Methamphetamine decreases levels of glutathione peroxidases 1 and 4 in SH-SY5Y neuronal cells: Protective effects of selenium

Methamphetamine interferes with dopamine reuptake, and the resulting increased dopamine oxidation that creates oxidative stress can lead to degeneration of dopaminergic terminals. Previous studies have shown that the trace element selenium protects against methamphetamine toxicity. However, the specific selenoproteins responsible for protection have not been elucidated. Glutathione peroxidases 1 and 4 (GPx1 and GPx4) incorporate selenium into the amino acid selenocysteine, and their known antioxidant functions make them good candidates for protection from methamphetamine-induced oxidative damage. We differentiated SH-SY5Y neuronal cells in serum-free media with defined supplement containing 0, 10 and 100 nM selenium, and then challenged the cells with a 24-h exposure to methamphetamine. We found that 100 μM methamphetamine decreased GPx1 and GPx4 protein levels. However, both proteins were upregulated with increasing media selenium concentration. GPx enzymatic activity was also increased by selenium and decreased by methamphetamine and correlated with GPx protein levels. Total glutathione levels were reduced by methamphetamine at lower selenium conditions, while the oxidized fraction of GSH was increased at higher selenium levels. Additionally, we observed an increased generation of reactive oxygen species with methamphetamine exposure in media with 0 nM selenium, which was ameliorated by selenium supplementation. These results show that methamphetamine increases oxidative stress by reducing GPx levels, and this can be reversed with addition of selenium. These findings have important implications for treating patients with acute methamphetamine toxicity.     

The Association of Measures of the Micro- and Macro-Vasculature with Selenium and GPx Activity in a Young Bi-Ethnic Population: The African-PREDICT Study

Abstract

Objective: Selenium plays an important physiological role as component for antioxidant selenoproteins such as glutathione peroxidase (GPx). Since oxidative stress contributes to hypertension development, it is likely that selenium deficiency may contribute to the burden of cardiovascular disease. To better understand the involvement of selenium and GPx in the early development of cardiovascular disease, we investigated in young, healthy black and white African men and women whether measures of the micro- and macrovasculature are related to selenium and GPx activity.

Methods: In young adults (N?=?394; aged 20–30?years) we determined serum selenium, GPx activity, microvascular measures (central retinal artery equivalent, central retinal vein equivalent, arteriolar-to-venular ratio [AVR], and estimated glomerular filtration rate [eGFR]), and macrovascular measures (pulse wave velocity, 24-hour pulse pressure [PP] and augmentation index [Aix]).

Results: In multivariable-adjusted regression analyses, there were vasculoprotective associations between serum selenium and a microvascular measure (AVR [β?=?0.23; p?=?0.036]) in black African women and with a macrovascular measure (24-hour PP [β = ?0.15; p?=?0.048]) in white African women. In turn, GPx activity also showed a protective association with a microvascular measure (eGFR) in white African men (β?=?0.23; p?=?0.035), as well as with macrovascular measures (AIx, PP) in the black (β = ?0.25; p?=?0.027) and white African men (β = ?0.22; p?=?0.035), and black African women (β = ?0.32; p?=?0.001).

Conclusions: Collectively the findings suggest a protective role for the micronutrient selenium and GPx on both the micro- and macrovasculature in a young, healthy bi-ethnic population.     

Chemoprevention of liver cancer by plant polyphenols

Primary liver cancer or hepatocellular carcinoma (HCC) is one of the most frequent tumors representing the fifth commonest malignancy worldwide and the third cause of mortality from cancer. Currently, the treatments for HCC are not so effective and new strategies are needed for its fight. Chemoprevention, the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenesis is considered an important way for confronting HCC. Many of the chemopreventive agents are phytochemicals, namely non-nutritive plant chemicals with protective or disease preventive properties. In this review, we focus on plant polyphenols, one of the most important classes of phytochemicals, their chemopreventive properties against HCC and discuss the molecular mechanisms accounting for this activity.     

How does tobacco smoke influence the morphometry of the fetus and the umbilical cord?—Research on pregnant women with intrauterine growth restriction exposed to tobacco smoke

Proper structure of the umbilical cord is important for the fetal development. We evaluated effects of toxic factors from tobacco smoke on fetal and umbilical cord morphometry. 109 women in weeks 29–40 of pregnancy (31 smokers with intrauterine growth restriction (IUGR); 28 non-smoking women with IUGR; 50 healthy pregnancies) were included. In smokers with IUGR, cotinine, cadmium and lead concentrations were significantly higher than in controls (mean 55.23 ng/l; 1.52 ng/ml; 14.85 ng/ml vs 1.07; 0.34; 9.42) and inverse correlation between lead concentration and uncoiled umbilical cord was significant (r = −0.80). In smokers with IUGR, area of Wharton’s jelly was increased compared to nonsmokers and controls. Inverse correlations occurred between cotinine and cadmium concentration and fetal percentile in smokers (r = −0.87; r = −0.87) and non-smokers (r = −0.47; r = −0.78) with IUGR. Exposure to tobacco smoke measured by cotinine, cadmium and lead concentration has an impact on fetal growth and umbilical cord morphometry and correlates with intensity of IUGR.     

The impact of thyroid abnormalities during pregnancy on subsequent neuropsychological development of the offspring: a meta-analysis

Objective: To investigate the relationship between specific thyroid abnormalities in women during pregnancy and the subsequent neuropsychological development of their offspring.

Methods: A systematic literature search of PubMed, Embase and Web of Science was conducted. Eligible studies were case-control or cohort study that explored this association with euthyroid thyroid abnormalities during pregnancy. The outcomes included intelligence scores and motor scores. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with Cochrane Q chi-square test and I² statistics. A fixed-effects or random-effects model was used to pool the estimates according to the heterogeneity among the included studies.

Results: Six studies, involving 4449 participants, were included. Children of women with thyroid abnormalities had mean intelligence score of 6.27 points and motor score of 5.99 points lower than that of children of euthyroid women. Subgroup analysis suggested that, children of women with hypothyroxinaemia, subclinical hypothyroidism and positive TPOAb had mean intelligence scores of 5.69 points, 8.76 points and 10.55 points, and mean motor scores of 4.19 points, 9.98 points and 9.03 points lower than those of the controls, respectively.

Conclusions: The thyroid abnormalities in pregnant women may adversely affect neuropsychological development of their offspring.     

Chronic methylphenidate induces increased quinone production and subsequent depletion of the antioxidant glutathione in the striatum

BackgroundMethylphenidate (Ritalin®) is a psychostimulant used chronically to treat attention deficit hyperactivity disorder. Methylphenidate acts by preventing the reuptake of dopamine and norepinephrine, resulting in an increase in these neurotransmitters in the synaptic cleft. Excess dopamine can be autoxidized to a quinone that may lead to oxidative stress. The antioxidant, glutathione helps to protect the cell against quinones via conjugation reactions; however, depletion of glutathione may result from excess quinone formation. Chronic exposure to methylphenidate appears to sensitize dopaminergic neurons to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that oxidative stress caused by the autooxidation of the excess dopamine renders dopaminergic neurons within the nigrostriatal pathway to be more sensitive to MPTP.MethodsTo test this hypothesis, male mice received chronic low or high doses of MPH and were exposed to saline or MPTP following a 1-week washout. Quinone formation in the striatum was examined via dot blot, and striatal GSH was quantified using a glutathione assay.ResultsIndeed, quinone formation increased with increasing doses of methylphenidate. Additionally, methylphenidate dose-dependently resulted in a depletion of glutathione, which was further depleted following MPTP treatment.ConclusionsThus, the increased sensitivity of dopamine neurons to MPTP toxicity following chronic methylphenidate exposure may be due to quinone production and subsequent depletion of glutathione.     

The effect of vitamin D on thyroid autoimmunity in euthyroid men with autoimmune thyroiditis and testosterone deficiency

BackgroundAutoimmune (Hashimoto’s thyroiditis) is characterized by a strong female preponderance, which may suggest that sex hormones have an impact on thyroid autoimmunity. The aim of this study was to investigate whether testosterone determines vitamin D action on thyroid antibody titers and thyroid function tests in men with autoimmune thyroiditis and low testosterone levels.MethodsThe study included 36 men with testosterone deficiency, 17 of whom had been treated for at least 26 weeks with oral testosterone undecanoate (120 mg daily). Because of coexistent euthyroid Hashimoto’s thyroiditis, all participants were then treated with vitamin D (100 μg daily). Serum titers of thyroid peroxidase and thyroglobulin antibodies, serum levels of thyrotropin, free thyroid hormones, testosterone and 25-hydroxyvitamin D, as well as Jostel’s thyrotropin index, SPINA-GT and SPINA-GD were assessed before vitamin D treatment and 26 weeks later.ResultsWith the exception of testosterone levels, there were no significant differences between both study groups in serum hormone levels, antibody titers and thyroid function tests. All participants completed the study. In addition to increasing 25-hydroxyvitamin D levels, vitamin D increased SPINA-GT and reduced thyroid peroxidase and thyroglobulin antibody titers. In testosterone-treated men, vitamin D increased testosterone levels. Vitamin D did not affect serum levels of thyrotropin, free thyroid hormones, Jostel’s thyrotropin index and SPINA-GD. Treatment-induced changes in thyroid antibody titers and SPINA-GT were more pronounced in testosterone-treated than testosterone-naïve men.ConclusionsThe obtained results suggest that the beneficial effect on thyroid autoimmunity and thyroid secretory function is stronger in men receiving testosterone therapy.     

Transdermal patches loaded with L-cysteine HCL as a strategy for protection from mobile phone emitting electromagnetic radiation hazards

Mobile phone usage has been increased in the last few years emitting electromagnetic radiation (EMR), which disturbs normal cellular processes via oxidative stress. L-cysteine, a glutathione precursor, prevents oxidative damage. Transdermal patches (TDPs) loaded with L-cysteine hydrochloride (L-CyS-HCL) were fabricated by dispersion of L-CyS-HCL 5% w/w and different concentrations of sorbitol as a plasticizer in room-temperature vulcanizable synthetic silicone matrices (RTV-Si). The effect of sorbitol on patch physicochemical parameters was assessed; in-vitro L-CyS-HCL release profiles and ex-vivo permeation were studied. Pharmacokinetic parameters of endogenous synthetized in-vivo glutathione, after receiving IV bolus dose of L-CyS-HCl and L-CyS-HCl-RTV-Si-TDPs were studied in rat model. The influence of L-CyS-HCL-RTV-Si-TDPs against damaging effects of mobile phone EMR on rats' blood and brain tissues was studied. The results revealed that patch plasticity, intensity reflections, surface porosity, L-CyS-HCL release rate and skin permeation increased with increasing sorbitol concentration. Pharmacokinetic profile for IV dose and L-CyS-HCl-RTV-Si-TDPs revealed that the L-CyS-HCl-RTV-Si-TDPs provided a sustained glutathione plasma concentration–time profile over entire patch application. High significant differences in biological parameters (blood and brain samples) were observed for radiated rats using the patch in study compared with positive control rats. Promising long-term strategy for protection against mobile phone hazards was obtained.     

Inhibition of microRNA-17-5p reduces the inflammation and lipid accumulation,and up-regulates ATP-binding cassette transporterA1 in atherosclerosis

Atherosclerosis (AS) is a chronic inflammatory disease of the arterial wall. Macrophages are considered to be closely associated with the development and progression of AS. However, the precise mechanism of miR-17-5p in the macrophages under AS remains incompletely clarified. This study investigated the regulatory effect of miR-17-5p on the inflammation and lipid accumulation in mouse macrophages both in vivo and in vitro. It was found that miR-17-5p was highly expressed with lowered ATP-binding cassette transporterA1 (ABCA1) level in the peripheral blood leucocytes (PBLs) of AS patients. Moreover, the level of miR-17-5p was up-regulated in the macrophages of ApoE^?/? mice fed with a high-cholesterol diet. Furthermore, we injected miR-17-5p antagomir into AS mice or transfected miR-17-5p inhibitors into mouse macrophage RAW264.7 cells. Results showed that downregulation of miR-17-5p significantly reduced the production of inflammatory cytokines, inhibited the lipid accumulation and up-regulated ABCA1, and activated peroxisome proliferator-activated receptor (PPAR) γ/Liver X receptor (LXR) α signaling pathway. Additionally, ABCA1 was found to be a target of miR-17-5p by directly binding to 3′-untranslated region (3′-UTR) of its mRNA. Our study indicates a novel regulatory mechanism for miR-17-5p by interacting with ABCA1, which could be a therapy-target for the treatment of AS.     

多烯磷脂酰胆碱联合谷胱甘肽治疗妊娠期肝内胆汁淤积症患者的效果及对围产结局的影响

目的探讨多烯磷脂酰胆碱联合谷胱甘肽治疗妊娠期肝内胆汁淤积症(ICP)患者的效果及对围产结局的影响。方法选取2015年1月～2018年12月ICP患者124例,随机分为两组。两组均予以卧床休息、间断吸氧、高渗葡萄糖、维生素C及能量合剂等治疗。对照组在此基础上予以多烯磷脂酰胆碱针15 mL静脉滴注,1次/d;观察组在对照组基础上再加谷胱甘肽针2.4 g静脉滴注,1次/d。两组均连用2周。观察两组治疗后临床症状及血清生化指标改善情况,并比较其围产结局。结果治疗2周后,两组瘙痒评分均较治疗前显著下降(P0.01或P0.05),且观察组下降幅度较对照组更明显(P0.05);观察组黄疸和瘙痒消失时间明显少于或短于对照组(P0.05)。治疗2周后,两组血清ALT、TBA和AST水平均较治疗前明显下降(P0.01或P0.05),且观察组下降幅度较对照组更明显(P0.05)。同时观察组宫内窘迫、早产和新生儿窒息发生率明显低于对照组,分娩出血量明显少于对照组,新生儿体重明显大于对照组(P0.05)。结论多烯磷脂酰胆碱联合谷胱甘肽治疗ICP患者不仅能明显改善其临床症状,降低肝酶指标与胆汁酸水平,而且能降低发生不良围产结局,有利于母婴安全。