteins ; RNA Splicing Factors ; RNA-Binding Proteins ; YTHDC1 protein, human ; YTHDF1 protein, human ; YTHDF2 protein, human ; DNA (9007-49-2) ; Histone Demethylases (EC 1.14.11.-) ; Methyltransferases (EC 2.1.1.-) ; Adenine (JAC85A2161)
Language	English
Publishing date	2020-08-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkaa604
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Article ; Online: Endogenous generation of nitro-fatty acid hybrids having dual nitrate ester (RONO

Fazzari, Marco / Woodcock, Steven R / Rowart, Pascal / Ricart, Karina / Lancaster, Jack R / Patel, Rakesh / Vitturi, Dario A / Freeman, Bruce A / Schopfer, Francisco J

Redox biology

2021 Volume 41, Page(s) 101913

Abstract	Organic nitrate esters, long-recognized therapies for cardiovascular disorders, have not been detected biologically. We characterize in rat stomach unsaturated fatty acid nitration reactions that proceed by generation of nitro-nitrate intermediates (NO
MeSH term(s)	Animals ; Esters ; Fatty Acids ; Nitrates ; Nitro Compounds ; Nitrogen Oxides ; Rats
Chemical Substances	Esters ; Fatty Acids ; Nitrates ; Nitro Compounds ; Nitrogen Oxides
Language	English
Publishing date	2021-02-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2021.101913
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Article ; Online: Preserving the Phosphoproteome of Clinical Biopsies Using a Quick-Freeze Collection Device.

Kennedy, Jacob J / Woodcock, Amanda / Ivey, Richard G / Lin, ChenWei / Corral, Guy / Hooper, Eli / Martin, Gregory / Longman, Gina / Stancik, Blake / Cromwell, Elizabeth A / Whiteaker, Jeffrey R / Zhao, Lei / Lorentzen, Travis D / Thielman, Scott / Paulovich, Amanda G

Biopreservation and biobanking

2022 Volume 20, Issue 5, Page(s) 436–445

Abstract: There is growing interest in proteomic analyses of tissue biopsies to reveal pathophysiology and identify biomarkers. The current gold standard for collecting tissue biopsies for preserving the proteome and post-translational modifications is flash ... ...

Abstract	There is growing interest in proteomic analyses of tissue biopsies to reveal pathophysiology and identify biomarkers. The current gold standard for collecting tissue biopsies for preserving the proteome and post-translational modifications is flash freezing in liquid nitrogen (LN2). However, in many clinical settings, this is not an option due to unavailability of LN2 nor trained personnel for rapid biospecimen processing. To address this need, we developed a proof-of-concept quick-freeze prototype device to rapidly freeze biospecimens at the point-of-care to preserve the phosphoproteome without the need for LN2. Our objectives were to develop the device, demonstrate the ease of use, confirm the ability to ship through existing cold chain logistics, and evaluate the cooling performance (i.e., cool a tissue sample to <0°C in <60 seconds, below -8°C in <120 seconds, and maintain temperature <0°C for >60 minutes) in the context of preserving the proteome in a tissue biospecimen. To demonstrate feasibility, the performance of the prototype was benchmarked against flash freezing in LN2 using a murine melanoma patient-derived xenograft model subjected to total body irradiation to elicit phosphosignaling in the DNA damage response network. Tumors were harvested and quadrisected, with two parts of the tumor being snap frozen in LN2, and the remaining two parts being rapidly cooled in the prototype quick-freeze biospecimen containers. Phosphoproteins were profiled by liquid chromatography tandem mass spectrometry and quantified by targeted multiple reaction monitoring MS. Overall, the phosphoproteome was equivalent in biospecimens processed using the quick-freeze containers to those using the LN2 gold standard, although the measurements of a subset of phosphopeptides in the device-frozen specimens were more variable than LN2-frozen specimens. The prototype device forms the framework for development of a commercial device that will improve tissue biopsy preservation for measurement of important phosphosignaling molecules.
MeSH term(s)	Humans ; Mice ; Animals ; Proteome/analysis ; Proteome/chemistry ; Proteomics ; Freezing ; Tissue Preservation ; Biopsy
Chemical Substances	Proteome
Language	English
Publishing date	2022-10-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2593993-2
ISSN	1947-5543 ; 1947-5535
ISSN (online)	1947-5543
ISSN	1947-5535
DOI	10.1089/bio.2022.0068
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Article ; Online: Chronic Contractile Dysfunction without Hypertrophy Does Not Provoke a Compensatory Transcriptional Response in Mouse Hearts.

Matkovich, Scot J / Grubb, David R / McMullen, Julie R / Woodcock, Elizabeth A

PloS one

2016 Volume 11, Issue 6, Page(s) e0158317

Abstract: Diseased myocardium from humans and experimental animal models shows heightened expression and activity of a specific subtype of phospholipase C (PLC), the splice variant PLCβ1b. Previous studies from our group showed that increasing PLCβ1b expression in ...

Abstract	Diseased myocardium from humans and experimental animal models shows heightened expression and activity of a specific subtype of phospholipase C (PLC), the splice variant PLCβ1b. Previous studies from our group showed that increasing PLCβ1b expression in adult mouse hearts by viral transduction was sufficient to cause sustained contractile dysfunction of rapid onset, which was maintained indefinitely in the absence of other pathological changes in the myocardium. We hypothesized that impaired contractility alone would be sufficient to induce a compensatory transcriptional response. Unbiased, comprehensive mRNA-sequencing was performed on 6 biological replicates of rAAV6-treated blank, PLCβ1b and PLCβ1a (closely related but inactive splice variant) hearts 8 weeks after injection, when reduced contractility was manifest in PLCβ1b hearts without evidence of induced hypertrophy. Expression of PLCβ1b resulted in expression changes in only 9 genes at FDR<0.1 when compared with control and these genes appeared unrelated to contractility. Importantly, PLCβ1a caused similar mild expression changes to PLCβ1b, despite a complete lack of effect of this isoform on cardiac contractility. We conclude that contractile depression caused by PLCβ1b activation is largely independent of changes in the transcriptome, and thus that lowered contractility is not sufficient in itself to provoke measurable transcriptomic alterations. In addition, our data stress the importance of a stringent control group to filter out transcriptional changes unrelated to cardiac function.
MeSH term(s)	Animals ; Dependovirus/genetics ; Gene Expression Profiling/methods ; Gene Expression Regulation ; Heart/physiopathology ; Mice ; Myocardial Contraction ; Myocardium/metabolism ; Phospholipase C beta/genetics ; Phospholipase C beta/metabolism ; RNA Splice Sites ; Sequence Analysis, RNA/methods ; Signal Transduction ; Transcription, Genetic
Chemical Substances	RNA Splice Sites ; Phospholipase C beta (EC 3.1.4.11) ; Plcb1 protein, mouse (EC 3.1.4.11)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0158317
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Article ; Online: Unlocking the phylogenetic diversity, primary habitats, and abundances of free-living Symbiodiniaceae on a coral reef.

Fujise, Lisa / Suggett, David J / Stat, Michael / Kahlke, Tim / Bunce, Michael / Gardner, Stephanie G / Goyen, Samantha / Woodcock, Stephen / Ralph, Peter J / Seymour, Justin R / Siboni, Nachshon / Nitschke, Matthew R

Molecular ecology

2020 Volume 30, Issue 1, Page(s) 343–360

Abstract: Dinoflagellates of the family Symbiodiniaceae form mutualistic symbioses with marine invertebrates such as reef-building corals, but also inhabit reef environments as free-living cells. Most coral species acquire Symbiodiniaceae horizontally from the ... ...

Abstract	Dinoflagellates of the family Symbiodiniaceae form mutualistic symbioses with marine invertebrates such as reef-building corals, but also inhabit reef environments as free-living cells. Most coral species acquire Symbiodiniaceae horizontally from the surrounding environment during the larval and/or recruitment phase, however the phylogenetic diversity and ecology of free-living Symbiodiniaceae on coral reefs is largely unknown. We coupled environmental DNA sequencing and genus-specific qPCR to resolve the community structure and cell abundances of free-living Symbiodiniaceae in the water column, sediment, and macroalgae and compared these to coral symbionts. Sampling was conducted at two time points, one of which coincided with the annual coral spawning event when recombination between hosts and free-living Symbiodiniaceae is assumed to be critical. Amplicons of the internal transcribed spacer (ITS2) region were assigned to 12 of the 15 Symbiodiniaceae genera or genera-equivalent lineages. Community compositions were separated by habitat, with water samples containing a high proportion of sequences corresponding to coral symbionts of the genus Cladocopium, potentially as a result of cell expulsion from in hospite populations. Sediment-associated Symbiodiniaceae communities were distinct, potentially due to the presence of exclusively free-living species. Intriguingly, macroalgal surfaces displayed the highest cell abundances of Symbiodiniaceae, suggesting a key role for macroalgae in ensuring the ecological success of corals through maintenance of a continuum between environmental and symbiotic populations of Symbiodiniaceae.
MeSH term(s)	Animals ; Anthozoa/genetics ; Coral Reefs ; Dinoflagellida/genetics ; Ecosystem ; Phylogeny
Language	English
Publishing date	2020-11-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.15719
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Article ; Online: Blood transcriptomic signature in type-2 biomarker-low severe asthma and asthma control.

Zeng, Xue / Qing, Jing / Li, Chi-Ming / Lu, Jiamiao / Yamawaki, Tracy / Hsu, Yi-Hsiang / Vander Lugt, Bryan / Hsu, Hailing / Busby, John / McDowell, P J / Jackson, David J / Djukanovic, Ratko / Matthews, John G / Arron, Joseph R / Bradding, Peter / Brightling, Christopher E / Chaudhuri, Rekha / Choy, David F / Cowan, D /

Fowler, S J / Hardman, Timothy C / Harrison, Tim / Howarth, Peter / Lordan, James / Mansur, A H / Menzies-Gow, Andrew / Pavord, Ian D / Walker, Samantha / Woodcock, Ashley / Heaney, Liam G

The Journal of allergy and clinical immunology

2023 Volume 152, Issue 4, Page(s) 876–886

Abstract: Background: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids.: Objectives: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker- ... ...

Abstract	Background: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. Objectives: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores. Methods: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. Results: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level. Conclusions: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.
MeSH term(s)	Humans ; Transcriptome ; Asthma/drug therapy ; Asthma/genetics ; Asthma/diagnosis ; Gene Expression Profiling ; Biomarkers ; Adrenal Cortex Hormones/therapeutic use
Chemical Substances	Biomarkers ; Adrenal Cortex Hormones
Language	English
Publishing date	2023-06-12
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2023.05.023
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Article ; Online: A Randomized Trial of a Composite T2-Biomarker Strategy Adjusting Corticosteroid Treatment in Severe Asthma: A Post Hoc Analysis by Sex.

Eastwood, Matthew C / Busby, John / Jackson, David J / Pavord, Ian D / Hanratty, Catherine E / Djukanovic, Ratko / Woodcock, Ashley / Walker, Samantha / Hardman, Timothy C / Arron, Joseph R / Choy, David F / Bradding, Peter / Brightling, Chris E / Chaudhuri, Rekha / Cowan, Douglas / Mansur, Adel H / Fowler, Stephen J / Howarth, Peter / Lordan, James /

Menzies-Gow, Andrew / Harrison, Timothy / Robinson, Douglas S / Holweg, Cecile T J / Matthews, John G / Heaney, Liam G

The journal of allergy and clinical immunology. In practice

2023 Volume 11, Issue 4, Page(s) 1233–1242.e5

Abstract: Background: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations ... ...

Abstract	Background: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex. Objective: To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust corticosteroid (CS) treatment in patients with severe asthma compared with standard care. Methods: This is a post hoc analysis, stratifying patient outcomes by sex, of a 48-week, multicenter, randomized controlled clinical trial comparing a biomarker-defined treatment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in CS treatment (inhaled and oral corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions, and lung function. Results: Of the 301 patients randomized, 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower CS dose versus standard care, which was not seen in males (effect estimate: females, 3.57; 95% CI, 1.14-11.18 vs males, 0.54; 95% CI, 0.16-1.80). In T2-biomarker-low females, reducing CS dose was not associated with increased exacerbations. Females scored higher in all domains of the 7-item Asthma Control Questionnaire, apart from FEV1, but with no difference when adjusted for body mass index/anxiety and/or depression. Dissociation between symptoms and T2 biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs 15.6%; P = .0002), whereas males were symptom low/T2-biomarker high (22.3% vs 11.4%; P < .0001). Conclusions: This exploratory post hoc analysis identified that females achieved a greater benefit from biomarker-directed CS optimization versus symptom-directed treatment.
MeSH term(s)	Male ; Female ; Humans ; Anti-Asthmatic Agents ; Asthma ; Adrenal Cortex Hormones ; Drug Therapy, Combination ; Biomarkers
Chemical Substances	Anti-Asthmatic Agents ; Adrenal Cortex Hormones ; Biomarkers
Language	English
Publishing date	2023-01-05
Publishing country	United States
Document type	Randomized Controlled Trial ; Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2843237-X
ISSN	2213-2201 ; 2213-2198
ISSN (online)	2213-2201
ISSN	2213-2198
DOI	10.1016/j.jaip.2022.12.019
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Article ; Online: Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease.

Potter, Huntington / Woodcock, Jonathan H / Boyd, Timothy D / Coughlan, Christina M / O'Shaughnessy, John R / Borges, Manuel T / Thaker, Ashesh A / Raj, Balaibail A / Adamszuk, Katarzyna / Scott, David / Adame, Vanesa / Anton, Paige / Chial, Heidi J / Gray, Helen / Daniels, Joseph / Stocker, Michelle E / Sillau, Stefan H

Alzheimer's & dementia (New York, N. Y.)

2021 Volume 7, Issue 1, Page(s) e12158

Abstract: Introduction: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal ...

Abstract	Introduction: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology. Methods: A randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. Results: Sargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline ( Discussion: The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted.
Language	English
Publishing date	2021-03-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12158
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Article ; Online: Fatty acid nitroalkenes induce resistance to ischemic cardiac injury by modulating mitochondrial respiration at complex II.

Koenitzer, Jeffrey R / Bonacci, Gustavo / Woodcock, Steven R / Chen, Chen-Shan / Cantu-Medellin, Nadiezhda / Kelley, Eric E / Schopfer, Francisco J

Redox biology

2016 Volume 8, Page(s) 1–10

Abstract: Nitro-fatty acids (NO2-FA) are metabolic and inflammatory-derived electrophiles that mediate pleiotropic signaling actions. It was hypothesized that NO2-FA would impact mitochondrial redox reactions to induce tissue-protective metabolic shifts in cells. ... ...

Abstract	Nitro-fatty acids (NO2-FA) are metabolic and inflammatory-derived electrophiles that mediate pleiotropic signaling actions. It was hypothesized that NO2-FA would impact mitochondrial redox reactions to induce tissue-protective metabolic shifts in cells. Nitro-oleic acid (OA-NO2) reversibly inhibited complex II-linked respiration in isolated rat heart mitochondria in a pH-dependent manner and suppressed superoxide formation. Nitroalkylation of Fp subunit was determined by BME capture and the site of modification by OA-NO2 defined by mass spectrometric analysis. These effects translated into reduced basal and maximal respiration and favored glycolytic metabolism in H9C2 cardiomyoblasts as assessed by extracellular H(+) and O2 flux analysis. The perfusion of NO2-FA induced acute cardioprotection in an isolated perfused heart ischemia/reperfusion (IR) model as evidenced by significantly higher rate-pressure products. Together these findings indicate that NO2-FA can promote cardioprotection by inducing a shift from respiration to glycolysis and suppressing reactive species formation in the post-ischemic interval.
Language	English
Publishing date	2016-08
Publishing country	Netherlands
Document type	Journal Article
ISSN	2213-2317
ISSN (online)	2213-2317
DOI	10.1016/j.redox.2015.11.002
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