Targeting oxidative stress response by green tea polyphenols: clinical implications

Abstract

Green tea polyphenols, the most interesting constituent of green tea leaves, have been shown to have both pro-oxidant and antioxidant properties. Both pro-oxidant and antioxidant properties are expected to contribute to modulation of oxidative stress response under ideal optimal dosage regimens. Exposure to a low concentration of a pro-oxidant prior to exposure to oxidative stress induces the expression of genes that code for proteins that induce adaptation in a subsequent oxidative stress. On the other hand, exposure to an antioxidant concurrently with exposure to the oxidative stress affords protection through free radical scavenging or through other indirect antioxidant mechanisms. In any case, the optimal conditions that afford protection from oxidative stress should be defined for any substance with redox properties. Green tea polyphenols, being naturally occurring substances, seem to be an ideal option for the modulation of oxidative stress response. This paper reviews available data on the pro-oxidant and antioxidant properties of green tea polyphenols focusing on their potential on the modulation of oxidative stress response.     

Dietary antioxidants provide differential subcellular protection in epithelial cells

Abstract

This study aimed to evaluate the organelle-specific antioxidant/pro-oxidant actions of clinically important dietary antioxidants against oxidative stress. An in vitro cellular model was employed to investigate the antioxidant/pro-oxidant effects of various concentrations (1, 10 and 100 μM) of ascorbic acid, α-tocopherol and β-carotene during H₂O₂-induced oxidative stress. Damage to nuclear and mitochondrial genomes was analyzed by quantitative polymerase chain reaction and oxidation of membrane lipids was measured via colorimetric assays. The key findings were: (i) dietary antioxidants conferred a dose-dependent protective effect (with a pro-oxidant shift at higher concentrations); (ii) the protection conferred to different sub-cellular organelles is highly specific to the dietary antioxidant; (iii) the mtDNA is highly sensitive to oxidative attack compared to nDNA (P < 0.05); and (iv) mtDNA protection conferred by dietary antioxidants was required to improve protection against oxidative-induced cell death. This study shows that antioxidant-induced protection of mtDNA is an important target for future oxidative stress therapies.     

A proteomic approach to the bilirubin‐induced toxicity in neuronal cells reveals a protective function of DJ‐1 protein

Unconjugated bilirubin (UCB) is a powerful antioxidant and a modulator of cell growth through the interaction with several signal transduction pathways. Although newborns develop a physiological jaundice, in case of severe hyperbilirubinemia UCB may become neurotoxic causing severe long‐term neuronal damages, also known as bilirubin encephalopathy. To investigate the mechanisms of UCB‐induced neuronal toxicity, we used the human neuroblastoma cell line SH‐SY5Y as an in vitro model system. We verified that UCB caused cell death, in part due to oxidative stress, which leads to DNA damage and cell growth reduction. The mechanisms of cytotoxicity and cell adaptation to UCB were studied through a proteomic approach that identified differentially expressed proteins involved in cell proliferation, intracellular trafficking, protein degradation and oxidative stress response. In particular, the results indicated that cells exposed to UCB undertake an adaptive response that involves DJ‐1, a multifunctional neuroprotective protein, crucial for cellular oxidative stress homeostasis. This study sheds light on the mechanisms of bilirubin‐induced neurotoxicity and might help to design a strategy to prevent or ameliorate the neuronal damages leading to bilirubin encephalopathy.     

Season of Birth and Early Neonatal Events. The Rise of Serum Bilirubin

A prospective study on the rise of serum bilirubin during the first 24 hours of life has been carried out in a sample of 343 newborns from the population of Rome. The rise of serum bilirubin level during the first 24 hours of life depends on season of birth showing a minimum in the Autumn. The phenomenon is much more marked in female than in male newborn infants. Recent studies suggest a beneficial action of bilirubin due to its protective effect from secondary oxidants. Since the newborn infant is very sensible to oxidative damage, it is possible that seasonal variation of bilirubin level during the first few days of life may influence further development and susceptibility to pathological manifestations.     

Season of Birth and Early Neonatal Events. The Rise of Serum Bilirubin

A prospective study on the rise of serum bilirubin during the first 24 hours of life has been carried out in a sample of 343 newborns from the population of Rome. The rise of serum bilirubin level during the first 24 hours of life depends on season of birth showing a minimum in the Autumn. The phenomenon is much more marked in female than in male newborn infants. Recent studies suggest a beneficial action of bilirubin due to its protective effect from secondary oxidants. Since the newborn infant is very sensible to oxidative damage, it is possible that seasonal variation of bilirubin level during the first few days of life may influence further development and susceptibility to pathological manifestations.     

Molecular mechanisms of oxidative stress-related neonatal jaundice

Oxidative stress is a pathological condition characterized by an overload of oxidant products, named free radicals, which are not well counteracted by antioxidant systems. Free radicals induce oxidative damage to many body organs and systems. In neonatal red blood cells, free-radical mediated-oxidative stress leads to eryptosis, a suicidal death process of erythrocytes consequent to alteration of cell integrity. Neonatal red blood cells are targets and at the same time generators of free radicals through the Fenton and Haber-Weiss reactions. Enhanced eryptosis in case of oxidative stress damage may cause anemia if the increased loss of erythrocytes is not enough compensated by enhanced new erythrocytes synthesis. The oxidative disruption of the red cells may cause unconjugated idiopathic hyperbilirubinemia in neonates. High levels of bilirubin are recognized to be dangerous for the central nervous system in newborns, however, many studies have highlighted the antioxidant function of bilirubin. Recently, it has been suggested that physiologic concentration of bilirubin correlates with higher antioxidant status while high pathological bilirubin levels are associated with pro-oxidants effects. The aim of this educational review is to provide an updated understanding of the molecular mechanisms underlying erythrocyte oxidant injury and its reversal in neonatal idiopathic hyperbilirubinemia.     

Human umbilical artery endothelial cells from Large-for-Gestational-Age newborn have increased antioxidant efficiency and gene expression

Obesity is a public health problem worldwide, and especially in women in reproductive age where more than one in three have obesity. Maternal obesity is associated with an increased maternal, placental, and newborn oxidative stress, which has been proposed as a central factor in vascular dysfunction in large-for-gestational-age (LGA) newborn. However, cellular and molecular mechanisms behind this effect have not been elucidated. Untreated human umbilical artery endothelial cells (HUAEC) from LGA (LGA-HUAEC) presented higher O₂⁻ levels, superoxide dismutase activity and heme oxygenase 1 messenger RNA (mRNA) levels, paralleled by reduced GSH:GSSG ratio and NRF2 mRNA levels. In response to an oxidative challenge (hydrogen peroxide), only HUAEC from LGA exhibited an enhanced Glutathione Peroxidase 1 (GPX1) expression, as well as a more efficient antioxidant machinery measured by the biosensor probe, HyPer. An open state of chromatin in the TSS region of GPX1 in LGA-HUAEC was evidenced by the DNase-HS assay. Altogether, our data indicate that LGA-HUAEC have an altered cellular and molecular antioxidant system. We propose that a chronic pro-oxidant intrauterine milieu, as evidenced in pregestational obesity, could induce a more efficient antioxidant system in fetal vascular cells, which could be maintained by epigenetic mechanism during postnatal life.     

Nicotine's oxidative and antioxidant properties in CNS

Nicotine has been reported to be therapeutic in some patients with certain neurodegenerative diseases and to have neuroprotective effects in the central nervous system. However, nicotine administration may result in oxidative stress by inducing the generation of reactive oxygen species in the periphery and central nervous system. There is also evidence suggesting that nicotine may have antioxidant properties in the central nervous system. The antioxidant properties of nicotine may be intracellular through the activation of the nicotinic receptors or extracellular by acting as a radical scavenger in that it binds to iron. The possibility that nicotine might be used to treat some symptoms of certain neurodegenerative diseases underlies the necessity to determine whether nicotine has pro-oxidant, antioxidant or properties of both. This review discusses the studies that have addressed this issue, the behavioral effects of nicotine, and the possible mechanisms of action that result from nicotine administration or nicotinic receptor activation.     

早期光疗对早产儿黄疸的影响

目的：探讨在经皮胆红素监测下早期蓝光干预对早产儿高胆红素血症的防治作用。方法：选择2009年10月-2011年10月我院新生儿科收治的86例出生体重≤2000g,无出生窒息史的早产儿,按住院号单双号分为观察组46例和对照组40例。对照组按照我国2000年制定的新生儿黄疸干预推荐方案的干预标准进行光疗。观察组于出现黄疸和／或经皮胆红素〉85．50μmol／L,但尚未达方案的干预标准就进行光疗,监测经皮胆红素至黄痘消失。经皮胆红素值达187．5μmol／L以上时同时查静脉血监测血清总胆红素。比较2组早产儿经皮胆红素峰值及恢复正常时间。结果：观察组与对照组比较经皮胆红素峰值较低,黄疸持续时间较短,两组比较P均〈0．05,有统计学差异。结论：早产儿在经皮胆红素监测下进行早期蓝光干预有利于降低早产儿胆红素峰值,缩短黄疸持续时间。有效预防早产儿胆红素脑病。     

Evaluation of transcutaneous bilirubinometry in preterm infants of gestational age 32-34 weeks

Aims: The aim of this prospective study was to evaluate the accuracy of transcutaneous bilirubinometry using the Minolta Air-Shields JM-103 device in preterm newborns of gestational age 32-34 weeks, and to identify the most appropriate measurement site. Methods: Transcutaneous bilirubin (TcB) measurements were performed over forehead, sternum and abdomen, if total serum bilirubin (TSB) had to be determined on clinical indication in neonates of selected gestational age. TSB levels were measured in a clinical laboratory using direct spectrophotometry. In order to assess transcutaneous bilirubinometry accuracy, differences between TSB and TcB, their CI95%, and correlation coefficients (r) between TcB and TSB were evaluated. Results: The study group consisted of 44 infants, including 6 very low birth weight (VLBW) neonates. The correlations between transcutaneous and laboratory values were found to be significant and close. Minimal differences were observed when measured over sternum. The measurements over forehead had a tendency to underestimate TSB levels. Conclusions: Noninvasive measurement by Minolta JM-103 demonstrated significant accuracy. The authors recommend measurements over sternum or abdomen in premature infants born within 32-34 gestational weeks as a reliable and accurate neonatal hyperbilirubinemia screening test. Transcutaneous bilirubinometry has the potential to reduce the number of blood samplings, thus reducing neonatal pain and discomfort, parental distress and medical care cost.     

Dietary antioxidants provide differential subcellular protection in epithelial cells

This study aimed to evaluate the organelle-specific antioxidant/pro-oxidant actions of clinically important dietary antioxidants against oxidative stress. An in vitro cellular model was employed to investigate the antioxidant/pro-oxidant effects of various concentrations (1, 10 and 100 microM) of ascorbic acid, alpha-tocopherol and beta-carotene during H2O2-induced oxidative stress. Damage to nuclear and mitochondrial genomes was analyzed by quantitative polymerase chain reaction and oxidation of membrane lipids was measured via colorimetric assays. The key findings were: (i) dietary antioxidants conferred a dose-dependent protective effect (with a pro-oxidant shift at higher concentrations); (ii) the protection conferred to different sub-cellular organelles is highly specific to the dietary antioxidant; (iii) the mtDNA is highly sensitive to oxidative attack compared to nDNA (P < 0.05); and (iv) mtDNA protection conferred by dietary antioxidants was required to improve protection against oxidative-induced cell death. This study shows that antioxidant-induced protection of mtDNA is an important target for future oxidative stress therapies.     

Potent antioxidant dendrimers lacking pro-oxidant activity

It is well known that antioxidants have protective effects against oxidative stress. Unfortunately, in the presence of transition metals, antioxidants, including polyphenols with potent antioxidant activities, may also exhibit pro-oxidant effects, which may irreversibly damage DNA. Therefore, antioxidants with strong free radical-scavenging abilities and devoid of pro-oxidant effects would be of immense biological importance. We report two antioxidant dendrimers with a surface rich in multiple phenolic hydroxyl groups, benzylic hydrogens, and electron-donating ring substituents that contribute to their potent free radical-quenching properties. To minimize their pro-oxidant effects, the dendrimers were designed with a metal-chelating tris(2-aminoethyl)amine (TREN) core. The dendritic antioxidants were prepared by attachment of six syringaldehyde or vanillin molecules to TREN by reductive amination. They exhibited potent radical-scavenging properties: 5 times stronger than quercetin and 15 times more potent than Trolox according to the 1,1-diphenyl-2-picrylhydrazyl assay. The antioxidant dendrimers also protected low-density lipoprotein, lysozyme, and DNA against 2,2'-azobis(2-amidinopropane) dihydrochloride-induced free radical damage. More importantly, unlike quercetin and Trolox, the two TREN antioxidant dendrimers did not damage DNA via their pro-oxidant effects when incubated with physiological amounts of copper ions. The dendrimers also showed no cytotoxicity toward Chinese hamster ovary cells.     

Antioxidant status in patients with psoriasis

Psoriasis is a chronic inflammatory skin disease with an unknown aetiology that has been associated with abnormal plasma lipid metabolism and oxidative stress. There are controversial results in the previous studies investigating oxidant/antioxidant systems in psoriasis. The aim of this work was to evaluate the plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total bilirubin (T. Bili), direct bilirubin (D. Bili), uric acid (UA), apolipoproteins (ApoA1 and ApoB), Lp(a) and activities of paraxonase 1 (PON1) in 100 patients with psoriasis and 100 controls, and to look for a correlation between these parameters in psoriasis. PON1, bilirubin and UA were measured spectrophotometrically, MDA by the high‐performance liquid chromatography method, apolipoproteins and Lp(a) by immunoprecipitation assays, and lipid and other biochemical parameters were determined by routine laboratory methods. In patients with psoriasis, there was a significant decrease in PON1, SOD and CAT activities (P < 0.05) and an increase in MDA levels (P < 0.01). Also, the levels of bilirubin (total and direct) and UA were decreased in patients with psoriasis but were not significant (P > 0.05). These results suggest that psoriasis was in a state of oxidative stress and that the protective effects of high‐density lipoprotein against atherosclerosis may be dependent on PON1 activity. Moreover, there is a negative correlation between antioxidant with Lp(a), apoB and MDA levels, suggesting that subjects with higher levels of Lp(a) and apoB and lower levels of antioxidant are more exposed to oxidative damage. These findings may explain in part the reported increase in cardiovascular mortality in psoriasis. Copyright © 2013 John Wiley & Sons, Ltd.     

早产儿超声心脏几何形态学与血流动力学的相关性分析

摘要 目的：探讨与分析早产儿超声心脏几何形态学与血流动力学的相关性。方法：研究时间为2018年8月到2020年6月,选择本院收治的早产儿150例(早产组)和足月儿150例(足月组)作为研究对象,两组新生儿都给予超声检查,记录、左心室舒张期内径(Left ventricular diastolic diameter,LVDd)、左心室收缩期内径(Left ventricular systolic diastolic,LVDs)、左房内径(Left atrial diameter,LAD)、左心室相对厚度(Left ventricular relative wall thickness,LVRWT)、左心室心肌质量(Left ventricular myocardial mass,LVM)、左室后壁舒张期厚度(Left ventricular posterior walldepth,LVPWd)、左心室舒张末期容积(Left ventricular end diastolic volume,LVDV)、左心室收缩末期容积(Left ventricular end systolic volume,LVSV)、每搏输出量(Stroke volume,SV)、左心室射血分数(Left ventricular ejection fraction,LVEF)、左心室缩短分数(Left ventricular fractional shortening,LVFS)等指标并进行相关性分析。结果：早产组的LVDd、LVDs、LAD、LVPWd、LVRWT、LVM值都显著低于足月组(P<0.05)。早产组的LVDV、LVSV、SV值低于足月组(P<0.05),两组LVEF、LVFS值对比差异无统计学意义(P>0.05)。在早产组中,Pearson相关性分析显示LVDd、LVDs、LAD、LVPWd、LVRWT、LVM值与LVDV、LVSV、SV值存在正相关性(P<0.05)。Cox比例风险回归模型显示早产儿的出生体重、身长为影响LVDd、LVDV值的主要因素(P<0.05)。结论：早产儿超声心脏几何形态学指标与血流动力学指标呈正相关,提示超声能准确记录和监测早产儿的心脏几何形态学与血流动力学,可作为评估早产儿心功能的一种可靠方法。     

Iron Release in Erythrocytes and Plasma Non Protein-bound Iron in Hypoxic and Non Hypoxic Newborns

Iron is released in a desferrioxamine (DFO)-chelatable form (DCI) when erythrocytes are challenged by an oxidative stress. In &#103 -thalassemic erythrocytes, both DCI content and release (after aerobic incubation for 24 h) are increased and correlated with the fetal hemoglobin (HbF) levels. Since erythrocytes from newborns have an extremely high content of HbF and are exposed to conditions of oxidative stress, the release of iron in these erythrocytes was investigated. The erythrocyte DCI content was increased in preterm but not in term newborns as compared to adults, while the release was increased in both preterm and term erythrocytes. The level of plasma non protein-bound iron (NPBI), which was not detectable in adults, was much higher in preterm than in term newborns. When term plus preterm newborns were divided in two groups, normoxic and hypoxic, according to cord blood pH, it was found that both iron release and NBPI were markedly higher in the hypoxic newborns compared to normoxic ones. Similar results were also obtained when the preterm and term infants were considered separately on the basis of cord blood pH. Therefore, iron release and NPBI are higher when conditions of hypoxia occur. In fact, when the values for iron release and NPBI were separately plotted against cord blood pH values, significant negative correlations were seen in both cases. NPBI was correlated with iron release seen in all the newborns and a significant part of the released iron could be recovered into the incubation medium at the end of the incubation.     

Iron release in erythrocytes and plasma non protein-bound iron in hypoxic and non hypoxic newborns

Iron is released in a desferrioxamine (DFO)-chelatable form (DCI) when erythrocytes are challenged by an oxidative stress. In β-thalassemic erythrocytes, both DCI content and release (after aerobic incubation for 24 h) are increased and correlated with the fetal hemoglobin (HbF) levels. Since erythrocytes from newborns have an extremely high content of HbF and are exposed to conditions of oxidative stress, the release of iron in these erythrocytes was investigated. The erythrocyte DCI content was increased in preterm but not in term newborns as compared to adults, while the release was increased in both preterm and term erythrocytes. The level of plasma non protein-bound iron (NPBI), which was not detectable in adults, was much higher in preterm than in term newborns. When term plus preterm newborns were divided in two groups, normoxic and hypoxic, according to cord blood pH, it was found that both iron release and NBPI were markedly higher in the hypoxic newborns compared to normoxic ones. Similar results were also obtained when the preterm and term infants were considered separately on the basis of cord blood pH. Therefore, iron release and NPBI are higher when conditions of hypoxia occur. In fact, when the values for iron release and NPBI were separately plotted against cord blood pH values, significant negative correlations were seen in both cases. NPBI was correlated with iron release seen in all the newborns and a significant part of the released iron could be recovered into the incubation medium at the end of the incubation.     

Antidepressant-like effect of a Ginkgo biloba extract (EGb761) in the mouse forced swimming test: role of oxidative stress

EGb761 is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves. This extract is used clinically due to its neuroprotective effects, exerted probably via its potent antioxidant or free radical scavenger action. Previous studies suggest that oxidative stress, via free radical production, may play an important role in depression and animal models for depression-like behavior. Preclinical studies have suggested that antioxidants may have antidepressants properties. The aim of this study was to investigate the antidepressant-like of EGb761 due to its antioxidant role against oxidative stress induced in the forced swimming test, the most widely used preclinical model for assessing antidepressant-like behavior. Male BALB/c mice were pretreated with EGb761 (10 mg/kg, ip) daily for 17 days followed by the forced swimming test and spontaneous locomotor activity. Animals were sacrificed to evaluate lipid peroxidation, different antioxidant enzyme activities, serotonin and dopamine content in midbrain, hippocampus and prefrontal cortex. EGb761 significantly decreased the immobility time (39%) in the forced swimming test. This antidepressant-like effect of EGb761 was associated with a reduction in lipid peroxidation and superoxide radical production (indicated by a downregulation of Mn-superoxide dismutase activity), both of which are indicators of oxidative stress. The protective effect of EGb761 is not related to excitatory or inhibitory effects in locomotor activity, and was also associated with the modulation of serotonergic and dopaminergic neurotransmission. It is suggested that EGb761 produces an antidepressant-like effect, and that an antioxidant effect against oxidative stress may be partly responsible for its observed neuroprotective effects.     

Glucose regulation in preterm newborn infants

After birth, continuous transplacental transfer of glucose is interrupted. Neonates have to provide brain and vital organs with sufficient glucose. In term newborn infants, this is accomplished through well-coordinated hormonal and metabolic adaptive changes. During the first week of life, preterm infants are at high risk of abnormal glucose homeostasis. They are at risk of hypoglycemia due to limited glycogen and fat stores that should have occurred in the third trimester. Continuous glucose infusion is always required soon after birth to maintain the glucose level. However, under such conditions, many preterm infants develop hyperglycemia. Defective islet beta-cell processing of proinsulin is likely related to hyperglycemia. There is also evidence that preterm infants are partially resistant to insulin. By contrast with adults, hepatic glucose production is not suppressed during parenteral glucose infusion. Exogenous insulin infusion partially reduces endogenous glucose production in preterm newborn infants. This treatment is efficient and safe when used with caution. More research is needed to understand the specificity of glucose homeostasis in preterm infants and to evaluate the long-term consequences of metabolic and nutritional support during early life.     

Effect of phototherapy on oxidant/antioxidant status: a randomized controlled trial

In order to evaluate the effect of different types of phototherapy on oxidant/antioxidant status in hyperbilirubinemic neonates, an interventional randomized control trial was conducted on 120 neonates ≥35 weeks’ gestational age with indirect hyperbilirubinemia reaching phototherapy level. This study is registered with ClinicalTrials.gov as NCT03074292. Neonates were assigned to three groups; 40 neonates received conventional phototherapy, 40 received intensive phototherapy and 40 received blue light-emitting diodes (LED) phototherapy. Complete blood count (CBC), total serum bilirubin (TSB), total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NO), copper (Cu), zinc (Zn), and iron (Fe) levels were measured before and 24?hours after phototherapy. TSB decreased postphototherapy in all three groups (p < .05 for all), with significantly lower levels following intensive and LED phototherapy compared to conventional phototherapy (p < .05 for both). TAC decreased postphototherapy in the three groups (p < .05 for all). MDA and NO increased postphototherapy (p < .05 for all), with the intensive phototherapy group having the highest levels followed by the conventional while LED phototherapy group showed the lowest levels in comparison to the other groups (p < .05). Cu, Zn and Fe increased postphototherapy in all three groups (p < .05 for all). Positive correlations were found between postphototherapy TSB with TAC, Cu and Zn (p < .05) and negative correlations with MDA, NO and Fe (p < .05) among neonates of the 3 studied groups. In conclusion, different photo therapies have an impact on oxidant/antioxidant balance and are associated with increased oxidative stress markers with the LED phototherapy being the safest.     

The Effect of Gestational Age and Labour on Markers of Lipid and Protein Oxidation in Cord Plasma

There are many potential sources of reactive oxidants around the time of birth and pre-term infants are considered to be particularly vulnerable to oxidative injury. To gain insight into these processes, we have measured biomarkers of lipid and protein oxidation in umbilical cord plasma and related concentrations to mode of delivery and gestational age. Protein carbonyls were measured by ELISA and malondialdehyde (MDA) by HPLC after reaction with thiobarbituric acid, for 54 pre-term (≤36 weeks gestational age) and 43 term infants. Protein carbonyls were significantly lower in pre-term (median for <32 weeks gestational age 0.048?nmol/mg protein) than in term infants (0.105?nmol/mg, p=0.004), and were unrelated to mode of delivery. In contrast, MDA concentrations were higher in the very pre-term (<32 weeks gestation) group (2.47 compared with 1.83?μM for term infants, p<0.0001). MDA concentrations were higher in infants who were born with labour compared with elective caesarean section. Pre-eclampsia in the mother was associated with higher cord blood MDA concentrations. The MDA results are consistent with other studies of this marker and could be interpreted as indicating increased oxidative stress associated with prematurity and labour. However, the lower protein carbonyls in pre-term infants would lead to an opposite interpretation. More information is needed on the source and fate of these and other biomarkers before drawing strong conclusions on how they reflect oxidative stress in this and other clinical situations.