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Role of ultraviolet ray filters and antioxidants in the prevention of DNA damage and oxidative stress associated with phototherapy in jaundiced term neonates
Abstract
Background
Phototherapy induces DNA damage by direct and indirect (oxidative) effects, which are prevented by ultraviolet (UV) filters and antioxidants.
Aim
Our goal was to assess DNA damage and oxidative stress associated with phototherapy and to prove the efficacy of UV filters and antioxidants for the prevention of DNA damage.
Patients and methods
The study included 160 jaundiced neonates who had been exposed to phototherapy for at least 48 h. The neonates were divided into four groups, 40 neonates in each group. The first (control) group received phototherapy only; the second group received antioxidants before and during phototherapy; the third group received phototherapy under an umbrella of UV filters; and the fourth group received phototherapy under both UV filters and antioxidants. DNA damage was assayed by the comet assay. Plasma total antioxidant capacity and total oxidant status levels were also measured and then oxidative stress index was calculated for all the four groups before and 48 h after phototherapy.
Results
The first group showed significant DNA damage accompanied with severe deterioration in all oxidative stress parameters by about 19%; the second group showed a decreasing trend as regards DNA damage and oxidative stress parameter deterioration to about 9%; the third group showed a more decreasing trend than group II to about 5%; but on the other hand, the fourth group showed complete DNA protection from damage with no changes in oxidative stress parameters.
Conclusion
Phototherapy causes DNA damage that can be completely prevented by combined concurrent use of UV filters and antioxidants.
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There is something intriguing and at the same time fascinating that a simple reaction (of Fe 2+ ions with H 2O 2), which was observed by H.J.H. Fenton over 110 years ago, proves to be very difficult to describe and understand. As yet the nature of the oxidizing species obtained in Fenton reaction is still a subject of deliberation, which may be explained by the fact that it is very common in both chemical and biological systems and in natural environment. It is a paradox that the Fenton reaction is successfully used in environmental protection (for example in wastewater treatment and remediation of groundwater) and it is thought to be a factor, which causes damage to biomolecules and plays a major role in the aging process and a variety of diseases. This article presents a short review on radical and non-radical mechanisms of the Fenton reaction postulated in literature, possible reaction pathways as well as various points of view in this field.
Background
Phototherapy has remained the standard therapeutic approach for neonatal hyperbilirubinemia. Oxidative effects of phototherapy on cell membranes and cell components may have a wide range of potential adverse effects, including enhanced lipid peroxidation and DNA damage. Apoptosis is an indispensable mechanism for maintaining many cellular functions, including cell replication, and removal of damaged cells with high burden of genetic mutations. Many genes function as apoptosis regulatory genes. Examples of these genes include the BCL2 gene which is an anti-apoptotic oncogene, and the BAX gene which acts as a promoter of apoptosis.
OBJECTIVE: Our aim was to determine whether endogenous mononuclear leukocyte DNA strand is a target of phototherapy. METHODS: The study included 65 term infants aged between 3-10 days that had been exposed to intensive (n = 23) or conventional (n = 23) phototherapy for at least 48 hours due to neonatal jaundice, and a control group (n = 19). DNA damage was assayed by single-cell alkaline gel electrophoresis (comet assay). Plasma total antioxidant capacity and total oxidant status levels were also measured, and correlation between DNA damage and oxidative stress was investigated. RESULTS: Mean values of DNA damage scores in both the intensive and conventional phototherapy groups were significantly higher than those in the control group (p 0.05). There were no significant correlations between DNA damage scores and bilirubin, total oxidant status and oxidative stress levels in either phototherapy group (p > 0.05). CONCLUSIONS: Both conventional phototherapy and intensive phototherapy cause endogenous mononuclear leukocyte DNA damage in jaundiced term infants.
Daily skin exposure to solar radiation causes cells to produce reactive oxygen species (ROS), which are a primary factor in skin damage. Although the contribution of the UV component to skin damage has been established, few studies have examined the effects of non-UV solar radiation on skin physiology. Solar radiation comprises <10% of UV, and thus the purpose of this study was to examine the physiological response of skin to visible light (400-700 nm). Irradiation of human skin equivalents with visible light induced production of ROS, proinflammatory cytokines, and matrix metalloproteinase (MMP)-1 expression. Commercially available sunscreens were found to have minimal effects on reducing visible light-induced ROS, suggesting that UVA/UVB sunscreens do not protect the skin from visible light-induced responses. Using clinical models to assess the generation of free radicals from oxidative stress, higher levels of free radical activity were found after visible light exposure. Pretreatment with a photostable UVA/UVB sunscreen containing an antioxidant combination significantly reduced the production of ROS, cytokines, and MMP expression in vitro, and decreased oxidative stress in human subjects after visible light irradiation. Taken together, these findings suggest that other portions of the solar spectrum aside from UV, particularly visible light, may also contribute to signs of premature photoaging in skin.
To assess the effect of phototherapy on serum oxidant and antioxidant status in hyperbilirubinemic full-term newborns.
Thirty-four full-term infants from 3 to 10 days of age exposed to phototherapy were studied. The serum antioxidant status was assessed by measuring the total antioxidant capacity (TAC) and individual antioxidant components: vitamin C, uric acid, albumin, thiol contents and total bilirubin. The oxidant status was assessed by determining the total oxidant status (TOS), oxidative stress index (OSI) and individual oxidant components: malondialdehyde (MDA), and lipid hydroperoxide levels.
Vitamin C, uric acid, total bilirubin and MDA concentration were significantly lower, whereas serum TOS, lipid hydroperoxide and OSI levels were significantly higher after phototherapy (p < 0.05). There were significant positive correlations between serum total bilirubin and MDA (r = 0.434, p = 0.001).
Although the MDA level was reduced after phototherapy, phototherapy has a negative impact on numerous parts of the oxidant/antioxidant defense system in jaundiced full-term newborns, exposing them to potential oxidative stress.
Our aim was to determine whether endogenous mononuclear leukocyte DNA strand is a target of phototherapy.
The study included 65 term infants aged between 3-10 days that had been exposed to intensive (n = 23) or conventional (n = 23) phototherapy for at least 48 hours due to neonatal jaundice, and a control group (n = 19). DNA damage was assayed by single-cell alkaline gel electrophoresis (comet assay). Plasma total antioxidant capacity and total oxidant status levels were also measured, and correlation between DNA damage and oxidative stress was investigated.
Mean values of DNA damage scores in both the intensive and conventional phototherapy groups were significantly higher than those in the control group (p < 0.001). Mean values and standard deviation were 32 (9), 28 (9), 21 (7) arbitrary unit, respectively. Total oxidant status levels in both the intensive and conventional phototherapy groups were significantly higher than those in the control group (p = 0.005). Mean (standard deviation) values were 18.1 (4.2), 16.9 (4.4), 13.5 (4.2) micromol H2O2 equivalent/L, respectively. Similarly, oxidative stress index levels in both the intensive and conventional phototherapy groups were significantly higher than those in the control group (p = 0.041). Plasma total antioxidant capacity and total bilirubin levels did not differ between the groups (p > 0.05). There were no significant correlations between DNA damage scores and bilirubin, total oxidant status and oxidative stress levels in either phototherapy group (p > 0.05).
Both conventional phototherapy and intensive phototherapy cause endogenous mononuclear leukocyte DNA damage in jaundiced term infants.
Phototherapy is commonly used in the treatment of hyperbilirubinemia in newborns. No serious side effects related to phototherapy have been observed, but concerns regarding its potential to damage DNA have been expressed, based on animal or cell-culture studies. The aim of this study was to investigate, in neonates with hyperbilirubinemia, the possible relation between phototherapy and DNA damage. The study included 33 full-term newborns with non-physiological jaundice and 14 healthy newborns with physiological jaundice as controls. Phototherapy was performed with an array of six fluorescent lamps producing radiation with wavelengths of 480-520 nm at 12 microW/cm(2)/nm. DNA damage in lymphocytes was determined by use of the alkaline comet assay. The DNA damage increased significantly with the duration of phototherapy, as shown by measurements at 24, 48, and 72 h (P<0.001). These findings indicate that phototherapy, widely used in neonatology units, increases DNA damage in newborns. It remains to be seen whether the genotoxic effect observed in the present study can cause any long-term health effect in phototherapy-treated infants in later life.
This book is a practical guide for pathophysiology of the role of oxidative stress in high prevalence diseases. In addition, the potential beneficial effects of antioxidants are discussed in the light of experimental studies, as well as clinical trials aimed to determine the outcome of patients, thus contributing to provide support to the use of these compounds as therapeutic resources against the injury caused by reactive oxigen species.
Jaundice is one of the most common conditions which requires medical attention in neonates. In addition to the short-term side effects, phototherapy may result in DNA damage. In this study the extent of DNA damage was assessed before and after phototherapy in cases with neonatal jaundice by single cell gel electrophoresis (Comet Assay). Eighty babies with neonatal jaundice were chosen for the study. Among them 40 babies whose total serum bilirubin level was >15mg/dl and received phototherapy formed the case group and the other 40 babies with total serum bilirubin level <15mg/dl who did not require phototherapy formed the control group. The comet head diameter was decreased in post phototherapy group (42.37±10.3) compared to pre phototherapy study group (49.34±10.7) with p < 0.05. The tail length was increased in post phototherapy group (25.19±11.77) compared to pre phototherapy (7.95±14.25) study group and controls (2.28±0.8) with p value < 0.05. We conclude that phototherapy causes significant DNA damage in babies with neonatal jaundice.
Bei 20 Neugeborenen, die wegen eines Ikterus neonatorum einer Phototherapie unterzogen wurden, wurde vor und nach dieser die Glutathionreduktaseaktivität in der Erythrozyten, die Serumharnsäurekonzentration, sowie Harnsäure, Xanthin und Hypoxanthin im Urin bestimmt. Die Glutathionreduktaseaktivität ist ein empfindlicher Parameter für den Versorgungszustand mit Riboflavin. Unter Phototherapie kam es zu einem signifikanten Abfall von Riboflavin und Harnsäure im Serum. Als Ursache des Abfalles der Serumharnsäurekonzentration werden die direkte Einwirkung von Licht, sowie eine Beeinträchtigung der Xanthinoxydase durch Riboflavinmangel diskutiert.
Materia: Regulatory overview: Environmental Protection Agency; Occupational Safety and Health Administration -- Principles of environmental engineering: Pollution Prevention; Air Pollution Engineering; Waste Treatment and Disposal Technologies; Wastewater and Water Quality; Storage and Containment; Statistical Applications -- Principles of safety engineering: Safety Management; Equipment Safety; Fire and Life Safety; Process and System Safety; Confined Space Safety; Construction Safety -- Principles of industrial hygiene and occupational Health engineering: Chemical Hazard Assessment and Communication; Personal Protective Equipment; Industrial Ventilation; Radiation Safety; Noise and Hearing Conservation; Ergonomics
Phototherapy (PT) is the most widely used form of treatment for unconjugated hyperbilirubinemia. One possible harmful consequence of PT is of a genetic nature. High levels of bilirubin may lead to oxidative damage in newborns: photochemical reactions may produce toxic photoproducts, probably peroxides. In order to investigate this hypothesis further under in vivo conditions, DNA strand-break frequency was examined by means of the comet assay in peripheral lymphocytes of icteric newborns undergoing PT treatment, and the levels of catalase, an antioxidant enzyme, were determined. We analyzed 20 term non-hemolitic hyperbilirubinemic jaundiced neonates before PT ('before PT' group) and just prior to ending PT ('after PT' group) and compared comet scores of these patients with those of 20 healthy term neonates who all had bilirubin levels in the physiological range. Comet scores (tail length, tail moment and %DNA in tail) of the group 'before phototherapy' were 23.5 +/- 16.3, 7.41 (0.97-40.7), 33.0 +/- 12.1, respectively and scores of after phototherapy group were 3.2 +/- 1.8, 0.29 (0.3-3.2), 10.7 +/- 3.7, respectively. Comet scores of the control group were 3.0 +/- 2.9, 0.25 (0.03-3.22), 10.9 +/- 4.5, respectively. Comet scores and plasma catalase activities in hyperbilirubinemic newborns were significantly higher before phototherapy, compared with the values after phototherapy and in the control groups (p < 0.001). There was no statistical difference between the 'after phototherapy' group and the controls (p > 0.05). These results indicate that high serum bilirubin level has genotoxic effects as is evident from the high rate of DNA strand-breaks in jaundiced newborns. Also PT does not cause an increase in DNA oxidation or induce the genotoxic effects of bilirubin. The counteracting effect of higher catalase activities in hyperbilirubinemic newborns may be responsible for the inactivating toxic and DNA-damaging effects of PT.
In experimental rodents, surgical removal of the pineal gland, the major source of circulating melatonin, causes a gradual and sustained rise in blood pressure. Conversely, when melatonin is chronically administered to pinealectomized rodents the increment in blood pressure is ameliorated. In humans as well, the night time rise in endogenous circulating melatonin levels may be inversely related to the reduction in night time blood pressure. Among patients with hypertension, some exhibit a much greater reduction in blood pressure at night (the so-called 'extreme dippers' and 'dippers'), whereas others exhibit only a slight night time reduction in systolic and diastolic pressure ('non-dippers' and 'inverted dippers'). Longitudinal studies of these patients show that inverted dippers and non-dippers die at a faster rate than do dippers and extreme dippers. The chronic administration of melatonin to individuals with hypertension induces a measurable drop in night time systolic and diastolic blood pressure. Moreover, the higher the night time level of endogenous melatonin (estimated from urinary metabolite of melatonin, 6-hydroxymelatonin sulphate), the greater the reduction in arterial blood pressure at night. The implication of these findings is that melatonin may have utility as an antihypertensive agent.
In this study, we aimed to make a comparison between chromosomal effects caused by conventional phototherapy and intensive phototherapy in jaundiced newborns. The study group included 83 newborns with gestation age of > or =35 weeks, and on days 3-10 after birth. Newborns were divided into four groups on the basis of total serum bilirubin (TSB) levels upon admission and need for phototherapy. The intensive group (n=19) consisted of newborns who received light-emitting diode (LED) phototherapy, the conventional group (n=23) consisted of newborns who received conventional phototherapy, the jaundiced control group (n=21) consisted of newborns whose TSB levels were higher than 10mg/dL (average = 13.7 + /-1.5 mg/dL) on admission and who did not receive phototherapy, and the non-jaundiced control group (n=20) consisted of newborns whose TSB levels were less than 5 mg/dl (average = 3.6 +/- 0.8 mg/dL). TSB level of the intensive group at admission was 20.2 +/- 1.3 mg/dL, whereas the level of conventional group was 19.6 +/- 1.5 mg/dL. Blood samples were taken from all infants on admission to determine sister chromatid exchange (SCE1) frequency. Blood sampling was repeated on discharge (SCE2) of infants who had received phototherapy. Demographic information, hospitalization details and the rate of decline in TSB were recorded, and frequencies of SCE1 and SCE2 were compared. There was no difference in demographic information among the four groups. SCE1 frequencies in 50 metaphases were evaluated in the intensive, conventional, jaundiced control and non-jaundiced control groups, and the SCE1 frequency was determined as 9.37/cell, 9.54/cell, 9.23/cell and 6.17/cell, respectively. The SCE1 frequency of the jaundiced groups (intensive, conventional and newborns-with-jaundice control group) was significantly higher than that in the non-jaundiced control group (p = 0.001). There was no significant difference between the intensive group and the conventional group in SCE2 frequency (13.5/cell vs. 13.55/cell, p = 0.39). SCE2 frequency was higher than SCE1 frequency in both the intensive and conventional groups (p = 0.001). A strong correlation was found between admission TSB and SCE1 frequency (p = 0.001; r = 0.79). The rate of decline in TSB was higher in the intensive group compared with the conventional group (0.26mg/(dLh) vs. 0.14 mg/(dLh); p = 0.001). We found that intensive and conventional phototherapies similarly increase SCE frequency in newborns. There was a strong, positive correlation between the TSB-on-admission level and SCE1 frequency. In the light of this study, we may conclude that intensive and conventional phototherapies may have an effect on chromosomes in jaundiced newborns. TSB levels higher than 10mg/dL are, too, reported hazardous on chromosomes. Further studies are warranted to elucidate this relationship.
20 newborn infants treated wih phototherapy for icterus neonatorum had analyzed their glutathione reductase activity in the erythrocytes, serum uric acid concentration and the urinary content of uric acid, xanthine and hypoxanthine before and after phototherapy. The activity of glutathione reductase is a sensitive indicator for the availability of riboflavine. There was a significant decrease of serum riboflavine and of serum uric acid during light therapy. The decrease of serum uric acid concentration is discussed as effect of direct photodecomposition on one hand and an inhibitory effect of riboflavine deficiency on uric acid formation on the other.
Hyperbilirubinemia is one of the most common problems encountered in term newborns. Historically, management guidelines were derived from studies on bilirubin toxicity in infants with hemolytic disease. More recent recommendations support the use of less intensive therapy in healthy term newborns with jaundice. Phototherapy should be instituted when the total serum bilirubin level is at or above 15 mg per dL (257 micromol per L) in infants 25 to 48 hours old, 18 mg per dL (308 micromol per L) in infants 49 to 72 hours old, and 20 mg per dL (342 micromol per L) in infants older than 72 hours. Few term newborns with hyperbilirubinemia have serious underlying pathology. Jaundice is considered pathologic if it presents within the first 24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dL (86 micromol per L) per day or is higher than 17 mg per dL (290 micromol per L), or an infant has signs and symptoms suggestive of serious illness. The management goals are to exclude pathologic causes of hyperbilirubinemia and initiate treatment to prevent bilirubin neurotoxicity.
The purpose of this study was to assess the effect of passive cigarette smoking on the oxidative and anti-oxidative status of plasma in infants. Eighty-four infants aged 6-28 weeks were divided into two groups: the study group included infants who had been exposed to passive smoking via at least five cigarettes per day for at least the past 6 weeks at home, while the control group included infants who had never been exposed to passive smoking. The antioxidative status of plasma was assessed by the measurement of individual antioxidant components: vitamin C, albumin, bilirubin, uric acid, thiol contents and total antioxidant capacity (TAC 1 and TAC 2). Oxidative status was assessed by the determination of total peroxide levels and the oxidative stress index (OSI 1 and OSI 2). Plasma vitamin C, thiol concentration and TAC 1 and TAC 2 levels were significantly lower, whereas plasma total peroxide levels and OSI 1 and OSI 2 were significantly higher, in passive smoking infants than in the controls (P<0.01). We conclude that passive smoking has a negative impact on numerous parts of the antioxidant defence system in infants, and exposes them to potent oxidative stress.
Improved survival because of advances in neonatal care has resulted in an increased number of infants at risk for chronic lung disease. Even though the etiology of lung injury is multifactorial, recent animal and clinical data indicate that pulmonary damage depends in large part on the ventilatory strategies used. Ventilator-associated lung injury was believed to result from the use of high pressure, thus, the term barotraumas. This trauma is believed to involve free-radical damage. Oxidant injury is a serious cause of lung injury. In the present study, 110 newborns with respiratory distress syndrome were studied; 55 were treated with melatonin and the other 55 with placebo. All the subjects were mechanically ventilated with or without guaranteed volume. Proinflammatory cytokines [interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha] were measured in tracheobronchial aspirate and the clinical outcome was evaluated. Melatonin treatment reduced the proinflammatory cytokines and improved the clinical outcome. The beneficial action of melatonin presumably related to its antioxidative actions.
To develop a new, colorimetric and automated method for measuring total oxidation status (TOS).
The assay is based on the oxidation of ferrous ion to ferric ion in the presence of various oxidant species in acidic medium and the measurement of the ferric ion by xylenol orange. The oxidation reaction of the assay was enhanced and precipitation of proteins was prevented. In addition, autoxidation of ferrous ion present in the reagent was prevented during storage. The method was applied to an automated analyzer, which was calibrated with hydrogen peroxide and the analytical performance characteristics of the assay were determined.
There were important correlations with hydrogen peroxide, tert-butyl hydroperoxide and cumene hydroperoxide solutions (r=0.99, P<0.001 for all). In addition, the new assay presented a typical sigmoidal reaction pattern in copper-induced lipoprotein autoxidation. The novel assay is linear up to 200 micromol H2O2 Equiv./L and its precision value is lower than 3%. The lower detection limit is 1.13 micromol H2O2 Equiv./L. The reagents are stable for at least 6 months on the automated analyzer. Serum TOS level was significantly higher in patients with osteoarthritis (21.23+/-3.11 micromol H2O2 Equiv./L) than in healthy subjects (14.19+/-3.16 micromol H2O2 Equiv./L, P<0.001) and the results showed a significant negative correlation with total antioxidant capacity (TAC) (r=-0.66 P<0.01).
This easy, stable, reliable, sensitive, inexpensive and fully automated method that is described can be used to measure total oxidant status.
To develop a novel colorimetric and automated direct measurement method for total antioxidant capacity (TAC).
A new generation, more stable, colored 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS(*+)) was employed. The ABTS(*+) is decolorized by antioxidants according to their concentrations and antioxidant capacities. This change in color is measured as a change in absorbance at 660 nm. This process is applied to an automated analyzer and the assay is calibrated with Trolox.
The novel assay is linear up to 6 mmol Trolox equivalent/l, its precision values are lower than 3%, and there is no interference from hemoglobin, bilirubin, EDTA, or citrate. The method developed is significantly correlated with the Randox- total antioxidant status (TAS) assay (r = 0.897, P < 0.0001; n = 91) and with the ferric reducing ability of plasma (FRAP) assay (r = 0.863, P < 0.0001; n = 110). Serum TAC level was lower in patients with major depression (1.69 +/- 0.11 mmol Trolox equivalent/l) than in healthy subjects (1.75 +/- 0.08 mmol Trolox equivalent/l, P = 0.041).
This easy, stable, reliable, sensitive, inexpensive, and fully automated method described can be used to measure total antioxidant capacity.
Jaundice and hyperbilirubinemia in the newborn
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- M K Robert
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Electrical Engineer’s Reference Book
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Laughton MA, Warne DF. Electrical Engineer's Reference Book. Sixteenth
Edition. Newnes; 2002 ISBN 0-7506-4637-3, 1504 p.
Academy of nutrition and dietetics complete food and nutrition guide
- R L Duyff
Duyff RL. Use supplements wisely. In: Beseler L, editor. Academy of
nutrition and dietetics complete food and nutrition guide. 5th ed. New York,
NY: Houghton Mifflin Harcourt; 2017: 842-844.
Dennis BL Hyperbilirubinemia in the term newborn
- M L Porter