Pharmacokinetic and Pharmacodynamic Effects of Oral<scp>CXA</scp>‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Garner, Rachel M.; Mould, Diane R.; Chieffo, Carla; Jorkasky, Diane K.

doi:10.1111/cts.12672

Cited by 26 publications

(25 citation statements)

References 26 publications

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“…9 , B and C ). Importantly, the concentration of NO 2 -OA required to activate cellular hSIRT6 (10 μ m ) is comparable with those shown to elicit physiologically relevant signaling events in vitro that then translate successfully to both animal and human studies ( 52 , 66 , 67 ). In this regard, administration of NO 2 -OA to both genetic and dietary mouse models of obesity results in improved insulin sensitivity and glucose tolerance, as well as in protection against mitochondrial dysfunction ( 68 , 69 ).…”

Section: Discussionmentioning

confidence: 65%

Nitro-fatty acids as activators of hSIRT6 deacetylase activity

Carreño

Bresque

Machado

et al. 2020

Journal of Biological Chemistry

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Sirtuin 6, SIRT6, is critical for both glucose and lipid homeostasis and is involved in maintaining genomic stability under conditions of oxidative DNA damage such as those observed in age-related diseases. There is an intense search for modulators of SIRT6 activity, however, not many specific activators have been reported. Long acyl-chain fatty acids have been shown to increase the weak in vitro deacetylase activity of SIRT6 but this effect is modest at best. Herein we report that electrophilic nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) potently activate SIRT6. Binding of the nitro-fatty acid to the hydrophobic crevice of the SIRT6 active site exerted a moderate activation (2-fold at 20 µM), similar to that previously reported for non-nitrated fatty acids. However, covalent Michael adduct formation with Cys18, a residue present at the N-terminus of SIRT6 but absent from other isoforms, induced a conformational change that resulted in a much stronger activation (40-fold at 20 µM). Molecular modeling of the resulting Michael adduct suggested stabilization of the co-substrate and acyl binding loops as a possible additional mechanism of SIRT6 activation by the nitro-fatty acid. Importantly, treatment of cells with nitro-oleic acid promoted H3K9 deacetylation, while oleic acid had no effect. Altogether, our results show that nitrated fatty acids can be considered a valuable tool for specific SIRT6 activation, and that SIRT6 should be considered as a molecular target for in vivo actions of these anti-inflammatory nitro-lipids.

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Section: Discussionmentioning

confidence: 65%

Nitro-fatty acids as activators of hSIRT6 deacetylase activity

Carreño

Bresque

Machado

et al. 2020

Journal of Biological Chemistry

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“…CXA-10 has successfully demonstrated safety in preclinical toxicology and Phase I studies, and Phase II studies in PAH are currently underway (NCT04053543, NCT03449524). 92 …”

Section: Mechanisms Underlying Obesity-associated Pahmentioning

confidence: 99%

“…CXA-10 has successfully demonstrated safety in preclinical toxicology and Phase I studies, and Phase II studies in PAH are currently underway (NCT04053543, NCT03449524). 92 Evidence from animal models with BMPR2 mutations suggests insulin resistance develops before PAH and that insulin resistance has a causative role in the development of pulmonary vascular disease. 80 As insulin resistance is common in obesity, this may provide another mechanism linking obesity to the development of PAH.…”

Section: Obesity Insulin Resistance and Pahmentioning

confidence: 99%

“…Beyond the TZDs, nitro‐oleic acid (NO 2 ‐OA) and its isomer CXA‐10 (10‐nitro‐9(E)‐octadec‐9‐enoic acid) have demonstrated therapeutic potential through stimulation of PPARγ, upregulation of Nrf‐2 and inhibition of NFκβ. CXA‐10 has successfully demonstrated safety in preclinical toxicology and Phase I studies, and Phase II studies in PAH are currently underway (NCT04053543, NCT03449524) 92 …”

Section: Mechanisms Underlying Obesity‐associated Pahmentioning

confidence: 99%

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Obesity, estrogens and adipose tissue dysfunction – implications for pulmonary arterial hypertension

2020

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Obesity is a prevalent global public health issue characterized by excess body fat. Adipose tissue is now recognized as an important endocrine organ releasing an abundance of bioactive adipokines including, but not limited to, leptin, adiponectin and resistin. Obesity is a common comorbidity amongst pulmonary arterial hypertension patients, with 30% to 40% reported as obese, independent of other comorbidities associated with pulmonary arterial hypertension (e.g. obstructive sleep apnoea). An ‘obesity paradox’ has been observed, where obesity has been associated with subclinical right ventricular dysfunction but paradoxically may confer a protective effect on right ventricular function once pulmonary hypertension develops. Obesity and pulmonary arterial hypertension share multiple pathophysiological mechanisms including inflammation, oxidative stress, elevated leptin (proinflammatory) and reduced adiponectin (anti-inflammatory). The female prevalence of pulmonary arterial hypertension has instigated the hypothesis that estrogens may play a causative role in its development. Adipose tissue, a major site for storage and metabolism of sex steroids, is the primary source of estrogens and circulating estrogens levels which are elevated in postmenopausal women and men with pulmonary arterial hypertension. This review discusses the functions of adipose tissue in both health and obesity and the links between obesity and pulmonary arterial hypertension. Shared pathophysiological mechanisms and the contribution of specific fat depots, metabolic and sex-dependent differences are discussed.

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“…10-nitro oleic acid (10-NO 2 -OA) is now being studied in fibrotic and inflammatory conditions. The drug has been shown to be safe and well-tolerated in a phase 1 study [ 14 ] and is being investigated in glomerulosclerosis (NCT03422510) and kidney injury (NCT02248051).…”

Section: Introductionmentioning

confidence: 99%

Nitro-fatty acids decrease type I interferons and monocyte chemoattractant protein 1 in ex vivo models of inflammatory arthritis

et al. 2021

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Background Inflammatory arthritis including rheumatoid arthritis (RA) and spondyloarthritis (SpA) is characterized by inflammation and destruction of the joints. Approximately one third of patients do not respond to first-line treatments. Nitro-fatty acids are bioactive lipids with anti-inflammatory properties and tissue-protective functions. The nitro-fatty acid 10-NO2-oleic acid (10-NO2-OA) is being tested in clinical trials for patients with fibrotic and inflammatory conditions. Here, we tested whether 10-NO2-OA could inhibit immune reactions involved in the inflammatory and joint destructive processes in inflammatory arthritis. Methods Synovial fluid and blood samples were obtained from 14 patients with active RA or SpA. The in vitro models consisted of synovial fluid mononuclear cells (SFMCs) cultured for 48 h, SFMCs cultured for 21 days, and fibroblast-like synovial cells (FLSs) co-cultured with peripheral blood mononuclear cells (PBMCs) for 48 h. Cells were treated with or without 10-NO2-OA or the tumor necrosis factor alpha (TNFα) inhibitor etanercept. Supernatants were analyzed for type I interferon, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase 3 (MMP3) and tartrate resistant acid phosphatase (TRAP). Results In SFMCs cultured for 48 h, 10-NO2-OA dose-dependently decreased the secretion of bioactive type I interferons and MCP-1 but not MMP3 (P = 0.032, P = 0.0001, and P = 0.58, respectively). Both MCP-1 and MMP3 were decreased by etanercept (P = 0.0031 and P = 0.026, respectively). In SFMCs cultured for 21 days, 10-NO2-OA significantly decreased the production of MCP-1 but not TRAP (P = 0.027 and P = 0.1523, respectively). Etanercept decreased the production of TRAP but not MCP-1 (P < 0.001 and P = 0.84, respectively). In co-cultures of FLSs and PBMCs, 10-NO2-OA decreased the production of MCP-1 (P < 0.0001). This decrease in MCP-1 production was not seen with etanercept treatment (P = 0.47). Conclusion 10-NO2-OA decreased the release of MCP-1 in three models of inflammatory arthritis. Of particular interest, 10-NO2-OA inhibited type I interferon, and 10-NO2-OA was more effective in reducing MCP-1 production in cultures dominated by FLSs compared with etanercept. Our results encourage clinical investigations of 10-NO2-OA in patients with inflammatory arthritis.

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

Cited by 26 publications

References 26 publications

Nitro-fatty acids as activators of hSIRT6 deacetylase activity

Nitro-fatty acids as activators of hSIRT6 deacetylase activity

Obesity, estrogens and adipose tissue dysfunction – implications for pulmonary arterial hypertension

Nitro-fatty acids decrease type I interferons and monocyte chemoattractant protein 1 in ex vivo models of inflammatory arthritis

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