Effects of oral <i>N</i>-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication

Silva, Natan Daniel da; Roseguini, Bruno T.; Chehuen, Marcel da Rocha; Fernandes, Tiago; Mota, Glória F.; Martin, Priscila Keiko Matsumoto; Han, Sang Won; Forjaz, C. L. M.; Wolosker, Nelson; Oliveira, Edilamar Menezes de

doi:10.1152/ajpheart.00158.2015

Cited by 22 publications

(19 citation statements)

References 70 publications

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“…We have shown that high‐dose oral NAC can increase peripheral antioxidant measures. In agreement with our observations, there have been several reports of increased antioxidant GSH/GSSG ratios with oral NAC therapy . In our study, despite the observed increase in antioxidant capacity (GSH/GSSG and catalase), oral NAC did not appreciably alter peripheral measures of oxidative damage (4‐HNE and MDA).…”

Section: Discussionsupporting

confidence: 93%

“…In agreement with our observations, there have been several reports of increased antioxidant GSH/GSSG ratios with oral NAC therapy. [33][34][35] In our study, despite the observed increase in antioxidant capacity (GSH/GSSG and catalase), oral NAC did not appreciably alter peripheral measures of oxidative damage (4-HNE and MDA). However, given that these measures were not elevated in patients, we might not expect to see a modulating effect.…”

Section: Discussionmentioning

confidence: 74%

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Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Coles

Tuite

Öz

et al. 2017

The Journal of Clinical Pharma

120

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Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 74%

Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Coles

Tuite

Öz

et al. 2017

The Journal of Clinical Pharma

120

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“…Because the molecular mechanisms regulating endothelial dysfunction are likely not isolated to a single pathway, more clinical studies that include molecular measurements are needed. The present study by da Silva et al (9) and the work by Ahimastos et al (1,2) show the value of such experiments in conjunction with clinical outcomes to gain insight into potential mechanisms regulating vascular function. In summary, it will be important to delineate the multiple mechanisms that mediate PAD-related vascular impairments and determine whether they vary by risk factor and patient makeup.…”

supporting

confidence: 55%

Understanding the role of antioxidant therapy for intermittent claudication; good, bad, or both?

Miller

Unthank

2015

American Journal of Physiology-Heart and Circulatory Physiology

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PERIPHERAL ARTERIAL DISEASE (PAD) is a global health issue, affecting 202 million people worldwide (12, 18). The most common symptom of PAD is intermittent claudication. Although claudication patients have a limited progression to chronic limb ischemia, PAD is associated with increased risk of cardiovascular morbidity and mortality (8). This fact, along with the impact on lifestyle and the large population affected, has caused PAD to be identified as an area where new therapies are urgently needed (15, 22). Currently, the only medications approved by the US Food and Drug Administration for treating PAD-associated walking impairment are the phosphodiesterase inhibitors pentoxifylline and cilostazol (22). However, these agents have been shown to produce only minimal improvement in maximal treadmill walking distance (33), are expensive, and have multiple side effects. There have been many clinical trials with various molecular and cell-related therapies with varying degrees of success [reviewed by Cooke and Losordo (7)] for both critical limb ischemia and intermittent claudication, but among the most effective therapies in claudicants have been those impacting vascular redox and inflammatory status (2, 4). Much evidence exists for a role of oxidant stress and inflammation in cardiovascular disease in general, and PAD patients have high circulating levels of inflammatory (6, 27) and oxidant stress markers (13, 20). Thus therapies targeted to address an abnormal redox state may have potential as mitigators of PAD. In the current issue of the American Journal of Physiology-Heart and Circulatory Physiology, da Silva Jr et al. (9) present results of a double-blind, randomized, crossover study designed to determine effects of acute administration of N-acetylcysteine (NAC) in patients with intermittent claudication on walking capacity, postocclusive reactive hyperemia in the leg, and circulating levels of inflammatory and angiogenic mediators. The rationale for the study was based, in part, on previous data that glutathione infusion improved pain-free walking distance (3), along with studies showing that NAC mitigated the inflammatory response to exercise (23, 31) and improved fatigue resistance in soleus muscle in a mouse model of PAD (30). NAC was administered in five doses over 4 days and found to increase the plasma ratio of reduced to oxidized glutathione. Unexpectedly, results were negative for increased walking tolerance and leg blood flow/reactive hyperemia, and NAC had no measureable effect on exercise-induced increases in soluble vascular cell adhesion protein-1, monocyte chemotactic protein-1, or endothelin-1. The authors examined the expression of several circulating angiogenic mediators, including microRNA (miRNA)-126, because it is known to be markedly reduced in patients with PAD (32).

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“…( 17 ) Circulating miR-126-3p is known to be suppressed in patients or animal models of cerebral ischemic stroke, diabetes, or peripheral arterial disease. ( 17 , 24 , 27 ) Furthermore, oxidative stress might play a role in releasing circulating miR-126-3p as oral treatment with the antioxidant N -acetylcysteine (NAC) was found to prevent the maximal exercise-induced increase of circulating miR-126-3p in patients with intermittent claudication. ( 24 ) Wang et al ( 23 ) reported that miR-126-3p contained in endothelial progenitor cell-derived microvesicles (EPC-MVs) can suppress oxidative stress and promote angiogenesis of endothelial cells via the PI3K/eNOS/NO pathway.…”

Section: Resultsmentioning

confidence: 99%

Extracellular microRNAs and oxidative stress in liver injury: a systematic mini review

Matsuzaki¹,

Ochiya²

2018

J. Clin. Biochem. Nutr.

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Recent evidence has suggested that extracellular microRNAs have crucial roles in intercellular communications and are promising as minimally invasive biomarkers for various diseases including cancers. Oxidative stress also plays an essential role in homeostasis and disease development. This systematic review aims to clarify the current evidence on the interaction between oxidative stress and extracellular microRNAs. We identified 32 studies that provided information regarding the association between oxidative stress and extracellular microRNAs: 9 focused on the central nervous system, 11 focused on cardiovascular diseases, and 4 focused on liver injury. Endothelial cell-specific miR-126-3p was the most studied extracellular miRNA associated with oxidative stress. In addition, we highlight some reports that describe the mechanisms of how oxidative stress affects extracellular microRNA profiles in liver injury. In liver injury, the levels of miR-122-5p, miR-192-5p, miR-223-3p, and miR-1224-5p were reported to be elevated in the sera. The release of miR-122-5p, miR-192-5p, and miR-1224-5p from hepatocytes may be attributed to oxidative stress. miR-223-3p could be released from neutrophils and suppress oxidative stress in the liver. Elucidation of the mechanisms of the interaction between extracellular microRNAs and oxidative stress would improve our pathophysiological understanding as well as future medical practice.

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Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication

Abstract: . Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication.

Cited by 22 publications

References 70 publications

Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Understanding the role of antioxidant therapy for intermittent claudication; good, bad, or both?

Extracellular microRNAs and oxidative stress in liver injury: a systematic mini review

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