Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

Fazzari, Marco; Vitturi, Darío A.; Woodcock, Steven R.; Salvatore, Sonia R.; Freeman, Bruce Α.; Schöpfer, Francisco J.

doi:10.1194/jlr.m088815

Cited by 34 publications

(34 citation statements)

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“…The present study also shows the important role that plasma proteins can play in non-covalent systemic transport of NO 2 -OA, since the large pool of plasma albumin has the capacity of binding and stabilizing extensive quantities of this and other electrophilic fatty acids. While we appreciate that esterification of NO 2 -OA into complex lipids such as triglycerides also contributes to the stabilization and transport of NO 2 -OA [72], more work is needed to fully understand the absorption, storage and transport of nitrated fatty acids that are orally consumed or formed during digestion.…”

Section: Resultsmentioning

confidence: 99%

Redox properties and human serum albumin binding of nitro-oleic acid

et al. 2019

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Nitro-fatty acids modulate inflammatory and metabolic stress responses, thus displaying potential as new drug candidates. Herein, we evaluate the redox behavior of nitro-oleic acid (NO 2 -OA) and its ability to bind to the fatty acid transporter human serum albumin (HSA). The nitro group of NO 2 -OA underwent electrochemical reduction at −0.75 V at pH 7.4 in an aqueous milieu. Based on observations of the R–NO 2 reduction process, the stability and reactivity of NO 2 -OA was measured in comparison to oleic acid (OA) as the negative control. These electrochemically-based results were reinforced by computational quantum mechanical modeling. DFT calculations indicated that both the C9-NO 2 and C10-NO 2 positional isomers of NO 2 -OA occurred in two conformers with different internal angles (69° and 110°) between the methyl- and carboxylate termini. Both NO 2 -OA positional isomers have LUMO energies of around −0.7 eV, affirming the electrophilic properties of fatty acid nitroalkenes. In addition, the binding of NO 2 -OA and OA with HSA revealed a molar ratio of ~7:1 [NO 2 -OA]:[HSA]. These binding experiments were performed using both an electrocatalytic approach and electron paramagnetic resonance (EPR) spectroscopy using 16-doxyl stearic acid. Using a Fe(DTCS) 2 spin-trap, EPR studies also showed that the release of the nitro moiety of NO 2 -OA resulted in the formation of nitric oxide radical. Finally, the interaction of NO 2 -OA with HSA was monitored via Tyr and Trp residue electro-oxidation. The results indicate that not only non-covalent binding but also NO 2 -OA-HSA adduction mechanisms should be taken into consideration. This study of the redox properties of NO 2 -OA is applicable to the characterization of other electrophilic mediators of biological and pharmacological relevance.

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Section: Resultsmentioning

confidence: 99%

Redox properties and human serum albumin binding of nitro-oleic acid

et al. 2019

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“…However, plasma concentrations of CXA‐10 in both animals and humans are in the low ng/mL range due to the bioanalytical assay measuring only free and albumin bound drug. It has been demonstrated that CXA‐10 also circulates in blood to a large extent esterified to triglycerides associated with lipoproteins …”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Effects of OralCXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Garner¹,

Mould

Chieffo³

et al. 2019

Clinical Translational Sci

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10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA‐10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA‐10. After single and multiple ascending doses, CXA‐10 demonstrated dose‐proportional increases in plasma exposure. CXA‐10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA‐10‐202, a consistent decrease from baseline was observed with CXA‐10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP‐1, and IL‐6. In CXA‐10‐203, after coadministration with CXA‐10, geometric mean peak plasma concentration (Cmax) and area under the plasma concentration‐time curve from time point 0 to the end of the dosing interval (AUC0−t) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA‐10. Adverse events (AEs) were dose‐related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA‐10 was safe and well‐tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA‐10 75–300 mg once daily.

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“…Consequently, the in vivo detection of 15 NO 2 -Ln-dependent generation of GS 15 NO will be apparently low compared with the initial concentration of the labeled nitro fatty acid. In addition, NO 2 -FAs are more abundant esterified in complex lipids than in the free form (Fazzari et al, 2019). In this line, oral administration of dogs with NO 2 -OA confirmed that the main distribution of this NO 2 -FA is esterified in different complex lipids, especially triacylglycerides (TAGs) (Fazzari et al, 2019).…”

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confidence: 66%

“…In addition, NO 2 -FAs are more abundant esterified in complex lipids than in the free form (Fazzari et al, 2019). In this line, oral administration of dogs with NO 2 -OA confirmed that the main distribution of this NO 2 -FA is esterified in different complex lipids, especially triacylglycerides (TAGs) (Fazzari et al, 2019). Thus, a similar situation could be happening in Arabidopsis plants incubated with NO 2 -Ln, in which a substantial percentage of the initial amount of NO 2 -Ln could be esterified in complex lipids, therefore not being able to release NO and, ultimately, generate GSNO.…”

mentioning

confidence: 99%

Endogenous Biosynthesis of S-Nitrosoglutathione From Nitro-Fatty Acids in Plants

et al. 2020

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Nitro-fatty acids (NO 2-FAs) are novel molecules resulting from the interaction of unsaturated fatty acids and nitric oxide (NO) or NO-related molecules. In plants, it has recently been described that NO 2-FAs trigger an antioxidant and a defence response against stressful situations. Among the properties of NO 2-FAs highlight the ability to release NO therefore modulating specific protein targets through post-translational modifications (NO-PTMs). Thus, based on the capacity of NO 2-FAs to act as physiological NO donors and using high-accuracy mass-spectrometric approaches, herein, we show that endogenous nitro-linolenic acid (NO 2-Ln) can modulate Snitrosoglutathione (GSNO) biosynthesis in Arabidopsis. The incubation of NO 2-Ln with GSH was analyzed by LC-MS/MS and the in vitro synthesis of GSNO was noted. The in vivo confirmation of this behavior was carried out by incubating Arabidopsis plants with 15 N-labeled NO 2-Ln throughout the roots, and 15 N-labeled GSNO (GS 15 NO) was detected in the leaves. With the aim to go in depth in the relation of NO 2-FA and GSNO in plants, Arabidopsis alkenal reductase mutants (aer mutants) which modulate NO 2-FAs levels were used. Our results constitute the first evidence of the modulation of a key NO biological reservoir in plants (GSNO) by these novel NO 2-FAs, increasing knowledge about S-nitrosothiols and GSNO-signaling pathways in plants.

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Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

Cited by 34 publications

References 50 publications

Redox properties and human serum albumin binding of nitro-oleic acid

Redox properties and human serum albumin binding of nitro-oleic acid

Pharmacokinetic and Pharmacodynamic Effects of OralCXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Endogenous Biosynthesis of S-Nitrosoglutathione From Nitro-Fatty Acids in Plants

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