Article
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Oxidative stress is considered to be the main cause of diabetic complications. As the role of antioxidants in diabetes therapy is still underestimated, the aim of the present investigation was to study the antioxidative action of melatonin in comparison with N-acetylcysteine (NAC) under diabetic conditions. Alloxan-diabetic rabbits were treated daily with either melatonin (1 mg/kg, i.p.), NAC (10 mg/kg, i.p.) or saline. Blood glutathione redox state and serum hydroxyl free radicals (HFR), creatinine and urea levels were monitored. After 3 wk of treatment animals were killed and HFR content, reduced glutathione/oxidized glutathione (GSH/GSSG) ratio as well as the activities of glutathione reductase, glutathione peroxidase and gamma-glutamylcysteine synthetase were estimated in both liver and kidney cortex. Diabetes evoked a several-fold increase in HFR levels accompanied by a significant decline in GSH/GSSG ratio in serum and the examined organs. In contrast to NAC, melatonin (at 1/10 the dose of NAC) attenuated diabetes-induced alterations in glutathione redox state and HFR levels, normalized creatinine concentration and diminished urea content in serum. Moreover, the indole resulted in an increase in glutathione reductase activity in both studied organs and in a rise in glutathione peroxidase and gamma-glutamylcysteine synthetase activities in the liver. In contrast to NAC, melatonin seems to be beneficial for diabetes therapy because of its potent antioxidative and nephroprotective action. The indole-induced increase in the activities of the enzymes of glutathione metabolism might be of importance for antioxidative action of melatonin under diabetic conditions.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Although melatonin was discovered to be a free radical scavenger just over a decade ago [32], the data documenting its ability to overcome oxidative stress has accumulated at a rapid pace and it is now abundant [24,25,1,15]. The efficacy of melatonin functioning in this capacity is related to its direct free radical scavenging actions [1,27], its ability to enhance the activities of a variety of antioxidative enzymes [3,29,36], its stimulatory actions on the synthesis of another important intracellular antioxidant, glutathione [37], its efficacy in reducing electron leakage from the mitochondrial electron transport chain [20], and its synergistic interactions with other antioxidants [21]. Moreover, in recent years, it has become apparent that, when melatonin scavenges radicals and related reactants, the products are generated are also free radical scavengers thereby greatly exaggerating the antioxidant potential of melatonin [15]. ...
... Melatonin is a potent free radical scavenger, more than vitamin E, which is the reference in the field [30]. Melatonin directly scavenges the highly toxic hydroxyl radical and other oxygen centered radicals and displays antioxidative properties: it increases the levels of several antioidative enzymes, including superoxide dismutase, glutathione peroxidase and glutathione reductase [36,37]. On the other hand; melatonin inhibits the pro-oxidative enzyme nitric synthase [13,11]. ...
Article
Full-text available
Melatonin, [N- acetyl- 5- methoxytryptamine] (ME), is an endocrine product of pineal gland. The present work was conducted to investigate the hepatoprotective effect of exogenous (ME). Thirty six healthy male rabbits weighting 1500-1700g.were divided into six groups with 6 animals in each group. Animals in the first group served as control, animals in the second, third, fourth, fifth, and sixth groups were intraperitoneally (i.p) injected with D-Galactosamine (GalN) in a single daily dose of 50mg/kg for the period of 20 days for the induction of hepatocellular injury. Animals in the third and fourth groups in addition to GalN were orally treated with ME in a single daily dose of 300µg/kg, as follows: animals in the third group received ME at 9am; and those in the fourth group received ME at 9pm, for the period of 20 days. Animals in the fifth and sixth groups, in addition to GalN, were orally treated with ME in a single daily dose of 600µg/kg, as follows: animals in the fifth group received ME at 9am, and animals in sixth group received ME at 9pm for the period of 20 days. The level of Albumin, Total Protein, Alanintransferase (ALT), Asparatatetransferase (AST), and Alkalin-phosphatase (ALP) in serum was estimated. Results showed that ME significantly (P<0.01) reduced the toxicity of GalN, and that ME is more effective when given at evening times.
... Rodriguez et al., [25] reported that melatonin antioxidative effect is one of the many functions of melatonin. Its ability to enhance the activities of varieties of antioxidative enzymes its stimulatory actions on the synthesis of another important intracellular antioxidant, glutathione has also been reported [26]. The result obtained, from 20% and 30% groups showing significant reduction when compared with the control and the reduction level in melatonin, present was sufficient to have sustained the glutathione production and hence reaffirming the fact that melatonin has stimulating effect on glutathione [26]. ...
... Its ability to enhance the activities of varieties of antioxidative enzymes its stimulatory actions on the synthesis of another important intracellular antioxidant, glutathione has also been reported [26]. The result obtained, from 20% and 30% groups showing significant reduction when compared with the control and the reduction level in melatonin, present was sufficient to have sustained the glutathione production and hence reaffirming the fact that melatonin has stimulating effect on glutathione [26]. ...
Article
Full-text available
The effect of Cola nitida consumption on melatonin production in albino male Wistar rats was investigated. Wistar rats weighing 150-220 g were fed for 30 days with different percentages of powdered Cola nitida (5%, 10%, 20%, 30% and 0% w/w). Serum concentrations of melatonin, ascorbic acid (AA), glutathione (GSH), serum alkaline phosphatase (ALP), serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of albino rats were determined using standard methods. Results show that melatonin level increased in the range of 14.8-23.8 ng/ml. As the concentration of Cola nitida in the exposed groups increased there was a decrease in melatonin concentration (9.3 ng/ml). There was a significant decrease (p<0.05) in the level of ascorbic acid (0.0085 to 0.0057 mg/dl) and glutathione (5.7 to 2.5 mg/dl) compared to the control group which showed 8.9 mg/dl and 6.7 mg/dl respectively. Similarly, aspartate aminotransferase (56.7 to 24.8 U/l) and alkaline phosphatase activities (54.5 to 25.3 Ul) decreased significantly (p<0.05) as the concentration of Cola nitida increased compared to control. However, alanine aminotransferase activity increased as the concentrations of Cola nitida increased between 20% to 30%. This study shows that Cola nitida reduce the levels of melatonin production in exposed rats and may consequently cause sleeping related disorders among consumers or exposed groups.
... Rodriguez et al., [25] reported that melatonin antioxidative effect is one of the many functions of melatonin. Its ability to enhance the activities of varieties of antioxidative enzymes its stimulatory actions on the synthesis of another important intracellular antioxidant, glutathione has also been reported [26]. The result obtained, from 20% and 30% groups showing significant reduction when compared with the control and the reduction level in melatonin, present was sufficient to have sustained the glutathione production and hence reaffirming the fact that melatonin has stimulating effect on glutathione [26]. ...
... Its ability to enhance the activities of varieties of antioxidative enzymes its stimulatory actions on the synthesis of another important intracellular antioxidant, glutathione has also been reported [26]. The result obtained, from 20% and 30% groups showing significant reduction when compared with the control and the reduction level in melatonin, present was sufficient to have sustained the glutathione production and hence reaffirming the fact that melatonin has stimulating effect on glutathione [26]. ...
... Surprisingly, although the nephroprotective action of melatonin has been widely reported (Hrenak et al., 2015;Promsan and Lungkaphin, 2020), including our previous studies (Winiarska et al., 2006(Winiarska et al., , 2016, there are no data available regarding melatonin effect on HIF-1 in kidneys. Thus, the aim of the present study was to elucidate how melatonin affects HIF-1α expression in renal proximal tubules. ...
... Melatonin's nephroprotective properties have been widely discussed, especially in the context of diabetic nephropathy [cf. Promsan and Lungkaphin (2020) and Hrenak et al. (2015) for the most recent reviews], including our previous studies on alloxan diabetic rabbits (model of type 1 diabetes) (Winiarska et al., 2006) and ZDF rats (model of type 2 diabetes) (Winiarska et al., 2016). Although numerous other mechanisms of melatonin action were proposed, its nephroprotective effects have never been attributed to the attenuation of HIF-1 activity. ...
Article
Full-text available
Although melatonin is widely known for its nephroprotective properties, there are no reports clearly pointing at its impact on the activity of hypoxia-inducible factor-1 (HIF-1), the main mediator of metabolic responses to hypoxia, in kidneys. The aim of the present study was to elucidate how melatonin affects the expression of the regulatory subunit HIF-1α in renal proximal tubules. HK-2 cells, immortalized human proximal tubular cells, were cultured under hypoxic conditions (1% O2). Melatonin was applied at 100 μM concentration. Protein and mRNA contents were determined by Western blot and RT-qPCR, respectively. HIF-1α acetylation level was established by means of immunoprecipitation followed by Western blot. Melatonin receptors MT1 and MT2 localization in HK-2 cells was visualized using immunofluorescence confocal analysis. It was found that melatonin in HK-2 cells (1) lowered HIF-1α protein, but not mRNA, content; (2) attenuated expression of HIF-1 target genes; (3) increased HIF-1α acetylation level; and (4) diminished sirtuin 1 expression (both protein and mRNA). Sirtuin 1 involvement in the regulation of HIF-1α level was confirmed applying cells with silenced Sirt1 gene. Moreover, the presence of membrane MT1 and MT2 receptors was identified in HK-2 cells and their ligand, ramelteon, turned out to mimic melatonin action on both HIF-1α and sirtuin 1 levels. Thus, it is concluded that the mechanism of melatonin-evoked decline in HIF-1α content in renal proximal tubular cells involves increased acetylation of this subunit which results from the attenuated expression of sirtuin 1, an enzyme reported to deacetylate HIF-1α. This observation provides a new insight to the understanding of melatonin action in kidneys.
... Antioxidant applications against diabetes complications are considered as an option in preventing various tissue damage and metabolic disorders (8). Melatonin, which is mainly produced in the pineal gland and released from many tissues including the gastrointestinal system, is an interesting hormone in recent studies due to its antioxidant effects (49,59). Melatonin regulating circadian and seasonal rhythm manages reproduction and retinal function in mammals through its many membrane receptors (7,9). ...
... MDA, a lipid peroxidation product, significantly increased compared to the control group (Table 2, p<0.05). The changes determined in MDA, GSH and SOD levels support the findings of increased oxidative stress in diabetes as expected (2,22,59). Although it was determined a little increase in the levels of GSH and SOD, there was no significantly changes in these enzymes levels with melatonin application to diabetic animals. ...
... 65 Moreover, the antioxidant effect of melatonin alone and in the combination for the prevention approach was clearly demonstrated through elevating the levels of both GPX and SOD. Various studies proved the role of melatonin in attenuating oxidative stress, 24,66 and demonstrated its role in the treatment of neurodegenerative illnesses because of its multiple roles in scavenging free radicals, regulating oxidant and prooxidant enzymes, and inhibiting the production of mitochondrial radicals. 41 The histopathological finding revealed a protective effect in all the treatment groups with maximum protection produced by the combination group for the protective approach. ...
Article
Full-text available
Objective: The present study was designed to investigate the possible synergistic effects of melatonin with zinc in the prevention and treatment of oxaliplatin-induced neurotoxicity in rats. Methodology: Forty-eight male Wistar albino rats were used and randomly allocated into six groups: The negative control group, oxaliplatin group, zinc + oxaliplatin group, melatonin + oxaliplatin group, zinc + melatonin + oxaliplatin prevention-approach group, and zinc + melatonin + oxaliplatin treatment-approach group. The thermal nociceptive/hyperalgesia tests were performed. Brain tissue homogenate was used for measuring GFAP, NCAM, TNF α, MAPK 14, NF-kB, GPX, and SOD. Brain tissue was sent for histopathological and immunohistochemistry studies. Results: The combination therapies showed improvement in the behavioral tests. A significant increase in GPX and SOD with a significant decrease in GFAP levels resulted in the prevention approach. TNF α decreased significantly in the treatment approach. No significant changes were seen in NCAM, NFkB, and MAPK-14. The histopathological findings support the biochemical results. Additionally, immunohistochemistry revealed a significant attenuation of p53 and a non-significant decrease in Bcl2 levels in the combination groups. Conclusion: The combination of zinc with melatonin for the prevention approach was effective in attenuating neurotoxicity induced by oxaliplatin. The proposed mechanisms are boosting the antioxidant system and attenuating the expression of p53, GFAP, and TNF-α.
... Melatonin has been reported to diminish oxidative stress in diabetes [21,22]. It still remains unclear about its therapeutic effect on critical diabetic vascular complications. ...
Article
Full-text available
Patients with diabetes mellitus tend to develop ischemia-related complications and have compromised endothelial progenitor cell (EPC) function. Melatonin protects against ischemic injury, possibly via EPC modulation. We investigated whether melatonin pretreatment could restore EPC function impairment and improve circulation recovery in a diabetic critical limb ischemia mouse model. Under 25 mM high-glucose medium in vitro, EPC proliferation, nitric oxide production, tube formation, and endothelial nitric oxide synthase (eNOS) phosphorylation were significantly suppressed. Hyperglycemia promoted EPC senescence and apoptosis as well as increased reactive oxygen species (ROS) production. Melatonin treatment reversed the harmful effects of hyperglycemia on EPC through adenosine monophosphate–activated protein kinase-related mechanisms to increase eNOS phosphorylation and heme oxygenase-1 expression. In an in-vivo study, after a 4-week surgical induction of hindlimb ischemia, mice with streptozotocin (STZ)-induced diabetes showed significant reductions in new vessel formation, tissue reperfusion, and EPC mobilization in ischemic hindlimbs compared to non-diabetic mice. Mice with STZ-induced diabetes that received melatonin treatment (10 mg/kg/day, intraperitoneal) had significantly improved blood perfusion ratios of ischemic to non-ischemic limb, EPC mobilization, and densities of capillaries. In addition, a murine bone marrow transplantation model to support these findings demonstrated that melatonin stimulated bone marrow-originated EPCs to differentiate into vascular endothelial cells in femoral ligation-induced ischemic muscles. In summary, this study suggests that melatonin treatment augments EPC function along with neovascularization in response to ischemia in diabetic mice. We illustrated the protective effects of melatonin on EPC H2O2 production, senescence, and migration through melatonin receptors and modulating eNOS, AMPK, and HO-1 activities at the cellular level. Thus, melatonin might be used to treat the impairment of EPC mobilization and circulation recuperation in response to ischemic injury caused by chronic hyperglycemia. Additional studies are needed to elucidate the applicability of the results in humans.
... It has a strong antioxidant effect and reduces lipid peroxidation [14]. There is increasing evidence showing that the antioxidant activity of melatonin may be beneficial for treating diabetes and losing weight [21,22]. According to Katarzyna et al., melatonin could contribute to the treatment of diabetes by regulating glucose metabolism and antioxidative stress [7], and it has a role in kidney protection, which can alleviate symptoms in the early stage of glomerular diseases [23]. ...
Article
Full-text available
Diabetic nephropathy (DN)—chronic kidney damage caused by hyperglycemia—eventually develops into end-stage renal disease (ESRD). Melatonin is a powerful antioxidant that has a wide range of biological activities. Potentially helpful effects of melatonin on diabetic kidney disease have been found in several studies. However, its protective mechanisms are not clear and remain to be explored. In this review (CRD42021285429), we conducted a meta-analysis to estimate the effects and relevant mechanisms of melatonin for diminishing renal injuries in diabetes mellitus models. The Cochrane Library, PubMed, and EMBASE databases up to September 2021 were used. Random- or fixed-effects models were used for calculating the standardized mean difference (SMD) or 90% confidence interval (CI). The risk of bias was estimated using the SYRCLE’s RoB tool. Statistical analysis was conducted with RevMan. A total of 15 studies including 224 animals were included in the analysis. The experimental group showed a remarkable decrease in serum creatinine ( P = 0.002 ), blood urea nitrogen ( P = 0.02 ), and urinary albumin excretion rate (UAER) ( P < 0.00001 ) compared with the control group, while the oxidative stress index improved. The experimental group also showed a remarkable increase in superoxide dismutase ( P = 0.21 ), glutathione ( P < 0.0001 ), and catalase ( P = 0.04 ) and a remarkable decrease in MDA ( P < 0.00001 ) content compared with the control group. We concluded that melatonin plays a role in renal protection in diabetic animals by inhibiting oxidative stress. Moreover, it should be noted that fasting blood glucose was reduced in the experimental group compared with the control group. The kidney and body weights of the animals were not decreased in the diabetic animal model compared with the control group.
... Studies on meditation have shown that hormonal reaction to stressors is affected where cortisol levels are decreased and melatonin levels are increased in meditators indicating that meditation is capable of modulating the neuroendocrine system through neurological pathways (Mahagita, 2010). Melatonin is a neurohormone that acts as a strong antioxidant because it increases several intracellular enzymatic antioxidant enzymes, such as SOD, catalase, and glutathione peroxidase (GSH-Px) (Reiter et al., 2005;Rodriguez et al., 2004) and induces the activity of γ-glutamyl cysteine synthetase, thereby stimulating the production of the intracellular antioxidant GSH (Winiarska et al., 2006) thus increasing antioxidant capacity. ...
Article
Full-text available
Objectives Recent medical research into meditation based on stress, pain, coping, and quality of life has shown an overall positive impact on health and immunological outcomes including oxidative stress. This study was aimed to assess the total nitric oxide, nitrite levels, and antioxidant capacity in experienced meditators compared to an age-, gender-, and education level–matched non-meditating group and to determine relationship between these parameters. Methods The total serum nitric oxide (NOx:NO3⁻ + NO2⁻) and nitrite (NO2⁻) levels of long-term, experienced meditators (n = 12), recruited using a validated interview, and age-, gender-, and educational level–matched control subjects (n = 12) who had never practiced meditation, were determined using the modified Griess and Griess assay respectively. The Trolox equivalent antioxidant capacity (TEAC) was determined using the ABTS assay using Trolox as a standard. Results Serum NOx 5.03 ± 0.31 (mean ± SD) and nitrite levels 0.52 ± 0.05 of the meditators were significantly lower and TEAC values 424.35 ± 41.53 of the meditators were significantly higher compared to control group who had serum NOx levels of 5.42 ± 0.42 (p = 0.016, d = − 1.05), nitrite levels of 0.92 ± 0.52 (p = 0.014, d = − 1.08), and TEAC values of 376.15 ± 12.69 (p = 0.001, d = 1.57). There was a correlation of the TEAC levels with NO2⁻ (r = 0.562; d = 0.316) and NOx (r = 0.664; d = 0.441). Conclusions These findings indicate a lower production of nitric oxide and a higher serum antioxidant capacity in the long-term meditators with potential beneficial effects against oxidative stress.
... It has a variety of physiologic, immunological and biochemical functions. It is an endogenous free-radical scavenger and exerts chemoprotective, immunostimluatory and myelostimulatory effect [43,44] . ...
Article
Full-text available
Introduction: Diabetes mellitus is a serious common metabolic disease. It causes a variety of functional and structural disorders in the central nervous systems. It induces alterations in the brain glucose metabolism and increase oxidative stress. Melatonin is a potent free radical scavenger and stimulates the major antioxidant enzymes. Aim: This study was aimed to evaluate the possible protective role of melatonin on the histological changes in the cerebral cortex and meninges after induction of diabetes in a rat model. Materials and Methods: In this study, forty adult male albino rats were divided into four groups (ten rats for each): Group I control rats, group II rats received intraperitoneal injection of Streptozotocin (STZ) (60 mg/kg, single dose), group III rats received intraperitoneal injection of melatonin (10 mg/kg/d) for six weeks, group IV received same previous doses of of STZ and melatonin for six weeks. At the end of experiment, the cerebral cortex was dissected and processed for light microscopic examinations and also for glial fibrillary acidic protein (GFAP) to demonstrate the astrocytes. Morphometrical and statistical analyses were carried out. Results: Examination of cerebral cortex of group II showed separation of the pia mater, congestion in the blood vessels and hemorrhage in intermediate lamella. There were multifocal histological changes and depletion of the cellular elements. The neuropil showed vacuolation. There were multiple areas of microinfarction and pericellular halos. Cresyl Violet stained sections showed karyolysis and immunohistochemical study showed significant increase in GFAP positive astrocytes. In contrary, Examination of cerebral cortex of group IV showed apparent improvement in almost all layers. Cresyl Violet stained sections showed darkly stained Nissel's granules. Immunohistochemical study showed significant decrease in GFAP positive astrocytes. Conclusion: Melatonin can ameliorate the effect of diabetes on the cerebral cortex and meninges through its antioxidant effect.
... It has a variety of physiologic, immunological and biochemical functions. It is an endogenous free-radical scavenger and exerts chemoprotective, immunostimluatory and myelostimulatory effect [43,44] . ...
Article
Introduction: Diabetes mellitus is a serious common metabolic disease. It causes a variety of functional and structural disorders in the central nervous systems. It induces alterations in the brain glucose metabolism and increase oxidative stress. Melatonin is a potent free radical scavenger and stimulates the major antioxidant enzymes. Aim: This study was aimed to evaluate the possible protective role of melatonin on the histological changes in the cerebral cortex and meninges after induction of diabetes in a rat model. Materials and Methods: In this study, forty adult male albino rats were divided into four groups (ten rats for each): Group I control rats, group II rats received intraperitoneal injection of Streptozotocin (STZ) (60 mg/kg, single dose), group III rats received intraperitoneal injection of melatonin (10 mg/kg/d) for six weeks, group IV received same previous doses of of STZ and melatonin for six weeks. At the end of experiment, the cerebral cortex was dissected and processed for light microscopic examinations and also for glial fibrillary acidic protein (GFAP) to demonstrate the astrocytes. Morphometrical and statistical analyses were carried out. Results: Examination of cerebral cortex of group II showed separation of the pia mater, congestion in the blood vessels and hemorrhage in intermediate lamella. There were multifocal histological changes and depletion of the cellular elements. The neuropil showed vacuolation. There were multiple areas of microinfarction and pericellular halos. Cresyl Violet stained sections showed karyolysis and immunohistochemical study showed significant increase in GFAP positive astrocytes. In contrary, Examination of cerebral cortex of group IV showed apparent improvement in almost all layers. Cresyl Violet stained sections showed darkly stained Nissel's granules. Immunohistochemical study showed significant decrease in GFAP positive astrocytes. Conclusion: Melatonin can ameliorate the effect of diabetes on the cerebral cortex and meninges through its antioxidant effect.
... Alloxan and STZ can induce diabetic status in animals by generating hydrogen peroxide and superoxide anion as well as by weakening antioxidant defence machineries (77,78). In mice and rabbit treated by these chemicals, melatonin treatment reduced their oxidative tissue injury and maintained their redox state (79)(80)(81). In diabetic individuals, melatonin application normalized their blood glucose levels and thus protected against morphological damages of β-cells to hinder insulin leakage from these cells (81,82). ...
Article
Full-text available
High level of glucose is hazardous for organisms since it leads to lipid peroxidation, protein glycation and free radical generation. Insulin can lower the high blood glucose by promoting cell’s glucose up-taking. Thus, the impeded insulin secretion in type 1-diabetes and insensitivity of cells to insulin in type 2-diabetes cause hyperglycaemia. Hyperglycaemia impairs mitochondrial function of pancreas to trigger ROS generation. The malfunctional mitochondria cause endoplasmic reticulum to produce misfolded non-functional insulin, finally leading to diabetes. Melatonin, the mitochondria targeted antioxidant, provides protection against diabetes by multiple ways. These include balancing cellular redox status, lowering blood glucose level by modulating metabolic pathways and, finally protecting cells/organelles from high glucose induced injury. Moreover, this indoleamine preserves pancreatic physiological normalcy to facilitate insulin secretion. Thus, melatonin can effectively mitigate diabetes and diabetic complications. Metformin, the most prescribed medicine for type 2diabetes, has similar antidiabetic activities as melatonin. Both the molecules share similar pathways to preserve stress-stricken pancreas and other organs, whereas, melatonin also potentiates the actions of metformin. The potentially synergistic actions of melatonin and metformin are expected and we strongly recommend a combined therapeutic application of these two molecules for treatment of diabetes.
... 111 That is the ability of melatonin to directly scavenge oxygencentered radicals and toxic ROS 98,112 and reduce oxidative damage to key cellular macromolecules. [113][114][115][116] Melatonin activates antioxidative enzymes, including glutathione peroxidase and glutathione reductase, 67,117 and accelerates the synthesis of glutathione, 118 making it a critical endogenous factor for limiting free radical damage. 81 Thus, melatonin neutralizes nitrogen-based toxicants and also inhibits the prooxidative enzyme, NO synthase. ...
Article
Full-text available
Osteoarthritis (OA), the most common arthritis worldwide, is a degenerative joint disease characterized by progressive cartilage breakdown, subchondral remodeling, and synovial inflammation. Although conventional pharmaceutical therapies aim to prevent further cartilage loss and joint dysfunction, there are no ideal strategies that target the pathogenesis of OA. Melatonin exhibits a variety of regulatory properties by binding to specific receptors and downstream molecules, and exerts a myriad of receptor-independent actions via intracellular targets as a chondrocyte protector, an anti-inflammation modulator, and a free radical scavenger. Melatonin also modulates cartilage regeneration and degradation by directly/indirectly regulating the expression of main circadian clock genes, such as transcriptional activators [brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (Bmal) and circadian locomotor output cycles kaput (Clock)], transcriptional repressors [period circadian regulator (Per)1/2, cryptochrome (Cry)1/2, and Dec2], and nuclear hormone receptors [Rev-Erbs and retinoid acid-related orphan receptors (Rors)]. Owing to its effects on cartilage homeostasis, we propose a potential role for melatonin in the prevention and therapy of OA via the modulation of circadian clock genes, mitigation of chondrocyte apoptosis, anti-inflammatory activity, and scavenging of free radicals.
... It has a number of functions and is an important antioxidant free radical scavenger (207,288). Specifically, it stimulates the production of GSH (349) and increases the expression of genes related to antioxidative functions, such as glutathione peroxidase and SOD (210). Melatonin also seems to directly enhance mitochondrial function since it activates ETC complexes, increases mitochondrial membrane fluidity, and closes the mPTP. ...
Article
Full-text available
Mitochondria are cellular organelles involved in several biological processes, especially in energy production. Several studies have found a relationship between mitochondrial dysfunction and mood disorders, such as major depressive disorder and bipolar disorder. Impairments in energy production are found in these disorders together with higher levels of oxidative stress. Recently, a number of agents capable of enhancing antioxidant defenses or mitochondrial functioning have been studied for the treatment of mood disorders as adjuvant therapy to current pharmacological treatments. A better knowledge of mitochondrial physiology and pathophysiology might allow the identification of new therapeutic targets and the development and study of novel effective therapies to treat these specific mitochondrial impairments. This could be especially beneficial for treatment-resistant patients. In this article, we provide a focused narrative review of the currently available evidence supporting the involvement of mitochondrial dysfunction in mood disorders, the effects of current therapies on mitochondrial functions, and novel targeted therapies acting on mitochondrial pathways that might be useful for the treatment of mood disorders.
... In a survey conducted by Abd-Elghaffar et al. antioxidant effects of melatonin were observed in reducing the neurological toxicity of aluminum [18].Winiarska et al. study showed the beneficial effect of melatonin in reducing oxidative stress and diabetes in rabbits [19]. Effect of melatonin on carbon tetrachloride hepatotoxicity in rats was observed by Ogeturk et al [10]. ...
Article
Full-text available
The study was performed on five groups of rabbits; one control group, and 4 amphotericin (1 mg/kg) receiving groups (2 to 5), group 3 received melatonin (1 mg/kg), group 4 received vitamin E (80 mg/kg), and group 5 received melatonin together with vitamin E. Alterations in enzyme activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase in serum and liver tissue were evaluated. Results: 4 T Results showed that administration of amphotericin had significantly increased the activity level of liver function related enzymes. But consumption of vitamin E and melatonin prevented this increase, while the combination of vitamin E and melatonin had a more significant effect on lactate dehydrogenase. Also compared with the control group, liver tissue damage and cellular damage were significant after amphotericin consumption and these changes were decreased by melatonin and vitamin E. Conclusion: 4 T Melatonin and vitamin E may prevent liver damage caused by amphotericin through their antioxidant properties.
... Meena et al. [84] identified its protective role against EMF exposure, where melatonin reversed the effect of microwaves on sperm parameters by decreasing oxidative stress. Melatonin was also reported to maintain membrane potential of mitochondria, thus preventing abnormal triggering of apoptosis [131][132][133]. It inhibits the arresting of germ cells at the pre-meiotic stage due to its anti-oxidative capacity and potential to improve DNA repair pathways, thus achieving normal sperm physiology with normal sperm concentration and morphology in RFR-exposed Swiss albino mice [74]. ...
Article
Radiofrequency exposure from man-made sources has increased drastically with the era of advanced technology. People could not escape from such RF radiations as they have become the essential part of our routine life such as Wi-Fi, microwave ovens, TV, mobile phones, etc. Although non-ionizing radiations are less damaging than ionizing radiations but its long term exposure effect cannot be avoided. For fertility to be affected, either there is an alteration in germ cell, or its nourishing environment, and RF affects both the parameters subsequently, leading to infertility. This review with the help of in vitro and in vivo studies shows that RF could change the morphology and physiology of germ cells with affected spermatogenesis, motility and reduced concentration of male gametes. RF also results in genetic and hormonal changes. In addition, the contribution of oxidative stress and protein kinase complex after RFR exposure is also summarized which could also be the possible mechanism for reduction in sperm parameters. Further, some preventative measures are described which could help in reverting the radiofrequency effects on germ cells.
... Since this discovery, the direct sweeping actions of free radicals through MEL and its metabolites have been described [49][50][51]. MEL stimulates the antioxidant enzymes of the organism such as glutathione peroxidase, and glutathione reductase [52,53] regulates the increase in glutathione [54], improving the reducing power of tissues and fluids [55], neutralizing the nitrogenous toxins such as nitric oxide, and peroxynitric anion, responsible for nitrosative damage [56,57], is capable of chelating heavy metals [58] and suppresses the nitric oxide synthase, known as prooxidative enzyme [59,60]. A positive correlation was found in humans comparing night and day MEL concentrations and antioxidant capacity of blood even at physiological doses [61]. ...
Article
Full-text available
Melatonin is a hormone secreted in the pineal gland with several functions, especially regulation of circadian sleep cycle and the biological processes related to it. This review evaluates the bioavailability of melatonin and resulting metabolites, the presence of melatonin in wine and beer and factors that influence it, and finally the different benefits related to treatment with melatonin. When administered orally, melatonin is mainly absorbed in the rectum and the ileum; it has a half-life of about 0.45–1 h and is extensively inactivated in the liver by phase 2 enzymes. Melatonin (MEL) concentration varies from picograms to ng/mL in fermented beverages such as wine and beer, depending on the fermentation process. These low quantities, within a dietary intake, are enough to reach significant plasma concentrations of melatonin, and are thus able to exert beneficial effects. Melatonin has demonstrated antioxidant, anticarcinogenic, immunomodulatory and neuroprotective actions. These benefits are related to its free radical scavenging properties as well and the direct interaction with melatonin receptors, which are involved in complex intracellular signaling pathways, including inhibition of angiogenesis and cell proliferation, among others. In the present review, the current evidence on the effects of melatonin on different pathophysiological conditions is also discussed.
... Melatonin administration is effective in protecting glutathione homeostasis disorders that occur with diabetes. After melatonin administration, an increase in diabetic animals' GSH level has been shown in the kidney, liver, brain, heart tissues and plasma [48][49][50] . It was determined that our findings were compatible with the type 1 diabetes model created by STZ and that biochemical parameters increased with oxidative stress. ...
Article
Purpose: This study aims at investigating the oxidative stress effect of antidiabetic drugs of Metformin (MET) and sitagliptin (STG) in the liver tissue of diabetic rats from streptozotocin (STZ). Materials and Methods: Thirty-five female Wistar rats (3-4 months old, weighing 200±25 g) were divided into five groups (with seven rats each) and treated as follows: control (Cont), streptozotocin alone (STZ), streptozotocin + metformin (STZ+MET), streptozotocin + sitagliptin (STZ+STG), streptozotocin + metformin + sitagliptin (STZ+MET+STG). Sitagliptin, Metformin, and combined metformin sitagliptin treated subgroups for four weeks. Malondialdehyde (MDA), total antioxidant status (TAS), total oxidant status (TOS) levels, and oxidative stress index (OSI) ratio were measured in rat liver tissue. Besides, cells undergoing apoptotic cell death were determined using the TUNEL technique through histopathological evaluation. Results: MDA, TAS, and OSI of STZ+MET+STG administered group decreased compared to STZ. TOS of STZ+MET+STG administered group decreased compared to STZ. Conclusion: In the experimental T2D model in rats, it shows protective effect when sitagliptin is used with metformin against oxidative damage in liver tissue caused by STZ.
... An oxidative emphasis normally occurs when the creation and elimination of free radicals (ROS) are unbalanced as the oxidative damage of cultured species is directly related to the quality of diet (Apel & Hirt, 2004;Winiarska, Fraczyk, Malinska, Drozak, & Bryla, 2006). Antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and CAT are important scavengers of ROS; they protect the body tissues from oxidative stress damage (Gaetani et al., 1996). ...
Article
Full-text available
In this study, we explored the effects of dietary administration of Aspergillus awamori on the growth, intestinal histomorphology, immune parameters and antioxidant enzyme activity of growing rabbits. The rabbits of 5 weeks of age (body weight, 855 ± 5.53 g) were allotted into four groups (12 rabbits per group) and fed four experimental diets enriched with A. awamori at 0, 50, 100 and 150 mg per kg diet for 8 weeks. After the feeding trial, an equal number of male APRI rabbits (3 months old; 4 groups, 5 rabbits per group) were housed in metabolism cages and fed the test diets for 14 days for the digestibility trial. All A. awamori-enriched diets induced a significant increase in the average body weight and weight gain of rabbits and significantly decreased the feed conversion ratio. In rabbits fed with A. awamori at 100 or 150 mg per kg diet, protein, lipid and fibber digestibility coefficients significantly increased compared with the control group. Intestinal villi measurements (length and thickness) were also enhanced in all rabbits fed with A. awamori. Adding A. awamori as a food supplement generally did not affect rabbit haematology and blood biochemistry values; however, at 150 mg per kg diet, it significantly increased the levels of haemoglobin and total protein, as well as red blood cell count. Furthermore, all enriched diets significantly increased rabbits' phagocytic activity and their phagocytic index. Rabbits fed with A. awamori also showed decreased malondialdehyde but increased catalase activity. In conclusion, A. awamori administered as feed supplement at 100-150 mg per kg of growing rabbits' diet enhances their growth, intestinal health and nutrient digestibility, and it raises the levels of their immune and antioxidative responses.
... ROS has a positive correlation with the serum level of creatinine [49]. Additionally, oxidative stress can decrease the serum level of urea [50]. Serum uric acid level has a negative correlation with oxidant factors [51,52]; consequently, increasing serum uric acid levels has protective effects in oxidative stress conditions [53]. ...
Article
The biological and renal effects made by simultaneous and non-simultaneous exposure to toluene and noise were investigated. Twenty-four New Zealand white rabbits were exposed to 100 dB of white noise and 1000 ppm of toluene vapor for two weeks. The examined biochemical factors were urea, uric acid, creatinine, glucose, triglyceride, cholesterol, and albumin serum levels, measured on different days after the end of the exposure. Moreover, glutathione peroxidase activity (GPX), malondialdehyde dismutase activity (MDA), and superoxide dismutase (SOD) parameters were measured in the kidney tissue. The hematoxylin and eosin staining method was used for histopathological experiments. Overall, the noise increased albumin, uric acid, creatinine, and glucose levels, but it decreased urea, cholesterol, and triglyceride levels. Toluene decreased albumin, uric acid, and urea levels, while it increased creatinine, triglyceride, cholesterol, and glucose levels. Simultaneous exposure to noise and toluene decreased albumin, uric acid, cholesterol, and urea levels, whereas it increased creatinine, glucose, and triglyceride levels. GPX, MDA, and SOD levels increased by simultaneous and non-simultaneous exposure to noise and toluene. Furthermore, massive tubular degeneration, tubular cell vacuolization, glomerular disorganization, congestion, glomerular cell shrinkage, and unclear brush border were detected in the kidney tissue.
... There is accumulating evidence that, due to its antioxidant properties, melatonin may play a role in ameliorating diabetes and attenuating diabetic nephropathy. 26,27 In vivo studies have demonstrated that melatonin have antioxidant and anti-inflammatory effects in subjects with diabetic nephropathy. 19,27,28 Furthermore, in an in vitro model of diabetic nephropathy, Ji and Xu revealed that melatonin has anti-apoptotic effects. ...
Article
Full-text available
Objectives Diabetes mellitus is associated with oxidative stress that leads to inflammation and diabetic nephropathy. This study aimed to determine the possible renoprotective effects of the antioxidants melatonin, vitamin D and vitamin E in diabetic rats. Methods We divided 108 albino rats into 12 groups. G1 group was fed a normal diet and did not receive any medication. G2 to G4 consisted of normal rats that were treated as follows: G2 with melatonin; G3 with vitamin E; G4 with vitamin D. Groups G5 to G12 consisted of diabetic rats that were treated as follows: G5 received no medication; G6 treated with insulin; G7 treated with melatonin; G8 treated with melatonin and insulin; G9 treated with vitamin E; G10 treated with vitamin E and insulin; G11 treated with vitamin D and G12 treated with vitamin D and insulin. Two months post-treatment, histological and biochemical examinations of glucose profile, oxidative stress status, renal function, homocysteine and TNF-α were performed. Results Total antioxidant capacity (TAC) increased significantly in groups G2, 7, 8, 10 and 11. TNF-α significantly increased in G2, but decreased in all other groups. Creatinine increased significantly in groups G5, 6, 7, 8, 9, 11 and 12. In the kidneys of the diabetic rats, thickening of the capillary basement membrane, diffuse mesangial sclerosis and nodular glomerulosclerosis was observed. Rats treated with melatonin showed marked improvement in these symptoms. However, in those treated with vitamin D and E, thickening of the capillary basement membrane and mesangial sclerosis was still present. Conclusions Melatonin, administered either with or without insulin had a significant biochemical antioxidant effect and histological renoprotective effect. Conversely, vitamin D and E did not appear to have any effects on the parameters measured.
... Melatonin (N-acetyl-5-methoxy tryptamine), a wellknown antioxidant hormone secreted by pineal gland is reported to be effective in alleviating oxidative stress hence reducing diabetic complications [16][17][18][19]. Melatonin has been shown to have protective effect on cardiovascular system. ...
Background Cardiovascular disease (CVD) is one of the major cause of mortality in diabetic patients. Evidence suggests that hyperglycemia in diabetic patients contributes to increased risk of CVD. This study is to investigate the therapeutic effects of melatonin on glucose-treated human umbilical vein endothelial cells (HUVEC) and provide insights on the underlying mechanisms. Materials and methods Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Reactive oxygen species (ROS) and membrane potential was detected using 2′,7′-dichlorofluorescein diacetate and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1) dye staining, respectively. While, cell apoptosis was determined by Annexin-V staining and protein expression was measured using Western blot. Results Our results suggested that melatonin inhibited glucose-induced ROS elevation, mitochondria dysfunction and apoptosis on HUVEC. Melatonin inhibited glucose-induced HUVEC apoptosis via PI3K/Akt signaling pathway. Activation of Akt further activated BcL-2 pathway through upregulation of Mcl-1 expression and downregulation Bax expression in order to inhibit glucose-induced HUVEC apoptosis. Besides that, melatonin promoted downregulation of oxLDL/LOX-1 in order to inhibit glucose-induced HUVEC apoptosis. Conclusions In conclusion, our results suggested that melatonin exerted vasculoprotective effects against glucose-induced apoptosis in HUVEC through PI3K/Akt, Bcl-2 and oxLDL/LOX-1 signaling pathways.
... 101 It can act as direct ROS scavenger and regulate endogenous antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) to fight oxidative damage. 101,102 It also promotes GSH production in cells by activating γ-glutamylcysteine synthase 103 and also stimulates the activity of GR. 101 The physiological levels of melatonin mitigate acute inflammatory responses like leukocyte rolling and adhesion in the microcirculation by activation of distinct melatonin receptors. 104 Recently, melatonin is shown to alleviate air pollution-induced oxidative stress by regulating the expression of SOD and CAT via MT1. ...
Article
Melatonin is a chronobiotic hormone, which can regulate human diseases like cancer, atherosclerosis, respiratory disorders and microbial infections by regulating redox system. Melatonin exhibits innate immunomodulation by communicating with immune system, and influencing neutrophils to fight infections and inflammation. However, sustaining redox homeostasis and reactive oxygen species (ROS) generation in neutrophils are critical during chemotaxis, oxidative burst, phagocytosis, and neutrophil extracellular traps (NETs) formation. Therefore, endogenous antioxidant glutathione (GSH) redox cycle is highly vital in regulating neutrophil functions. Reduced intracellular GSH levels and glutathione reductase (GR) activity in the neutrophils during clinical conditions like autoimmune disorders, neurological disorders, diabetes and microbial infections lead to dysfunctional neutrophils. Therefore, we hypothesized that redox modulators like melatonin can protect neutrophil health and functions under GSH and GR activity deficient conditions. We demonstrate the dual role of melatonin wherein, it protects neutrophils from oxidative stress‐induced apoptosis by reducing ROS generation, in contrast, it restores neutrophil functions like phagocytosis, degranulation and NETosis in GSH and GR activity deficient neutrophils by regulating ROS levels both in vitro and in vivo. Melatonin mitigates LPS‐induced neutrophil dysfunctions by rejuvenating GSH redox system, specifically GR activity by acting as a parallel redox system. Our results indicate that melatonin could be a potential auxiliary therapy to treat immune dysfunction and microbial infections, including virus, under chronic disease conditions by restoring neutrophil functions. Further, melatonin could be a promising immune system booster to fight unprecedented pandemics like the current COVID‐19. However, further studies are indispensable to address the clinical usage of melatonin.
... 68,69 Kidney oxidative stress as indicated by the increases in kidney MDA, plasma nitric oxide, and plasma lipid peroxidation (LPO) levels has been observed in hyperglycemia condition, 65 whereas antioxidant enzymes including GSH, GPx, and GSH/ GSSG ratio are decreased. 72 High blood glucose has been shown to attenuate after melatonin administration and resulting to reduce oxidative stress condition. 62,65 Nevertheless, some studies found that melatonin could not reduce blood glucose in streptozotozin-induced diabetic rat model. ...
Article
Obesity is a common and complex health problem worldwide and can induce the development of Type 2 diabetes. Chronic kidney disease (CKD) is a complication occurring as a result of obesity and diabetic conditions that lead to an increased mortality rate. There are several mechanisms and pathways contributing to kidney injury in obese and diabetic conditions. The expansion of adipocytes triggers proinflammatory cytokines release into blood circulation and bind with the receptors at the cell membranes of renal tissues leading to kidney injury. Obesity‐mediated inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction are the important causes and progression of CKD. Melatonin (N‐acetyl‐5‐methoxytryptamine) is a neuronal hormone that is synthesized by the pineal gland and plays an essential role in regulating several physiological functions in the human body. Moreover, melatonin has pleiotropic effects such as antioxidant, anti‐inflammation, antiapoptosis. In this review, the relationship between obesity, diabetic condition, and kidney injury and the renoprotective effect of melatonin in obese and diabetic conditions from in vitro and in vivo studies have been summarized and discussed.
... Melatonin is one of the strongest antioxidants hormones whereas, it is considered as free radical scavenger leading to attenuation of oxidative stress. Thus, it has a strong chemoprotective, immunostimluatory effect to neurons (Winiarska et al., 2006;Motawi et al., 2017). In the present study, examination of stained cerebellar sections of deltamethrin rats that simultaneously Post-treatment of melatonin with deltamethrin in this work caused a significant decrease in serum MDA level and a significant increase in GSH, catalase and SOD levels. ...
... Melatonin acts as an ROS scavenger through upregulating gene expression and activity of several antioxidant enzymes, such as copper and zinc superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. Also, melatonin downregulates nitric oxide synthase in a synergistic manner with other antioxidants, including vitamin C and vitamin E, to prevent the generation of ONOO − (peroxynitrite; unstable structural isomer of nitrate) in an oxidative environment [7,8] ...
Article
Background Vitiligo is the most common skin depigmentation disorder. Melatonin is a hormone that affects melanogenesis and pigmentation. The possible role of melatonin in the pathogenesis of vitiligo remains unclear. Objective The aim was to estimate immunohistochemical expression of melatonin in lesional and nonlesional skin of patients with nonsegmental vitiligo in comparison to healthy controls in order to detect the possible variable expression of melatonin and its possible role in the pathogenesis of vitiligo. Patients and methods In all, 40 lesional and 40 nonlesional skin biopsies from 40 patients with nonsegmental vitiligo and 40 healthy control biopsies were included. Immunohistochemistry of melatonin expression in skin biopsies was performed. Vitiligo area scoring index score was used to assess vitiligo severity. Results Melatonin expression was significantly lower in lesional and nonlesional skin of vitiligo patients (P
... In addition, melatonin also has antioxidant properties, acting directly in the elimination of free radicals, aiding antioxidant defense enzymes, and stimulating mRNA synthesis of the glutamylcysteine synthetase enzyme, responsible for GSH biosynthesis (Urata et al. 1999;Winiarska et al. 2006;Reiter et al. 2007;Hardeland et al. 2011;Ramis et al. 2015;Reiter et al. 2018). Melatonin may also decrease the formation of MDA probably due to its ability to interact with lipid bilayers, preventing changes in membrane fluidity and contributing to the reduction in lipid peroxidation (García et al. 1997;García et al. 2014;Ramis et al. 2015), as found for Oncorhynchus mykiss (Gülçin et al. 2009). ...
Article
Full-text available
Melatonin is a hormone that can modulate aggressive interactions in fish, stimulate antioxidant enzymes, and neutralize the biological damage caused by high free radical production. Fish, especially those kept in artificial environments, are subject to damage caused by free radicals resulting from stressful conditions, such as a social challenge. The matrinxã (Brycon amazonicus) arouses great commercial interest and has been widely used in farming systems. However, these animals have a high frequency of aggressive behavior and cannibalism, which is considered a limiting factor for the production system. Thus, we evaluated the influence of melatonin on aggressiveness and oxidative stress parameters in matrinxã juveniles, testing whether melatonin increases glutathione concentrations and reduces lipid peroxidation (thiobarbituric acid–reactive substances) during social challenge. For this, 24 fish were subjected to three concentrations of melatonin in water: control (0 μmol/L), low MEL (1 μmol/L), and high MEL (10 μmol/L), with eight replicates each. The fish were isolated for 96 h, subjected to the mirror test (social challenge), and then euthanized and dissected to remove the liver. Melatonin reduced total aggressive interactions in animals treated with melatonin (P = 0.036), increased glutathione concentrations (P = 0.002), and decreased levels of lipid peroxidation (P = 0.001). We concluded that melatonin reduces aggressiveness and acts as a potent antioxidant in matrinxã juveniles, contributing to the reduction in stress levels and thus improving the maintenance conditions of animals in production systems.
... As a hormone secreted by the pineal gland, poor secretion of melatonin was associated with a high risk of type 2 diabetes, implying the potential benefits of melatonin in met-abolic diseases [55]. Besides, melatonin significantly alleviated metabolic disorder and oxidative stress in the diabetic state [56,57]. Furthermore, 6melatonin was shown to protect diabetic hearts via an apoptosis-and Mst1/Sirt3-dependent mechanism [58,59]. ...
Article
Full-text available
Diabetes mellitus, a worldwide health threat, is considered an independent risk factor for cardiovascular diseases. The overall cardiovascular risk of diabetes is similar to the one having one myocardial infarction (MI) attack although the precise impact of diabetes on MI-induced myocardial anomalies remains elusive. Given that mortality following MI is much greater in diabetic patients compared to nondiabetic patients, this study was designed to examine the effect of melatonin on MI injury-induced myocardial dysfunction in diabetes. Adult mice were made diabetic using high-fat feeding and streptozotocin (100 mg/kg body weight) prior to MI and were treated with melatonin (50 mg/kg/d, p.o.) for 4 weeks prior to assessment of cardiac geometry and function. The MI procedure in diabetes displayed overt changes in cardiac geometry (chamber dilation and interstitial fibrosis) and functional anomalies (reduced fractional shortening and cardiomyocyte contractile capacity) in association with elevated c-Jun N-terminal kinase (JNK) phosphorylation and p53 level. Melatonin treatment markedly attenuated cardiac dysfunction and myocardial fibrosis in post-MI diabetic mice. Furthermore, melatonin decreased JNK phosphorylation, reduced p53 levels, and suppressed apoptosis in hearts from the post-MI diabetic group. In vitro findings revealed that melatonin effectively counteracted high-glucose/high fat-hypoxia-induced cardiomyocyte apoptosis and contractile dysfunction through a JNK-mediated mechanism, the effects of which were impaired by the JNK activator anisomycin. In summary, our study suggests that melatonin protects against myocardial injury in post-MI mice with diabetes, which offers a new therapeutic strategy for the management of MI-induced cardiac injury in diabetes.
... The biological effects of melatonin are extremely widespread. Melatonin could control molecular action such as oxidative stress signaling (Galano et al. 2011;Reiter et al. 2000), inflammatory pathways (Li et al. 2005;Kim et al. 2012), immune responses (Moore and Siopes 2000;Carrillo-Vico et al. 2006), apoptosis (Mayo et al. 1998;Muñoz-Casares et al. 2006), physiological rhythm (Zawilska et al. 2009;Skene and Arendt 2006) as well as influencing chronic diseases, such as, diabetes (Winiarska et al. 2006;Espino et al. 2011), obesity (Agil et al. 2011Hussein et al. 2007), kidney injuries (Hussein et al. 2007;Leibowitz et al. 2016), cardiovascular diseases (Dominguez-Rodriguez 2012; Dominguez-Rodriguez et al. 2012), cancers (Tamtaji et al. 2019b), neurological disorders (Wang and Wang 2006;Yang et al. 2011;Farez et al. 2015) and aging-related conditions (Karasek and Reiter 2002;Wu and Swaab 2005). Circulating melatonin levels are reduced in patients with PD (Breen et al. 2014). ...
Article
Full-text available
Parkinson disease (PD) is a chronic and neurodegenerative disease with motor and nonmotor symptoms. Multiple pathways are involved in the pathophysiology of PD, including apoptosis, autophagy, oxidative stress, inflammation, α-synuclein aggregation, and changes in the neurotransmitters. Preclinical and clinical studies have shown that melatonin supplementation is an appropriate therapy for PD. Administration of melatonin leads to inhibition of some pathways related to apoptosis, autophagy, oxidative stress, inflammation, α-synuclein aggregation, and dopamine loss in PD. In addition, melatonin improves some nonmotor symptom in patients with PD. Limited studies, however, have evaluated the role of melatonin on molecular mechanisms and clinical symptoms in PD. This review summarizes what is known regarding the impact of melatonin on PD in preclinical and clinical studies.
... In 1999, Urata and colleagues reported that melatonin elevated the intracellular levels of another critically important antioxidant, glutathione (GSH), by stimulating its synthesis at the level of its rate limiting enzyme gamma-glutamylcysteine synthase (now know as glutamyl cysteine ligase) (24). This finding did not receive much attention nor interest although the observation was later confirmed by Winiarska et al (25). Recently, however, Sainz and co-workers reported that the incubation of either LNCap or PC3 prostate cells with melatonin almost doubled the already high concentrations of GSH and protected the cells from ionizing radiation, a treatment associated with excessive free radical generation (26). ...
... Elle peut agir directement en piégeant de nombreux radicaux libres tels que le radical hydroxyle (-OH), le peroxyde d'hydrogène (H2O2), le monoxyde d'azote (NO), l'anion peroxynitrite (ONOO − ), ou indirectement en améliorant l'activité d'enzymes antioxydantes (Reiter et al., 2001;Rodriguez et al., 2004) et en stimulant la synthèse et le recyclage d'un autre antioxydant endogène, le glutathion (Winiarska et al., 2006). ...
... Thus, one MLT molecule is capable to scavenge up to 10 ROS versus the traditional antioxidants that scavenge one or less ROS (Tan, Manchester, Esteban-Zubero, Zhou, & Reiter, 2015) which make MLT superior to other antioxidants and more efficient to protect cells against oxidative stress than other antioxidants (Tan et al., 2003;Elbe et al., 2015;Gitto et al., 2001;Tunez et al., 2007). Also, MLT increases the antioxidant capacity of the cells through activating intracellular antioxidant enzymes such as glutathione (Hardeland, Tan, & Reiter, 2009;Winiarska, Fraczyk, Malinska, Drozak, & Bryla, 2006) and modulate the gene expression of antioxidative enzyme glutathione peroxidase, catalase and superoxide dismutase (Tomas-Zapico & Coto-Montes, 2005). Additionally, the small size and the great lipophilicity of the MLT molecule permits it to diffuse easily through bio-membranes (Reiter, 1993), and can simply pass through the blood-testes barrier to protect the germinal epithelium (Aitken & Roman, 2008). ...
Article
Full-text available
Bisphenol A (BPA) is a synthetic monomer produced in large quantities worldwide for manufacturing polycarbonate plastics and epoxy resins used in many consumer items. Several studies have reported the correlativity between the growing BPA levels in the surroundings and the incidence of male and female infertility thus, due to the steady daily exposure and its affinity to bio-accumulation; the effects of BPA on human health have become a great concern. Therefore, the present study was directed to investigate the protective effects of melatonin (MLT) and quercetin (Q) on BPA-induced reproductive and genotoxicity in male albino mice. BPA (50 and 100 mg/kg b.w.) was administered alone or in combination with MLT (10 mg/kg b.w.) or Q (10 mg/kg b.w.) 3 times per week for 6 weeks. Results displayed that BPA administration significantly elevated oxidative stress in the testicular tissue. BPA disturbed male fertility by altering different sperm parameters, increasing the % of sperm shape anomalies and DNA fragmentation in testicular tissues. This was associated with a decline in the serum testosterone levels as well as inducing deleterious effects in the histological structure of the testis. Additionally, cytogenetic studies revealed strong effects of BPA on both mitotic and meiotic cells via increasing the frequencies of micronucleated polychromatic erythrocytes (MNPCEs) in bone marrow cells and chromosomal aberrations in primary spermatocytes. Moreover, BPA administration significantly increased apoptosis in the testicular tissue via increasing the expression of the proapoptotic protein caspase 3 and lessening the expression of the antiapoptotic protein Bcl-2. MLT or Q co-treatment with BPA significantly prevented oxidative stress thru modulating the levels of total antioxidant activity and catalase enzyme as well as the malondialdehyde, maintained the testosterone levels, improved sperm quality and quantity, restored testis architecture and decreased the frequencies of MNPCEs and chromosomal anomalies. Furthermore, MLT and Q sustained Bcl-2, caspase 3 expressions, and controlled apoptosis. In conclusion, the data obtained in this study suggest that both MLT and Q administration confers protection against damage inflicted by BPA. MLT showed slightly better activity as compared to Q.
... In addition, it acts as potent antioxidant to detoxify ROS and stimulates antioxidative enzymes [139,165]. Moreover, melatonin not only protects the cells from EMF-induced oxidative damage, but also prevents a decline in the mitochondrial membrane potential, which may trigger mitochondrial transition pore opening and triggering the apoptotic cascade [166][167][168]. A study by Meena et al. reported a protective role of melatonin against microwave radiations [25]. ...
Article
Full-text available
During recent years, an increasing percentage of male infertility has to be attributed to an array of environmental, health and lifestyle factors. Male infertility is likely to be affected by the intense exposure to heat and extreme exposure to pesticides, radiations, radioactivity and other hazardous substances. We are surrounded by several types of ionizing and non-ionizing radiations and both have recognized causative effects on spermatogenesis. Since it is impossible to cover all types of radiation sources and their biological effects under a single title, this review is focusing on radiation deriving from cell phones, laptops, Wi-Fi and microwave ovens, as these are the most common sources of non-ionizing radiations, which may contribute to the cause of infertility by exploring the effect of exposure to radiofrequency radiations on the male fertility pattern. From currently available studies it is clear that radiofrequency electromagnetic fields (RF-EMF) have deleterious effects on sperm parameters (like sperm count, morphology, motility), affects the role of kinases in cellular metabolism and the endocrine system, and produces genotoxicity, genomic instability and oxidative stress. This is followed with protective measures for these radiations and future recommendations. The study concludes that the RF-EMF may induce oxidative stress with an increased level of reactive oxygen species, which may lead to infertility. This has been concluded based on available evidences from in vitro and in vivo studies suggesting that RF-EMF exposure negatively affects sperm quality.
... It has been reported that streptozotocin treatment significantly increased lipid peroxides and decreased nonenzymatic, antioxidant levels and antioxidant enzyme activities in the plasma and livers of mice studied. In addition, the streptozotocin-induced diabetes is accompanied by an increased generation of reactive species [55]. Fig. 6b showed that the incorporation of Retama reatam galactomannan could lower the glycemic index of corn starch. ...
Article
Abstract In this study, physicochemical, interfacial and emulsifying properties of Retama reatam and guar galactomannans were comparatively investigated. The results showed that Retama reatam galactomannan is mainly composed of total carbohydrates (95.52%) and lower protein contents (0.87%). The sugars identified were mannose (Man) and galactose (Gal), with a Man:Gal ratio of 1.85 compared to guar gum (1.83). The results of thermal properties indicated were transition temperature (Tg) and melting temperature (Tm) very similar to those of the guar gum. Moreover, results also revealed that there is no significant difference in terms of equilibrium interfacial tension of Retama reatam gum at 10 and 20 °C. Moreover, preliminary tests show that stable oil-in-water nanoemulsions may be formulated using Retama reatam gum. Therefore, measurement of mean oil droplet diameter d (Wu et al., 2009; Huang et al., 2001) after heating at 80 °C, shows that stable nanoemulsions may be formulated using Retama reatam galactomannan. Further in vivo experiments confirmed that Retama reatam gum can reduce the glycemic index of starchy foods and inhibit the surge of postprandial blood glucose level.
... Later, some studies also showed the indirect anti-oxidative properties of this substance. The multiple working pathways of MLT include, among others, the stimulation of anti-oxidative enzymes, the upregulation of glutathione synthesis, the neutralization of nitrogen-based toxicants, and the suppression of pro-oxidative enzymes activity [26][27][28][29][30]. However, for a long time, it was considered as a strict immune-stimulator and did not attract the attention of the transplantation community. ...
Article
Full-text available
Solid organ transplantation is the "gold standard" for patients with end-stage organ disease. However, the supply of donor organs is critical, with an increased organ shortage over the last few years resulting in a significant mortality of patients on waiting lists. New strategies to overcome the shortage of organs are urgently needed. Some experimental studies focus on melatonin to improve the donor pool and to protect the graft; however, current research has not reached the clinical level. Therefore, this review provides a comprehensive overview of the data available, indicating that clinical evaluation is warranted.
... Several studies in vivo on this indolamine concluded that, the antioxidant properties of melatonin might justify its therapeutic use in diseases in which free-radical damage is a major aspect of the condition like infectious and inflammatory disorders [59][60][61][62][63]. ...
Article
PurposeMelatonin (Mel) is an indolamine mainly synthesized by the pineal gland and many other organs. It plays an important role in scavenging free radicals and stimulating antioxidant enzymes. The goal of this study was to investigate the effect of Mel and/or insulin treatment on oxidative liver and pancreas injuries in diabetic rats.Methods Male Wistar albino rats were assigned into 5 groups. Group I: control animals. Group II: diabetes was induced via a single dose of STZ (60 mg/kg) administered intraperitoneally. Group III: diabetic rats treated with Mel (10 mg/kg/day). Group IV: diabetic rats given insulin (6U/kg) subcutaneously. Group V: diabetic rats that received insulin and Mel at the same dose and time. After 12 weeks of the experiment, the animals were decapitated, liver and pancreas tissues were collected.ResultsThe results indicated that reduced glutathione levels in liver and pancreatic tissue decreased, while protein carbonyl, advanced oxidized protein products and lipid peroxidation levels were elevated in diabetic group. Antioxidant enzyme activities decreased in liver tissues but increased in pancreatic tissues of the diabetic group. Administration of Mel, insulin or Mel + insulin reversed these biochemical changes in the diabetic animals.Conclusion This work shows that in long-term oxidative stress conditions caused by STZ-induced diabetes, either Mel or Mel + insulin administration may improve the deteriorated oxidant/antioxidant system in both the liver and pancreas tissues. These results suggested that Mel alone or Mel + insulin treatments might have a significant role in protecting against liver and pancreatic damage in STZ diabetic rats via different antioxidant effects.
Chapter
Hormones have been considered as key factors involved in the maintenance of the redox status of the body. We are making considerable progress in understanding interactions between the endocrine system, redox status, and oxidative stress with the dynamics of life, which encompasses fertilization, development, growth, aging, and various pathophysiological states. One of the reasons for changes in redox states of vertebrates leading to oxidative stress scenario is the disruption of the endocrine system. Comprehending the dynamics of hormonal status to redox state and oxidative stress in living systems is challenging. It is more difficult to come to a unifying conclusion when some hormones exhibit oxidant properties while others have antioxidant features. There is a very limited approach to correlate alteration in titers of hormones with redox status and oxidative stress with growth, development, aging, and pathophysiological stress. The situation is further complicated when considering various tissues and sexes in vertebrates. This chapter discusses the beneficial impacts of hormones with antioxidative properties, such as melatonin, glucagon, insulin, estrogens, and progesterone, which protect cells from oxidative damage and reduce pathophysiological effects. Additionally, we discuss the protective effects of antioxidants like vitamins A, E, and C, curcumin, tempol, N-acetyl cysteine, α-lipoic acid, date palm pollen extract, resveratrol, and flavonoids on oxidative stress triggered by hormones such as aldosterone, glucocorticoids, thyroid hormones, and catecholamines. Inflammation, pathophysiology, and the aging process can all be controlled by understanding how antioxidants and hormones operate together to maintain cellular redox status. Identifying the hormonal changes and the action of antioxidants may help in developing new therapeutic strategies for hormonal imbalance-related disorders.
Article
Exposure to the space environment induces a number of pathophysiological outcomes in astronauts, including bone demineralization, sleep disorders, circadian clock dysregulation, cardiovascular and metabolic dysfunction, and reduced immune system function. A recent report describing experiments aboard the Space Shuttle mission, STS‐132, showed that the level of melatonin, a hormone that provides the biochemical signal of darkness, was decreased during microgravity in an in vitro culture model. Additionally, abnormal lighting conditions in outer space, such as low light intensity in orbital spacecraft and the altered 24‐hour light‐dark cycles, may result in the dysregulation of melatonin rhythms and the misalignment of the circadian clock from sleep and work schedules in astronauts. Studies on Earth have demonstrated that melatonin regulates various physiological functions including bone metabolism. These data suggest that the abnormal regulation of melatonin in outer space may contribute to pathophysiological conditions of astronauts. In addition, experiments with high‐linear energy transfer radiation, a ground‐based model of space radiation, showed that melatonin may serve as a protectant against space radiation. Gene expression profiling using an in vitro culture model exposed to space flight during the STS‐132 mission, showed that space radiation alters the expression of DNA repair and oxidative stress response genes, indicating that melatonin counteracts the expression of these genes responsive to space radiation to promote cell survival. These findings implicate the use of exogenous melatonin and the regulation of endogenous melatonin as countermeasures for the physiological consequences of space flight. This article is protected by copyright. All rights reserved.
Article
Full-text available
Introduction: Diabetes Mellitus is a major health problem characterized by hyperglycemia and disturbances in metabolism and implicated in causing oxidative stress. Treatment includes administration of oral hypoglycaemic agents with lifestyle modifications, these offer glycemic control, however, present limitations about availability, affordability and side effects. Traditional anti-diabetic plants are becoming popular in management of diabetes mellitus. This study was carried out to determine the efficacy of Leptadenaia hastata in treatment of diabetes.Materials and methodsDiabetes mellitus was induced in using a single injection of streptozotocin (50 mg kg− 1 i.p.). The rats were divided into four groups of 5 rats each. Groups 3–6 received olive oil, 100 mg kg− 1 extract, 200 mg.kg− 1 extract and insulin (6IU kg− 1), respectively. 10 non-diabetic rats were grouped into two group receiving olive oil and 200 mg kg− 1 extract for 28 days. All groups were sacrificed by injecting with ketamine hydrochloride, blood was collected by cardiac puncture and centrifuged. The serum was analyzed for biochemical parameters. The liver was removed and homogenized with the supernatant of the resultant homogenate collected and used for analysis of oxidative stress enzymes.ResultsThe extract significantly decreased serum AST (p < 0.05), ALP (p < 0.001), ALT (p < 0.05), TG (p < 0.01), TC (p < 0.001), creatinine (p < 0.001). It had no effect on SOD and CAT levels but it significantly increased (p < 0.001) GSH levels and reduced (p < 0.05) MDA level.Conclusions The n-hexane extract of Leptadenia hastata significantly decreased the levels of hepatic and renal serum biomarkers proving that it was beneficial in ameliorating diabetic related complications. The extract significantly increased GSH levels and reduced MDA level.
Article
Full-text available
Diabetic cardiovascular complications and impaired cardiac function are considered to be the main causes of death in diabetic patients worldwide, especially patients with type 2 diabetes mellitus (T2DM). An increasing number of studies have shown that melatonin, as the main product secreted by the pineal gland, plays a vital role in the occurrence and development of diabetes. Melatonin improves myocardial cell metabolism, reduces vascular endothelial cell death, reverses microcirculation disorders, reduces myocardial fibrosis, reduces oxidative and endoplasmic reticulum stress, regulates cell autophagy and apoptosis, and improves mitochondrial function, all of which are the characteristics of diabetic cardiomyopathy (DCM). This review focuses on the role of melatonin in DCM. We also discuss new molecular findings that might facilitate a better understanding of the underlying mechanism. Finally, we propose potential new therapeutic strategies for patients with T2DM.
Article
Full-text available
Over the last decade, aggregating evidence has been suggested that there is a causative link between mitochondrial dysfunction and aging in the individuals. Several studies on animal models of ageing and neurodegenerative diseases have provided compelling evidence that mitochondria are in the development and progression of diseases such as AD. Further, a role for mitochondrial dysfunction associated with ageing is supported by studies, which have revealed that amyloid-β enters mitochondria and disrupts the electron transport chain (ETC) which generates reactive oxygen species (ROS) and inhibits the cellular ATP production which in turn results into the progression of neurodegenerative diseases like AD. In addition, "free radical mitochondrial theory" associated with oxidative stress has been reported as a key common pathway for cellular dysfunction and death and a possible therapeutic target during a broad spectrum of human medical conditions including cancer, diabetes, various neurodegenerative disorders. Furthermore, recent evidence suggests that chain reaction of lipidperoxidation due to oxidative stress leads to cell injury and DNA damage. Melatonin have ability to protect against damaging oxygen reactants under various extreme oxidative stress conditions and also, various studies have revealed that melatonin has been very effective in the prevention ofamyloid-β peptide(Aβ) induced toxic effects on neuronal cells in AD patients. Here we discuss the different theories associated with the mitochondrial dysfunction which leads to the different relevant diseases that underlie the central role of mitochondria in the aging process and role of the melatonin in diseases associated with mitochondrial dysfunction.
Article
Full-text available
Melatonin is the primary circadian output signal from the brain and is mainly synthesized in pinealocytes. The rhythm and secretion of melatonin is under the control of an endogenous oscillator located in the SCN or the master biological clock. Disruptions in circadian rhythms by shift work, aging, or light at night is associated with bone loss and increased fracture risk. Restoration of nocturnal melatonin peaks to normal levels or therapeutic levels through timed melatonin supplementation has been demonstrated to provide bone-protective actions in various models. Melatonin is a unique molecule with diverse molecular actions targeting melatonin receptors located on the plasma membrane or mitochondria or acting independently of receptors through its actions as an antioxidant or free radical scavenger to stimulate osteoblastogenesis, inhibit osteoclastogenesis, and improve bone density. Its additional actions on entraining circadian rhythms and improving quality of life in an aging population coupled with its safety profile makes it an ideal therapeutic candidate for protecting against bone loss in susceptible populations. The intent of this review is to provide a focused discussion on bone loss and disorders of the bone as it relates to melatonin and conditions that modify melatonin levels with the hope that future therapies include those that include melatonin and correct those factors that modify melatonin levels like circadian disruption.
Article
Full-text available
Oxidative injury is one of the mechanisms involved in thyroid dysfunctions following pesticide exposure. The present study evaluated the mitigating effect of melatonin (ML) on thyroid dysfunctions induced by gestational and lactational exposure to chlorpyriphos (CP) and cypermethrin (CY) in male rats. Six groups of 5 male rats in each group were exposed in utero and via lactation up till postnatal day (PND) 21 to the following regimens: DW, SO, and ML groups were administered distilled water (2 ml/kg), soya oil (2 ml/kg), and ML (0.5 mg/kg) while CM group was co-administered with CP (1.9 mg/kg) and CY (7.5 mg/kg). The MC group was pretreated with ML (0.5 mg/kg) followed by co-exposure to CP (1.9 mg/kg) and CY (7.5 mg/kg), 30 min later while the CM group was given CP (1.9 mg/kg) and CY (7.5 mg/kg) and then administered ML (0.5 mg/kg), 30 min later. Thereafter, sera obtained from blood samples collected at PND 91 were assayed for the concentrations of triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH). The thyroid gland (TG) was evaluated for acetylcholinesterase (AChE) activity and level of oxidative injuries by determining the levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase. Alterations in TH concentrations, AChE activity, and oxidative changes to the TG in the CM group were mitigated by pre- and post-exposure administration of ML. Melatonin mitigated thyroid dysfunction and oxidative injury induced by prenatal and lactational exposure to CP and CY partly due to its antioxidant properties.
Article
In view of reported discrepancies concerning antioxidant activity of dehydroepiandrosterone (DHEA), a widely used dietary supplement, the current investigation was undertaken to evaluate the antioxidant properties of DHEA in both kidney-cortex and liver of alloxan (ALX)-induced diabetic rabbits, as this diabetogenic compound exhibits the ROS-dependent action. ALX was injected to animals following 7 days of DHEA administration. Four groups of rabbits were used in the experiments: control, DHEA-treated control, diabetic and DHEA-treated diabetic. Our results show for the first time, that in kidney-cortex DHEA resulted in normalization of hydroxyl free radicals (HFR) levels and restoration of catalase (CAT) and glutathione peroxidase (GPx) activities to near the control values, while in liver DHEA prevented the malondialdehyde (MDA) accumulation and normalized glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PDH) activities. Moreover, in both kidney-cortex and liver DHEA supplementation prevented GSSG elevation accompanied by a decrease in GSH/GSSG ratio. Although DHEA attenuated oxidative stress in both kidney-cortex and liver of ALX-induced diabetic rabbits and significantly delayed the onset of diabetes in time, it did not protect against the final development of diabetes. In conclusion, the current investigation underscores the complexity of the antioxidant action of DHEA. The data are of clinical interest since DHEA supplementation could prevent the deleterious effects of ROS and delay, or even prevent the onset of many diseases. However, in view of the reported pro-oxidant effects of high DHEA doses, the potential use of this agent as a supplement needs a careful evaluation.
Article
Full-text available
Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.
Chapter
So far, many basic studies addressing the concept of stem cell therapy for ED. The stem cells mechanism of action is to induce angiogenesis and so increase the cavernosal smooth muscle cells within corporal bodies. Generally, erectile dysfunction treatment focuses on the symptomatic reprieve and, thus, aims to provide a temporary relief rather than cure or reverse the cause. The large number of difficult-to-treat patients has motivated the researchers to look for new treatment approaches that instead of offering ad hoc symptomatic care focus on the cure and restoration of the underlying cause. Regenerative medicine has evolved widely over the past few decades and the effects of growth factor therapy, gene transfer, stem cells, and tissue engineering to restore erectile function have been demonstrated in preclinical trials.
Article
Full-text available
Ischemia/reperfusion injury (IRI) can lead to cellular and, eventually, organ dysfunction, with the liver being one of the most frequently aff ected organs. Melatonin, a molecule that has notable antioxidant and anti-infl ammatory properties, has been shown to protect against hepatic IRI. The purpose of this review is to summarize the protective eff ects of melatonin on hepatic IRI. The review initially summarizes the antioxidant properties of melatonin. We then discuss the protective eff ects of melatonin against endothelial and mitochondrial dysfunction. Thereafter, we introduce some information covering melatonin-related signaling pathways, including heme oxygenase-1 (HO-1), toll-like receptor (TLR), c-Jun N-terminal kinase (JNK), and so on. Furthermore, the clinical application of melatonin to hepatic diseases is considered. Finally, the safety of melatonin is evaluated. Taken together, the information compiled in this review will serve as a comprehensive reference regarding the pharmacological benefi ts of melatonin on hepatic IRI, aid in the design of future experimental research, and promote melatonin as a new therapeutic target.
Article
Full-text available
The tropical parasite Schistosoma mansoni causes granulomatous inflammation after its eggs lodge in hepatic portal capillaries. In vitro studies indicate that the host’s response involves the production of reactive oxygen species, although whether this occurs in vivo at the site of the infection is unknown. The role of oxidative processes in mice infected with S. mansoni was investigated in the current study using the antioxidant melatonin. In Experiment 1, the survival rate of infected mice with and without daily melatonin (10 mg/kg) administration was determined. After 56 d, 25 of 25 infected mice that were diluent treated had died. In contrast, 22 or 25 infected mice (88%) given melatonin were still alive at 56 d. Of these 22 surviving mice, melatonin injections were continued in 11 while the 11 others were switched to diluent. Within 10 d, 11 of 11 diluent-injected mice that were infected with S. mansoni were dead while 6 of 11 melatonin-treated mice survived. In Experiment 2, S. mansoni-infected mice were treated for 30 d with either melatonin or diluent. Uninfected, untreated mice served as controls. In these mice, the levels of lipid peroxidation (LPO) products, vitamin E, nitric oxide (NO), glutathione (GSH), and superoxide dismutase (SOD) activity in the liver, kidney, and spleen were measured. In the serum, cholesterol levels and liver damage (alkaline phosphatase (ALP), aspartate transaminases (AST), total protein, and albumin) were monitored. In addition, peroxynitrite anion (ONOO−) in the liver and kidney and inducible nitric oxide synthase (iNOS) in the spleen were immunocytochemically localized. Also, histopathological changes in the liver, kidney, and spleen were examined. The results documented increased LPO and NO levels and decreased vitamin E, GSH, and SOD activity in the liver, kidney, and spleen of S. mansoni-infected mice. Also, there was an increase in serum cholesterol and evidence of liver damage in the infected mice. Immunohistochemical results indicated positive staining of ONOO− in the liver and kidney and positive iNOS staining in the spleen of S. mansoni-infected mice. Histopathological observations revealed granuloma formation in the liver with eosinophil infiltration, a large number of megakaryocytes in the spleen, and degeneration with necrotic cells in some tubules of the kidney cortex in the infected mice. Melatonin administration after S. mansoni infection prevented most of the previously described changes. These results suggest that oxidative processes occur at the site of inflammation and are involved in the damaging effects of schistosomiasis and indicate that free radicals may be a major component of the disease. Likewise, melatonin, presumably due to its antioxidant and free radical scavenging activity, is highly protective against the pathological changes associated with schistosomiasis.
Article
Full-text available
Liver cytosol from mice fed on a normal diet contains Alpha-class glutathione S-transferase (GST) subunits of Mr 25,800, Mu-class GST subunits of Mr 26,400 and Pi-class GST subunits of Mr 24,800. Feeding female mice with a diet containing the anticarcinogenic antioxidant butylated hydroxyanisole (BHA) causes induction of the constitutively expressed Mu-class and Pi-class subunits. BHA also induces an Alpha-class GST comprising subunits of Mr 25,600, which is not expressed at detectable levels in normal mouse liver [McLellan & Hayes (1989) Biochem. J. 263, 393-402]. Data are now presented that show that administration of the anticarcinogen beta-naphthoflavone (BNF), like BHA, induces the Alpha-class 25,600-Mr subunits but not the constitutive Alpha-class GST with subunits of Mr 25,800. The effects of BNF on expression of hepatic GST were studied in both DBA/2 and C57BL/6 mice; these studies revealed a preferential induction of the Alpha-class 25,600-Mr subunits and of the Pi-class 24,800-Mr subunits in those mice in possession of a functional Ah receptor. The BHA/BNF-inducible Alpha-class GST can be resolved into two separate, non-interconvertible peaks by reverse-phase h.p.l.c. Automated amino acid sequence analysis of CNBr-derived peptides from each of these h.p.l.c.-purified peaks showed that the peaks contained at least two very similar subunits. These have been named Ya1 and Ya2. The amino acid sequence of the Ya1 subunit was compared with sequences deduced from a genomic clone, lambda mYa1 (Daniel, Sharon, Tichauer & Sarid (1987) DNA 6, 317-324], and a cDNA clone, pGT41 [Pearson, Reinhart, Sisk, Anderson & Adler (1988) J. Biol. Chem. 263, 13324-13332]. Our data suggest that the Ya1 subunit represents the subunit encoded by the genomic clone, lambda mYa1. Sequence analysis of the constitutive Alpha-class Ya3 subunit (Mr 25,800) shows that, although it is a member of the same gene family as the Ya1 and Ya2 subunits, it represents a distinct sub-family of Alpha-class GST, containing subunits that are more similar to rat Yc. Our data indicate that, of these Alpha-class GST subunits, the two with Mr 25,600 (Ya1 and Ya2) are selectively induced by BHA or BNF in mouse liver; neither BHA nor BNF induces significantly the GST subunit with Mr 25,800 (Ya3).
Article
Full-text available
In diabetes, the persistence of hyperglycemia has been reported to cause increased production of oxygen free radicals through glucose autooxidation and nonenzymatic glycation. The aim of this study was to determine whether oxidative cellular damage occurs at the clinical onset of diabetes and in later stages of the disease in young patients. Indicative parameters of lipoperoxidation, protein oxidation, and changes in the status of antioxidant defense systems were evaluated in single blood samples from 54 diabetic children, adolescents, and young adults and 60 healthy age- and sex-matched control subjects. Malondialdehyde and protein carbonyl group levels in plasma were progressively higher in diabetic children and adolescents than in control subjects (P < 0.0001). The highest erythrocyte superoxide dismutase (SOD) activity was found in diabetic children at onset of clinical diabetes. In diabetic adolescents, SOD was also significantly higher (P < 0.0001) than in control subjects. Erythrocyte glutathione peroxidase was significantly lower in diabetic children and adolescents compared with control subjects (P < 0.002). A significant decline in blood glutathione content at the recent onset of diabetes was found (P < 0.0001). Furthermore, our results demonstrated progressive glutathione depletion during diabetes evolution. The plasma alpha-tocopherol/total lipids ratio and beta-carotene levels during diabetes development (P < 0.001) were low. This cross-sectional study in young diabetic patients showed that systemic oxidative stress is present upon early onset of type 1 diabetes and is increased by early adulthood. Decreased antioxidant defenses may increase the susceptibility of diabetic patients to oxidative injury. Appropriate support for enhancing antioxidant supply in these young diabetic patients may help prevent clinical complications during the course of the disease.
Article
Full-text available
To assess in vivo effects of antioxidants on vascular cell adhesion molecule (VCAM)-1 expression, circulating soluble VCAM-1 and intraerythrocytic reduced glutathione (GSH) and GSH disulphide (GSSG) concentrations were evaluated in non-insulin-dependent diabetic patients without complications (9 men, 6 women, 48 +/- 6 years old) before and after 1 month of either oral N-acetyl-L-cysteine (1.200 mg/day) or placebo treatments, given in randomized, cross-over, double-blind fashion. Ten healthy subjects (7 men, 3 women, 52 +/- 4 years old) served as control subjects. Baseline plasma VCAM-1 concentrations were higher (p = 0.007) in non-insulin-dependent diabetic patients (707.9 +/- 52.5 ng/ml) than in control subjects (627.3 +/- 84.6 ng/ml). Intraerythrocytic GSSG content was higher (non-insulin dependent diabetic patients: 0.618 +/- 0.185 micromol/g Hb; control subjects: 0.352 +/- 0.04 micromol/g Hb, p = 0.0002), whereas intraerythrocytic GSH concentrations were lower (p = 0.001) in non-insulin dependent diabetic patients (6.0 +/- 0.7 micromol/g Hb) than in control subjects (7.1 +/- 0.5 micromol/g Hb). The mean GSH:GSSG ratio was also lower (p = 0.0001) in the first (10.9 +/- 4.5) than in the second group (20.2 +/- 1.4). Circulating VCAM-1 and intraerythrocytic GSH concentrations were negatively correlated in non-insulin diabetic patients (r = 0.605, p = 0.01). Treatment with N-acetyl-L-cysteine decreased plasma VCAM-1 (p = 0.01) and intraerythrocytic GSSG (p = 0.006) but increased GSH concentrations (p = 0.04) and the GSH:GSSG ratio (p = 0.004) in non-insulin dependent diabetic patients. Our data indicate that the vascular endothelium is activated in non-insulin dependent diabetes. Antioxidant treatment counterbalanced such endothelial activation. Thus, antioxidant agents might protect against oxidant-related upregulation of endothelial adhesion molecules and slow down the progression of vascular damage in non-insulin dependent diabetes.
Article
Full-text available
Although N-acetylcysteine is an antioxidant which has been expected to be a cancer chemopreventive agent, its safety and risk assessment have not been evaluated. N-acetylcysteine increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, whereas the amount of 8-oxodG in HP100, which is a hydrogen peroxide (H(2)O(2))-resistant cell line derived from HL-60, was not increased. To clarify the mechanism of cellular DNA damage, we investigated DNA damage and its site specificity induced by N-acetylcysteine, using (32)P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. N-acetylcysteine induced extensive DNA damage in the presence of Cu(II). The DNA cleavage was enhanced by piperidine treatment, suggesting that N-acetylcysteine plus Cu(II) caused not only deoxyribose phosphate backbone breakage but also base modification. N-acetylcysteine plus Cu(II) frequently modified thymine and guanine residues. Bathocuproine, a specific Cu(I) chelator, and catalase inhibited the DNA damage, indicating the participation of Cu(I) and H(2)O(2) in the DNA damage. Typical hydroxyl radical scavengers did not inhibit N-acetylcysteine plus Cu(II)-induced DNA damage, whereas methional completely inhibited it. These results suggest that reactive species derived from the reaction of H(2)O(2) with Cu(I) participates in N-acetylcysteine plus Cu(II)-induced DNA damage. The content of 8-oxodG in calf thymus DNA was increased by N-acetylcysteine in the presence of Cu(II). The present study has demonstrated that N-acetylcysteine could induce metal-dependent H(2)O(2) generation and, subsequently, damage to cellular and isolated DNA. Therefore, it is reasonable to consider that N-acetylcysteine may have the dual function of carcinogenic and anti-carcinogenic potentials. This work requires further studies on safety and risk assessment of N-acetylcysteine.
Article
Full-text available
Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.
Article
Full-text available
This study was carried out to investigate whether Nigella sativa could decrease the lipid peroxidation, increase the anti-oxidant defence system and also prevent the lipid-peroxidation-induced liver damage in experimentally induced diabetic rabbits. Fifteen New Zealand male rabbits were divided into three experimental groups: control, diabetic and diabetic and N. sativa-treated. The diabetes mellitus (DMI) was induced in the rabbits using 150 mg/kg of 10% alloxan. The diabetic + N. sativa-treated group was given extract of N. sativa seeds orally every day for 2 months after induction of DM. At the end of the 2-month experiment, blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), ceruloplasmin and glucose concentration, and livers were harvested for histopathological analysis. Treatment with N. sativa decreased the elevated glucose and MDA concentrations, increased the lowered GSH and ceruloplasmin concentrations, and prevented lipid-peroxidation-induced liver damage in diabetic rabbits. It was concluded that N. sativa might be used in diabetic patients to prevent lipid peroxidation, increase anti-oxidant defence system activity and also prevent liver damage.
Article
Full-text available
Melatonin was found to be a potent free radical scavenger in 1993. Since then over 800 publications have directly or indirectly confirmed this observation. Melatonin scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide and peroxynitrite anion. Based on the analyses of structure-activity relationships, the indole moiety of the melatonin molecule is the reactive center of interaction with oxidants due to its high resonance stability and very low activation energy barrier towards the free radical reactions. However, the methoxy and amide side chains also contribute significantly to melatonin's antioxidant capacity. The N-C=O structure in the C3 amide side chain is the functional group. The carbonyl group in the structure of N-C=O is key for melatonin to scavenge the second reactive species and the nitrogen in the N-C=O structure is necessary for melatonin to form the new five membered ring after melatonin's interaction with a reactive species. The methoxy group in C5 appears to keep melatonin from exhibiting prooxidative activity. If the methoxy group is replaced by a hydroxyl group, under some in vitro conditions, the antioxidant capacity of this molecule may be enhanced. However, the cost of this change are decreased lipophility and increased prooxidative potential. Therefore, in in vivo studies the antioxidant efficacy of melatonin appears to be superior to its hydroxylated counterpart. The mechanisms of melatonin's interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through an radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4 and C7 and nitrosation. Melatonin also has the ability to repair damaged biomolecules as shown by the fact that it converts the guanosine radical to guanosine by electron transfer. Unlike the classical antioxidants, melatonin is devoid of prooxidative activity and all known intermediates generated by the interaction of melatonin with reactive species are also free radical scavengers. This phenomenon is defined as the free radical scavenging cascade reaction of the melatonin family. Due to this cascade, one melatonin molecule has the potential to scavenge up to 4 or more reactive species. This makes melatonin very effective as an antioxidant. Under in vivo conditions, melatonin is often several times more potent than vitamin C and E in protecting tissues from oxidative injury when compared at an equivalent dosage (micromol/kg). Future research in the field of melatonin as a free radical scavenger might be focused on: 1), signal transduction and antioxidant enzyme gene expression induced by melatonin and its metabolites, 2), melatonin levels in tissues and in cells, 3), melatonin structure modifications, 4), melatonin and its metabolites in plants and, 5), clinical trials using melatonin to treat free radical related diseases such as Alzheimer's, Parkinson's, stroke and heart disease.
Chapter
The turbidity produced when protein is mixed with low concentrations of any of the common protein precipitants can be used as an index of protein concentration. The resulting turbidity is maximum after about 10 minutes and may be measured spectrophotometrically in the wavelength region of 600 m. Standardization may be effected by comparison with the turbidity produced by a suspension of a dried protein precipitate, or reference may be had to the methyl acrylate-styrene polymer. Turbidimetric techniques are rapid and convenient, but they yield different values with different proteins. They do not permit differentiation between protein and acid-insoluble compounds such as nucleic acids. Protein estimation with the Folin-Ciocalteu reagent include (1) biuret reaction of protein with copper ion in alkali, and (2) reduction of the phosphomolybdic-phosphotungstic reagent by the tyrosine and tryptophan present in the treated protein. Protein estimation by ultraviolet absorption takes advantage of the fact that nucleic acid, however, absorbs much more strongly at 260 mμ than at 280 mμ, whereas with protein the reverse is true. This advantage is used to eliminate, by calculation, the interference of nucleic acids in the estimation of protein.
Article
Our goal was to assess the effect of chronic vs acute hyperglycemia on free radicals (FR)/antioxidants balance in serum and leukocytes in an older (>65 years old) population with type II diabetes mellitus (DM). Case-control study comparing older male patients with type II DM with normal controls. FRs and antioxidants were measured at baseline and 120 min after an oral 100-g glucose load. Baseline measurements showed an increased level of oxidized glutathione (GSSG) (p = .01) in the serum of diabetic subjects. Similar findings were observed at the intracellular level in the same group for GSSG (p = .0004), total glutathione (GSH + GSSG) (p = .0001) (GSH is reduced glutathione), decreased GSH/GSSG ratio (p = .0001), and ascorbic acid (p = .008). Monocytes from diabetic subjects produced larger amounts of nitric oxide (NO) in vitro (p = .03). After the oral glucose challenge, between-group comparisons demonstrated similar findings at the intracellular level for increased oxidized glutathione (p = .0004), GSH + GSSG (p = .0001), decreased GSH/GSSG (p = .0001), ascorbic acid (p = .02), and increased NO (p = .02) for the diabetic subjects. Within-group comparisons showed a significant drop of ascorbic acid in the control and the diabetic groups (p < .01), an increased level of GSSG in the diabetic group (p < .01), a decreased GSH/GSSG ratio (p < .05), and decreased production of NO by monocytes after in vitro stimulation in the control group (p < .05). Our results suggest that type II diabetes in an older population is associated with increased basal oxidative stress. Hyperglycemic challenge is associated with an accentuation of this phenomenon as measured in the leukocytes.
Article
Oxidative stress occurs in diabetic patients and experimental models of diabetes. We examined whether two antioxidants, melatonin and taurine, can ameliorate diabetic nephropathy. Enhanced expression of glomerular TGF-β1 and fibronectin mRNAs and proteinuria were employed as indices of diabetic nephropathy. Experimental diabetes was induced by intravenous injection of streptozotocin 50 mg/kg. Two days after streptozotocin, diabetic rats were assigned to one of the following groups: i) untreated; ii) melatonin supplement by 0.02% in drinking water; or iii) taurine supplement by 1% in drinking water. Four weeks after streptozotocin, diabetic rats (n = 6: plasma glucose 516 ± 12 mg/dl) exhibited 6.1 fold increase in urinary protein excretion, 1.4 fold increase in glomerular TGF-β1 mRNA, 1.7 fold increase in glomerular fibronectin mRNA, 2.2 fold increase in plasma lipid peroxides (LPO), and 44 fold increase in urinary LPO excretion above the values in control rats (n = 6: plasma glucose 188 ± 14 mg/dl). Chronic administration of melatonin (n = 6) and taurine (n = 6) prevented increases in glomerular TGF-β1 and fibronectin mRNAs and proteinuria without having effect on blood glucose. Both treatments reduced lipid peroxidation by nearly 50%. The present data demonstrate beneficial effects of melatonin and taurine on early changes in diabetic kidney and suggest that diabetic nephropathy associated with hyperglycemia is largely mediated by oxidative stress. Science
Article
The levels of catalase (CAT), glutathione-s-transferase (GST), reduced glutathione (GSH) and oxidised glutathione (GSSG) were measured in red blood cells from control (C) and diabetic rats (D). Diabetes was induced by alloxan administration and diabetic rats were treated with insulin (D+I) and thyroxine (D+T4). On the third day of insulin withdrawal the CAT activity increased significantly. The GST activity showed an increase in D and D+I for one week, thyroxine treatment to D rats resulted in maintaining the GST activity at control levels. The levels of GSH and GSSG increased in D red cells after one week of insulin withdrawal but later, the GSH level was below the control level while the GSSG was at its control level. Insulin treatment to D rats did not reverse GSH level to control initially but controlled it at a later stage. Thyroxine, though, reversed GSH levels but enhanced GSSG in D rat red cells.
The influence of the sample pCO2 on the rate of ammonia formation was studied with gas equilibrated blood samples, using different gas mixtures for the equilibration. The rate of increase in plasma ammonia concentration at a mean pCO2 of 62 mm Hg = 8.2 kPa (mean pH = 7.282) was significantly lower than at 36 mm Hg = 4.8 kPa (pH = 7.438). In CO2-depleted blood (pH > 8) ammonia formation was strongly accelerated. This was reversible by readjusting the pH to 7.4 by addition of Tris-HCl solution. In stoppered containers with or without enclosed atmospheric air, a decrease of blood pCO2 or an increase of pH values was not observed during storage over 15 minutes at 0 or 20 degrees C. Although this study confirms that the pCO2 (or rather the pH) is an important analytical influence quantity in the determination of plasma ammonia, strictly anaerobic processing of the blood samples is not necessary; the usual technique of transporting and preprocessing blood samples in partially filled and stoppered containers appears to be adequate. Mainly due to the deamination of intracellular AMP (1), the ammonia1) concentration in blood increases continuously after sampling. Rates of increase in plasma ammonia concentration have recently been investigated thoroughly with blood samples from healthy probands to define the maximum delay between sampling and separation of the blood cells that can be tolerated if the in vivo existing plasma ammonia concentration has to be measured (2). Strictly speaking, the guidelines for handling the blood samples (2) apply to blood stored under anaerobic conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Rabbits were given gentamicin over a period of 10 days. At 1, 3, 5 and 10 days renal proximal tubules were isolated and glucose synthesis from several substrates was measured. A relationship between the inhibition of renal gluconeogenesis, accompanied by a decline of both pyruvate carboxylase and phosphoenopyruvate carboxykinase (PEPCK) activities, and an increased gentamicin level in kidney-cortex was noticed after 5 days of therapy. Both the rates of glucose formation from various substrates as well as pyruvate carboxylase and the cytosolic PEPCK activity recovered fully within 3 weeks after cessation of antibiotic treatment while an increase of activity of the mitochondrial PEPCK occurred during chronic administration of the drug for 10 days. It is concluded, that gentamicin-induced inhibition of gluconeogenesis is one of the events occurring during complex action of this drug on renal cortex.
Article
N-acetylcysteine has been widely used as an antioxidant in vivo and in vitro. Its reaction with four oxidant species has therefore been examined. N-acetylcysteine is a powerful scavenger of hypochlorous acid (H--OCl); low concentrations are able to protect alpha 1-antiproteinase against inactivation by HOCl. N-acetylcysteine also reacts with hydroxyl radical with a rate constant of 1.36 X 10(10) M-1s-1, as determined by pulse radiolysis. It also reacts slowly with H2O2, but no reaction of N-acetylcysteine with superoxide (O2-) could be detected within the limits of our assay procedures.
Article
An assay procedure is described in which blood cell glutathione peroxidase may be accurately measured by a direct spectrophotometric procedure. Glutathione peroxidase activity is found to be associated with a relatively stable, nondialyzable, heat-labile, intracellular component which is separable from hemoglobin, by gel filtration and ammonium sulfate precipitation. The activity appears to be dependent upon active sulfhydryl groups and is unaffected by low concentrations of azide, cyanide, or ferricyanide.
Article
We previously reported that the activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, is under both hormonal and cell density regulation in cultured rat hepatocytes. Specifically, the addition of insulin or hydrocortisone to culture media or the lowering of the initial plating cell density increased cell GSH by increasing the activity of GCS. In the present study, we examined the molecular mechanism of these effects. To determine whether the increase in GCS activity is associated with an increase in GCS heavy subunit (GCS-HS) mRNA expression, the steady state mRNA levels of GCS-HS were examined with the use of Northern blots. After 24-hr treatment of high density (0.6 x 10(5) cells/cm2) cultured rat hepatocytes with insulin (1 micrograms/ml) or hydrocortisone (50 nM), the steady state GCS-HS mRNA level increased by approximately 1-2 fold. When the plating density was decreased to 0.1 x 10(5) cells/cm2, the steady state GCS-HS mRNA level also increased by 1-2 fold 24 hr later. An increase in the steady state GCS-HS mRNA level was found within 4 hr of either hormonal treatment or cell density manipulation. The increase in steady state GCS-HS mRNA level resulted from increased gene transcription, as the transcriptional rates of GCS-HS after hormonal or cell density manipulation were increased by 2-3-fold, whereas the rates of GCS-HS mRNA degradation remained unchanged. Western blotting confirmed the increase in GCS-HS protein level after hormone treatment or lowering of plating cell density. When examined in vivo, the steady state GCS-HS mRNA level decreased by 50% in a rat in which diabetes had been induced with streptozotocin for 1 week; this was prevented with insulin replacement. In summary, GCS-HS gene expression is under both hormonal and cell density regulation.
Free radical damage to proteins, lipids, DNA and RNA has been thought to play an important role in many diseases as well as the aging process. One free radical, the hydroxyl free radical (HFR), is extremely reactive and is difficult to measure directly. HFRs were quantified by measuring the hydroxylation products 2,3- and 2,5-dihydroxybenzoic acids (DHBAs) formed as a result of the reaction between HFR and systemically administered salicylate (SAL). DHBAs and SAL concentrations were determined using RP-HPLC with dual coulometric electrode detection. The method has limits of detection of 1 pg for the DHBAs and 100 pg for SAL (signal-to-noise ratio 3:1). A detailed interference study as well as analyte stability and linearity studies were performed. This method was used to determine basal ratios of DHBA/SAL in a variety of tissues and to study the effects of glutamatergic and dopaminergic drugs on DHBA/SAL ratios in brain region homogenates.
Article
We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on oxidative stress, lung damage, and mortality induced by an endotoxin (lipopolysaccharide, or LPS) in the rat. Continuous intravenous infusion of 275 mg NAC/kg in 48 h, starting 24 h before LPS challenge, decreased hydrogen peroxide (H2O2) concentrations in whole blood (p < 0.01). This decrease was accompanied by fewer histologic abnormalities of the lung and decreased mortality (p < 0.025), compared with rats receiving LPS alone. N-Acetylserine, which has no sulfhydryl group, did not protect rats against LPS toxicity. Improved survival was not associated with an increase in pulmonary reduced glutathione, nor with inhibition of serum tumor necrosis factor (TNF) activity. In vitro, TNF production and DNA binding of nuclear factor kappa B (NF-kappaB) in human Mono Mac 6 cells was only inhibited at concentrations of NAC above 20 mM. High-dose NAC treatment (550 and 950 mg/kg in 48 h) decreased lung GSH (p < 0.05) and resulted in a significantly smaller number of surviving animals when compared with the low-dose NAC group (p < 0.025). In vitro, NAC increased hydroxyl radical generation in a system with Fe(III)-citrate and H2O2 by reducing ferric iron to its catalytic, active Fe2+ form. We conclude that low-dose NAC protects against LPS toxicity by scavenging H2O2, while higher doses may have the opposite effect.
Article
Blood samples were analyzed for GSH and GSH redox state in 40 age-related macular degeneration (ARMD) patients (> 60 y), 33 non-ARMD diabetic patients (> 60 years), 27 similarly aged non-ARMD and nondiabetic individuals (> 60 years), and 19 younger individuals (< 60 years) without ARMD or diabetes. Results showed a significantly lower plasma GSH in older individuals (ARMD, diabetes, and controls) than in younger individuals (p < .01). Total GSH (GSHt) obtained following treatment with dithiothreitol was significantly lower only in diabetic cases (p < .05) but also approached significance for ARMD cases (p = .089). Estimation of redox potential indicated that the plasma GSH pool is considerably more oxidized in all of the older groups. Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups, but did not reveal any difference associated with age or ARMD. In contrast, GSSG in whole blood was significantly higher in the older groups compared to the younger controls. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.
Article
Reactive oxygen species are involved in the pathogenesis of cancer and other chronic degenerative diseases through a variety of mechanisms, including DNA damage. We investigated by 32p and 33P postlabeling analyses the nucleotidic modifications induced in vitro by treating calf thymus DNA with H2O2 and CuSO4, interacting in a Fenton type reaction. Six different enrichment procedures and three chromatographic systems were comparatively assayed. The chromatographic system using phosphate/urea, which is more suitable for detecting bulky DNA adducts, was rather insensitive. In contrast, the system using acetic acid/ammonium formate revealed high levels of mononucleotidic modifications. In terms of ratio of adduct levels in treated and untreated DNA, the enrichment procedures ranked as follows: nuclease P1 (19.6), no enrichment (18.3), digestion to trinucleotides (17.6), digestion to monophosphate mononucleotides (8.4), digestion to dinucleotides (3.4), and extraction with butanol (<1.0). The system using formic acid/ammonium formate was quite efficient in detecting 8-hydroxy-2'-deoxyguanosine. Labeling with 33p further enhanced the sensitivity of the method. The oxidative damage was so intense to produce a strong DNA fragmentation detectable by agarose gel electrophoresis, and nucleotidic modifications were more intense when DNA fragmentation was greater. The DNA alterations produced by H2O2 alone were significantly lower than those produced following reaction of H2O2 with CuSO4. The thiol N-acetylcysteine (NAC) was quite efficient in inhibiting both nucleotidic modifications and DNA fragmentation produced in vitro by either H2O2 or the .OH generating system. These results support at a molecular level the findings of previous studies showing the ability of NAC to inhibit the genotoxicity of peroxides and of reactive oxygen species generated by electron transfer reactions.
Article
Oxidative stress is believed to play an important role in the development of vascular complications associated with diabetes mellitus. In this study, we examined the efficacy of long-term treatment with the antioxidant, N-acetylcysteine, in preventing the development of defective endothelium-dependent relaxation in streptozotocin-induced, Sprague-Dawley diabetic rats. At 48 h after injection of streptozotocin, a portion of diabetic rats received 250 mg/L N-acetylcysteine in drinking water for a total duration of 8 weeks. Oral administration did not alter the increase in blood glucose or the reduction in serum insulin but did modestly reduce total glycosylated hemoglobin. In precontracted thoracic aortic rings suspended in isolated tissue baths, endothelium-dependent relaxation to acetylcholine was impaired in diabetic rings compared with control rings. Endothelium-independent relaxation to nitroglycerin was unaltered. Long-term oral administration of N-acetylcysteine did not alter responses to nitroglycerin but completely prevented the defective relaxation to acetylcholine. These studies indicate a dissociation between glycemic control and correction of endothelial dysfunction and suggest that long-term exposure to reactive oxygen subsequent to diabetes rather than hyperglycemia per se is responsible for the development of endothelial dysfunction in diabetes mellitus.
Article
We have studied the effect of the administration of two doses of melatonin (melatonin 100 and melatonin 200 microg/kg bw) on diabetes and oxidative stress experimentally induced by the injection of streptozotocin (STZ) in female Wistar rats. STZ was injected as a single dose (60 mg/kg i.p. in buffered citrate solution, pH 4.0) and melatonin (melatonin 100, 100 microg/kg/day i.p.; melatonin 200, 200 microg/kg/day i.p.) beginning 3 days before diabetes induction and continuing until the end of the study (8 weeks). The parameters analysed to evaluate oxidative stress and the diabetic state were a) for oxidative stress, changes of lipoperoxides (i.e., malondialdehyde, MDA) in plasma and erythrocytes and the changes in reduced glutathione (GSH) in erythrocytes and b) for diabetes, changes in glycemia, lipids (triglycerides: TG; total cholesterol: TC; HDL-cholesterol, HDL-c), percentage of glycosylated hemoglobin (Hb%), and plasma fructosamine. The injection of STZ caused significant increases in the levels of glycemia, percentage of glycosylated hemoglobin, fructosamine, cholesterol, triglycerides, and lipoperoxides in plasma and erythrocytes, whereas it decreased the levels of HDL-c and the GSH content in erythrocytes. The melatonin 100 dose reduced significantly all these increases, except the percentage of glycosylated hemoglobin. With regard to the decreases of plasma HDL-c and GSH content in erythrocytes, this melatonin dose returned them to normal levels. The melatonin 200 dose produced similar changes, though the effects were especially noticeable in the decrease of glycemia (55% vs. diabetes), percentage of hemoglobin (P < 0.001 vs diabetes), and fructosamine (31% vs. diabetes). This dose also reversed the decreases of HDL-c and GSH in erythrocytes. Both doses of melatonin caused significant reduction of the percentage of glycosylated hemoglobin in those groups that were non-diabetic. These illustrate the protective effect of melatonin against oxidative stress and the severity of diabetes induced by STZ. In particular, this study confirms two facts: 1) the powerful antioxidant action of this pineal indole and 2) the importance of the severity of oxidative stress to maintain hyperglycemia and protein glycosylation, two pathogenetic cornerstones indicative of diabetic complications. Melatonin reduces remarkably the degree of lipoperoxidation, hyperglycemia, and protein glycosylation, which gives hope to a promising perspective of this product, together with other biological antioxidants, in the treatment of diabetic complications where oxidative stress, either in a high or in a low degree, is present.
Article
This chapter discusses the measurement of glutathione, glutathione disulfide, and other thiols in mammalian cell and tissue homogenates using high-performance liquid chromatography (HPLC) separation of N-(1-Pyrenyl)maleimide (NPM) derivatives. As glutathione and cellular thiol-related research progresses, the role of these thiols has been extended from acting only in the maintenance of steady-state redox equilibrium to a proposed involvement in many stress induced metabolic and bioregulator functions, including signal transduction and gene expression. The NPM assay provides a rapid and simple method for analyzing both oxidized and reduced glutathione, as well as other thiols, including cysteine, 7-glutamylcysteine, homocysteine, cysteinylglycine, and N-acetylcysteine. The NPM assay provides an excellent method for determining modulations in intracellular thiols caused by oxidative stress. Because changes in redox potential have been associated with alterations in metabolism, signal transduction, and gene expression, the NPM assay provides a sensitive and accurate means of correlating thiol status with these biological processes.
Article
Various one-electron oxidants such as OH*, tert-BuO*, CCl3OO*, Br2*- and N3*, generated pulse radiolytically in aqueous solutions at pH 7, were scavenged by melatonin to form two main absorption bands with lambda(max) = 335 nm and 500 nm. The assignment of the spectra and determination of extinction coefficients of the transients have been reported. Rate constants for the formation of these species ranged from 0.6-12.5x10(9) dm3 mol(-1) s(-1). These transients decayed by second order, as observed in the case of Br2*- and N3* radical reactions. Both the NO2* and NO* radicals react with the substrate with k = 0.37x10(7) and 3x10(7) dm3 mol(-1) s(-1), respectively. At pH approximately 2.5, the protonated form of the transient is formed due to the reaction of Br2*- radical with melatonin, pKa ( MelH* <=> Mel* + H+) = 4.7+/-0.1. Reduction potential of the couple (Mel*/MelH), determined both by cyclic voltammetric and pulse-radiolytic techniques, gave a value E(1)7 = 0.95+/-0.02 V vs. NHE. Repair of guanosine radical and regeneration of melatonin radicals by ascorbate and urate ions at pH 7 have been reported. Reactions of the reducing radicals e(aq)- and H* atoms with melatonin have been shown to occur at near diffusion rates.