Antioxidants & bronchopulmonary dysplasia: Beating the system or beating a dead horse?

Preterm birth is a primary cause of worldwide childhood mortality. Bronchopulmonary dysplasia, characterized by impaired alveolar and lung vascular development, affects 25-50% of extremely low birth weight (BW; <1 kg) infants. Abnormalities in lung function persist into childhood in affected infants and are second only to asthma in terms of childhood respiratory disease healthcare costs. While advances in the medical care of preterm infants have reduced mortality, the incidence of BPD has not decreased in the past 10 years. Reactive oxygen intermediates play a key role in the development of lung disease but, despite promising preclinical therapies, antioxidants have failed to translate into meaningful clinical interventions to decrease the incidence of lung disease in premature infants. In this review we will summarize the state of the art research developments in regards to antioxidants and premature lung disease and discuss the limitations of antioxidant therapies in order to more fully comprehend the reasons why therapeutic antioxidant administration failed to prevent BPD. Finally we will review promising therapeutic strategies and targets.

Characterization of Naïve and Vitamin C-Treated Mouse Schwann Cell Line MSC80: Induction of the Antioxidative Thioredoxin Related Transmembrane Protein 1.

Schwann cells (SCs) are essential in the production of the axon-wrapping myelin sheath and provide trophic function and repair mechanisms in the peripheral nerves. Consequently, well-characterized SC in vitro models are needed to perform preclinical studies including the investigation of the complex biochemical adaptations occurring in the peripheral nervous system (PNS) under different (patho)physiological conditions. MSC80 cells represent a murine SC line used as an in vitro system for neuropathological studies. Here, we introduce the most abundant 9532 proteins identified via mass spectrometry-based protein analytics, and thus provide the most comprehensive SC protein catalogue published thus far. We cover proteins causative for inherited neuropathies and demonstrate that in addition to cytoplasmic, nuclear and mitochondrial proteins and others belonging to the protein processing machinery are very well covered. Moreover, we address the suitability of MSC80 to examine the molecular effect of a drug-treatment by analyzing the proteomic signature of Vitamin C-treated cells. Proteomic findings, immunocytochemistry, immunoblotting and functional experiments support the concept of a beneficial role of Vitamin C on oxidative stress and identified TMX1 as an oxidative stress protective factor, which might represent a promising avenue for therapeutic intervention of PNS-disorders with oxidative stress burden such as diabetic neuropathy.

A thioredoxin reductase and/or thioredoxin system-based mechanism for antioxidant effects of ambroxol.

Long-term treatment with ambroxol (ABX), a bronchial expectorant, was found to prevent acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The underlying mechanism remains unclear. To address this, we have investigated the effect of ABX on critical antioxidant proteins thioredoxin (Trx) and thioredoxin reductase (TrxR) that are decreased in patients with AECOPD. Trx, TrxR and NADP(H) form Trx system, which is involved in regulating numerous oxidative stress-related events. In human bronchial epithelial cells, treatment with ABX from 0 to 200 µM gradually increased mRNA and protein levels of TrxR/Trx. At these ABX concentrations, TrxR activity was elevated progressively, whereas Trx activity exhibited a dose-dependent biphasic response, increasing at 50 and 75 µM, but decreasing at ABX over 150 µM. Pre-treatment with 75 µM ABX enhanced the capacity of the cells to eliminate reactive oxygen species, which was largely prevented by knockdown of cytosolic Trx (hTrx1). In a purified system, ABX shortened the initial lag phase during the reduction of insulin disulfide by Trx system. Pre-treatment of NADPH-reduced TrxR with ABX caused a dose- and time-dependent increase in thiolate/selenolate species, i.e. the catalytically active form of TrxR. Kinetic analysis demonstrated that the reduction of H2O2 by TrxR or Trx system were enhanced by 100 or 200 µM ABX. When hTrx1 was mixed with ABX in a molar ratio of 1:1 to 1:100 (which could occur in human plasma), changes in intrinsic Trp fluorescence occurred, and the response of reduced hTrx1 was especially remarkable. These data reveal an ABX-sensing mechanism of TrxR/Trx. We therefore conclude that the antioxidant actions of ABX at physiological concentrations are, at least partially, mediated by TrxR and/or Trx system.

Low-volume exercise training and vitamin E supplementation attenuates oxidative stress in postmenopausal women.

The purpose of this study was to investigate the effects of low-volume exercise training (90 min/wk) and vitamin E supplementation on oxidative stress markers in postmenopausal women. The participants were non-randomly assigned the following four groups: control (C, n=8), vitamin E (S, n=8), exercise (Ex, n=6), or vitamin E and exercise (S+Ex, n=7). The S and S+Ex groups were instructed to take vitamin E (α-tocopherol, 300 mg/d) capsules for 12 wk. The exercise program of Ex and S+Ex groups consisted of walking for a 30-60 min/session 2 d per week for 12 wk. The serum derivatives of reactive oxygen metabolites concentrations were significantly decreased in the Ex, and S+Ex groups after 12 wk compared with the baseline values (three-factor ANOVA, an interaction between exercise and time, p<0.05). Conversely, serum biological antioxidant potential concentrations in the S and Ex groups were significantly higher at 12 wk than at the baseline, but not in the S+Ex group (three-factor ANOVA, an interaction between supplementation, exercise and time, p<0.05). Plasma thioredoxin concentrations in the S, Ex, and S+Ex groups were significantly higher at 12 wk than at the baseline values (three-factor ANOVA, interactions between exercise and time, and between supplementation, exercise and time, p<0.05). Our findings suggest that low-volume physical activity may improve resting oxidative stress status in postmenopausal women.

Panaxatriol saponins extracted from Panax notoginseng induces thioredoxin-1 and prevents 1-methyl-4-phenylpyridinium ion-induced neurotoxicity.

AIM OF THE STUDY: Thioredoxin-1 has various biologic activities, including the control of redox balance and the inhibition of apoptosis. The current study was designed to examine the effects of panaxatriol saponins (PTS) extracted from Panax notoginseng on thioredoxin-1 expression and 1-methyl-4-phenylpyridinium ion-induced injury. MATERIALS AND METHODS: Using PC12 cells and Kunming mice, we test thioredoxin-1 expression after PTS treatment by Western blot. The protective effect of PTS against 1-methyl-4-phenylpyridinium ion-induced injury was assessed by MTT assay and LDH release assay. RESULTS: PTS induced thioredoxin-1 expression in vitro and in vivo, and attenuated 1-methyl-4-phenylpyridinium ion-induced cell death of PC12 cells. CONCLUSIONS: PTS is a new inducer of thioredoxin-1 and has a possible potential as a therapeutic agent for neurodegenerative diseases including Parkinson's disease.

Targeting the human thioredoxin system by diverse strategies to treat cancer and other pathologies.

Redox control is an important determinant of cellular function and viability. The thioredoxin system is a major antioxidant system that influences cellular redox state, stimulates cell growth, inhibits apoptosis, activates numerous transcription factors and regulates immune function. Both over and under expression of the thioredoxin system can result in a disease phenotype and therefore it has been the target of many therapeutic strategies. High levels of thioredoxin expression have been associated with aggressive cancers, poor patient prognosis and resistance to some chemotherapy treatments. In contrast, low levels of thioredoxin can cause diseases that develop because of an imbalance between antioxidant systems and oxidative stress, stimulants. A number of recent patents and patent applications have been published that describe inventions that either inhibit or enhance thioredoxin functionality. Thioredoxin expression levels have been decreased through antisense approaches and thioredoxin functionality has been inhibited by synthetic compounds or by stimulating the production of VDUP1, a natural thioredoxin inhibitor. Strategies designed to enhance thioredoxin functionality include the addition of recombinant thioredoxin or using gene delivery to treat hepatic disease, inflammatory bowel disease, cardiovascular disease, skin damage or cystic fibrosis. Mutant thioredoxin molecules that target specific pathways or that exhibit increased stability are also utilised.