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Synthesis and Structure of Novel Copper(II) Complexes with N,O- or N,N-Donors as Radical Scavengers and a Functional Model of the Active Sites in Metalloenzymes.
Masternak, J, Zienkiewicz-Machnik, M, Łakomska, I, Hodorowicz, M, Kazimierczuk, K, Nosek, M, Majkowska-Młynarczyk, A, Wietrzyk, J, Barszcz, B
International journal of molecular sciences. 2021;(14)
Abstract
To evaluate the antioxidant activity of potential synthetic enzyme mimetics, we prepared new five copper(II) complexes via a self-assembly method and named them [Cu(2-(HOCH2)py)3](ClO4)2 (1), [Cu(2-(HOCH2)py)2(H2O)2]SiF6 (2), [Cu2(2-(HOCH2CH2)py)2(2-(OCH2CH2)py)2](ClO4)2 (3), [Cu(pyBIm)3](BF4)2·1.5H2O (4) and [Cu(py2C(OH)2)2](ClO4)2 (5). The synthetic protocol involved N,O- or N,N-donors: 2-(hydroxymethyl)pyridine (2-(HOCH2)py), 2-(hydroxyethyl)pyridine (2-(HOCH2CH2)py), 2-(2-pyridyl)benzimidazole (pyBIm), di(2-pyridyl)ketone (py2CO). The obtained Cu(II) complexes were fully characterised by elemental analysis, FTIR, EPR, UV-Vis, single-crystal X-ray diffraction and Hirshfeld surface analysis. Crystallographic and spectroscopic analyses confirmed chromophores of both monomeric ({CuN3O3} (1), {CuN2O4} (2), {CuN6} (4), {CuN4O2} (5)) and dimeric complex ({CuN2O3} (3)). Most of the obtained species possessed a distorted octahedral environment, except dimer 3, which consisted of two copper centres with square pyramidal geometries. The water-soluble compounds (1, 3 and 5) were selected for biological testing. The results of the study revealed that complex 1 in solutions displayed better radical scavenging activity than complexes 3, 5 and free ligands. Therefore, complex 1 has been selected for further studies to test its activity as an enzyme mimetic. The chosen compound was tested on the erythrocyte lysate of two groups of patients after undergoing chemotherapy and chemoradiotherapy. The effect of the tested compound (1) on enzyme activity levels (TAS, SOD and CAT) suggests that the selected complex can be treated as a functional mimetic of the enzymes.
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Reactive Oxygen Species Scavenger in Acute Intracerebral Hemorrhage Patients: A Multicenter, Randomized Controlled Trial.
Kim, M, Byun, J, Chung, Y, Lee, SU, Park, JE, Park, W, Park, JC, Ahn, JS, Lee, S
Stroke. 2021;(4):1172-1181
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Abstract
[Figure: see text].
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MitoQ Is Able to Modulate Apoptosis and Inflammation.
Piscianz, E, Tesser, A, Rimondi, E, Melloni, E, Celeghini, C, Marcuzzi, A
International journal of molecular sciences. 2021;(9)
Abstract
Mitoquinone (MitoQ) is a mitochondrial reactive oxygen species scavenger that is characterized by high bioavailability. Prior studies have demonstrated its neuroprotective potential. Indeed, the release of reactive oxygen species due to damage to mitochondrial components plays a pivotal role in the pathogenesis of several neurodegenerative diseases. The present study aimed to examine the impact of the inflammation platform activation on the neuronal cell line (DAOY) treated with specific inflammatory stimuli and whether MitoQ addition can modulate these deregulations. DAOY cells were pre-treated with MitoQ and then stimulated by a blockade of the cholesterol pathway, also called mevalonate pathway, using a statin, mimicking cholesterol deregulation, a common parameter present in some neurodegenerative and autoinflammatory diseases. To verify the role played by MitoQ, we examined the expression of genes involved in the inflammation mechanism and the mitochondrial activity at different time points. In this experimental design, MitoQ showed a protective effect against the blockade of the mevalonate pathway in a short period (12 h) but did not persist for a long time (24 and 48 h). The results obtained highlight the anti-inflammatory properties of MitoQ and open the question about its application as an effective adjuvant for the treatment of the autoinflammatory disease characterized by a cholesterol deregulation pathway that involves mitochondrial homeostasis.
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Pleiotropic Effects of Isoflavones in Inflammation and Chronic Degenerative Diseases.
Bernatoniene, J, Kazlauskaite, JA, Kopustinskiene, DM
International journal of molecular sciences. 2021;(11)
Abstract
Isoflavones are phytoestrogens of plant origin, mostly found in the members of the Fabaceae family, that exert beneficial effects in various degenerative disorders. Having high similarity to 17-β-estradiol, isoflavones can bind estrogen receptors, scavenge reactive oxygen species, activate various cellular signal transduction pathways and modulate growth and transcription factors, activities of enzymes, cytokines, and genes regulating cell proliferation and apoptosis. Due to their pleiotropic activities isoflavones might be considered as a natural alternative for the treatment of estrogen decrease-related conditions during menopause. This review will focus on the effects of isoflavones on inflammation and chronic degenerative diseases including cancer, metabolic, cardiovascular, neurodegenerative diseases, rheumatoid arthritis and adverse postmenopausal symptoms.
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Associations of methyl donor and methylation inhibitor levels during anti-oxidant therapy in heart failure.
Joseph, J, Giczewska, A, Alhanti, B, Cheema, AK, Handy, DE, Mann, DL, Loscalzo, J, Givertz, MM
Journal of physiology and biochemistry. 2021;(2):295-304
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Redox balance and methylation are crucial to homeostasis and are linked by the methionine-homocysteine cycle. We examined whether differences in methylation potential, measured as plasma levels of S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH), occur at baseline and during anti-oxidant therapy with the xanthine oxidase inhibitor allopurinol in patients with heart failure with reduced ejection fraction. We analyzed plasma samples collected at baseline and 24 weeks in the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) study, which randomized patients with heart failure with reduced ejection fraction to allopurinol or placebo. Associations between plasma levels of SAM, SAH, SAM/SAH ratio, and outcomes, including laboratory markers and clinical events, were assessed. Despite randomization, median SAM levels were significantly lower at baseline in the allopurinol group. SAH levels at 24 weeks, and change in SAM from baseline to week 24, were significantly higher in the group of patients randomized to allopurinol compared to the placebo group. A significant correlation was observed between change in SAH levels and change in plasma uric acid (baseline to 24-week changes) in the allopurinol group. There were no significant associations between levels of SAM, SAH, and SAM/SAH ratio and clinical outcomes. Our results demonstrate significant biological variability in SAM and SAH levels at baseline and during treatment with an anti-oxidant and suggest a potential mechanism for the lack of efficacy observed in trials of anti-oxidant therapy. These data also highlight the need to explore personalized therapy for heart failure.
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Bisphenol A and Male Fertility: Myths and Realities.
Castellini, C, Totaro, M, Parisi, A, D'Andrea, S, Lucente, L, Cordeschi, G, Francavilla, S, Francavilla, F, Barbonetti, A
Frontiers in endocrinology. 2020;:353
Abstract
Bisphenol A (BPA) represents the main chemical monomer of epoxy resins and polycarbonate plastics. The environmental presence of BPA is widespread, and it can easily be absorbed by the human body through dietary and transdermal routes, so that more than 90% of the population in western countries display detectable BPA levels in the urine. As BPA is qualified as an endocrine disruptor, growing concern is rising for possible harmful effects on human health. This review critically discusses the available literature dealing with the possible impact of BPA on male fertility. In rodent models, the in vivo exposure to BPA negatively interfered with the regulation of spermatogenesis throughout the hypothalamic-pituitary-gonadal axis. Furthermore, in in vitro studies, BPA promoted mitochondrial dysfunction and oxidative/apoptotic damages in spermatozoa from different species, including humans. To date, the claimed clinical adverse effects on male fertility are largely based on the results from studies assessing the relationship between urinary BPA concentration and conventional semen parameters. These studies, however, produced controversial evidence due to heterogeneity in the extent of BPA exposure, type of population, and enrollment setting. Moreover, the cause-effect relationship cannot be established due to the cross-sectional design of the studies as well as the large spontaneous between- and within-subject variability of semen parameters. The best evidence of an adverse effect of BPA on male fertility would be provided by prospective studies on clinically relevant endpoints, including natural or medically assisted pregnancies among men either with different exposure degrees (occupational/environmental) or with different clinical conditions (fertile/subfertile).
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Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies.
Todd, JJ, Lawal, TA, Witherspoon, JW, Chrismer, IC, Razaqyar, MS, Punjabi, M, Elliott, JS, Tounkara, F, Kuo, A, Shelton, MO, et al
Neurology. 2020;(13):e1434-e1444
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OBJECTIVE To investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM). METHODS In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance. RESULTS When compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] -1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI -5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study. CONCLUSION In ambulatory RYR1-RM-affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane. CLASSIFICATION OF EVIDENCE This study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane. CLINICALTRIALSGOV IDENTIFIER NCT02362425.
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Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial.
Qi, Q, Ailiyaer, Y, Liu, R, Zhang, Y, Li, C, Liu, M, Wang, X, Jing, L, Li, Y
Respiratory research. 2019;(1):73
Abstract
BACKGROUND N-acetylcysteine is a classic mucolytic agent. This study aimed to investigate the efficacy of N-acetylcysteine on reducing the risk of exacerbations in bronchiectasis patients. METHODS A prospective, randomized, controlled trial was conducted between April 1, 2014 and December 31, 2016 in five general hospitals in Shandong Province, China. Adult bronchiectasis patients with at least two exacerbations in the past year were potentially eligible. Patients were randomly assigned to receive oral N-acetylcysteine (600 mg, twice daily, 12 months) or on-demand treatment. RESULTS A total of 161 patients were eligible for randomization (81 to the N-acetylcysteine group and 80 to the control group). During the 12-month follow-up, the incidence of exacerbations in the N-acetylcysteine group was significantly lower than that in the control group (1.31 vs. 1.98 exacerbations per patient-year; risk ratio, 0.41; 95% CI, 0.17-0.66; P = 0.0011). The median number of exacerbations in the N-acetylcysteine group was 1 (0.5-2), compared with 2 (1-2) in the control group (U = - 2.95, P = 0.003). A total of 24.7% of the N-acetylcysteine group patients and 11.3% of the control group patients remained exacerbation-free throughout the 12-month follow-up (χ2 = 4.924, P = 0.026). Compared with the control group, the volume of 24-h sputum in the N-acetylcysteine group was significantly reduced (t = - 3.091, P = 0.002). Additionally, the N-acetylcysteine group showed a significant improvement in the quality of life. No severe adverse events were reported in the intervention group. CONCLUSION The long-term use of N-acetylcysteine is able to reduce the risk of exacerbations for bronchiectasis patients in Shandong Province, China. The results of this study should be verified in a larger randomized controlled trial. TRIAL REGISTRATION ClinicalTrials.gov (NCT02088216) (Registered date: March 5, 2014).
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Lessons learned from the PRESERVE trial.
Partovi, S, Trischman, T, Kang, PS
The British journal of radiology. 2018;(1087):20180092
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The recently published Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial is presently the largest and most comprehensive clinical trial comparing commonly applied strategies for prevention of iodinated contrast-induced acute kidney injury in high-risk patients. The fundamental conclusion of the PRESERVE trial is that oral acetylcysteine and i.v. sodium bicarbonate are not superior to simple i.v. hydration with isotonic saline for the prevention of contrast-induced renal sequelae. In this commentary, we discuss the results in the context of selected past major trials, and provide insights into the strengths and potential weaknesses of the PRESERVE trial. In the future, developing individualized preventive approaches to avoid contrast-induced acute kidney injury for different patient populations is recommended.
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The role of depressive symptoms in treatment of adolescent cannabis use disorder with N-Acetylcysteine.
Tomko, RL, Gilmore, AK, Gray, KM
Addictive behaviors. 2018;:26-30
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Abstract
Relative to adults, adolescents are at greater risk of developing a cannabis use disorder (CUD) and risk may be exacerbated by co-occurring depressive symptoms. N-Acetylcysteine (NAC), an over-the-counter antioxidant, is thought to normalize glutamate transmission. Oxidative stress and glutamate transmission are disrupted in both depression and CUD. Thus, NAC may be particularly effective at promoting cannabis abstinence among adolescents with elevated depressive symptoms. Secondary analyses were conducted using a sub-sample of adolescents with CUD (N = 74) who participated in an 8-week randomized placebo-controlled clinical trial examining the efficacy of NAC for cannabis cessation. It was hypothesized that NAC would reduce severity of depressive symptoms, and that decreases depressive symptom severity would mediate decreases in positive weekly urine cannabinoid tests (11-nor-9-carboxy-Δ9-tetrahydrocannabinol). Additionally, it was expected that adolescents with greater severity of baseline depressive symptoms would be more likely to become abstinent when assigned NAC relative to placebo. Results from linear mixed models and generalized estimating equations did not suggest that NAC reduced severity of depressive symptoms, and the hypothesis that NAC's effect on cannabis cessation would be mediated by reduced depressive symptoms was not supported. However, an interaction between treatment condition and baseline severity of depressive symptoms as a predictor of weekly urine cannabinoid tests was significant, suggesting that NAC was more effective at promoting abstinence among adolescents with heightened baseline depressive symptoms. These secondary findings, though preliminary, suggest a need for further examination of the role of depressive symptoms in treatment of adolescent CUD with NAC.