Zinc and energy requirements in induction of oxidative stress to retinal pigmented epithelial cells
TL;DR: It is concluded that a combination of zinc and antioxidants or energy substrates rather that zinc alone should provide a safer and more effective way to treat a disease such as AMD.
Abstract: In age-related macular degeneration (AMD), retinal pigmented epithelium (RPE) cells are believed to be detrimentally affected. It is thought that zinc may play a part in this process. In the past, therefore, zinc supplementation has been suggested as a treatment for AMD. Experimental data shown here confound this view by indicating that whereas low amounts of zinc do protect RPE cells in culture from stress-induced effects, greater amounts of zinc have the opposite influence. These effects are partly dependent upon the “health status” of the cells. Experimental data presented herein also show that zinc-induced death of RPE cells can, however, be attenuated by compounds such as antioxidants (α-tocopherol, trolox, and metipranolol), or cellular energy substrates (pyruvate and oxaloacetate). It is therefore concluded that a combination of zinc and antioxidants or energy substrates rather that zinc alone should provide a safer and more effective way to treat a disease such as AMD.
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TL;DR: Given the increasing understanding of the events involved in ischemic neuronal injury, it is hoped that clinically effective treatments for retinal ischemia will soon be available.
886 citations
TL;DR: The salient features of light damage are reviewed, recently joined by evidence for retinal remodeling which has implications for the prognosis of recovery of function in retinal degenerations and select factors that influence the progression of the damage process and the extent of visual cell loss are considered.
473 citations
TL;DR: The motivation of this review is to provide an overview of the general requirements, composition, structure-property relationship with hydroxyapatite formation and future perspectives of bioglasses.
Abstract: Bioactive glass and glass-ceramics are used in bone repair applications and are being developed for tissue engineering applications. Bioactive glasses/Bioglass are very attractive materials for producing scaffolds devoted to bone regeneration due to their versatile properties, which can be properly designed depending on their composition. An important feature of bioactive glasses, which enables them to work for applications in bone tissue engineering, is their ability to enhance revascularization, osteoblast adhesion, enzyme activity and differentiation of mesenchymal stem cells as well as osteoprogenitor cells. An extensive amount of research work has been carried out to develop silicate, borate/borosilicate bioactive glasses and phosphate glasses. Along with this, some metallic glasses have also been investigated for biomedical and technological applications in tissue engineering. Many trace elements have also been incorporated in the glass network to obtain the desired properties, which have beneficial effects on bone remodeling and/or associated angiogenesis. The motivation of this review is to provide an overview of the general requirements, composition, structure-property relationship with hydroxyapatite formation and future perspectives of bioglasses.Attention has also been given to developments of metallic glasses and doped bioglasses along with the techniques used for their fabrication.
444 citations
TL;DR: Induction of the ARE-Nrf2 pathway by zinc provides powerful and prolonged antioxidation and detoxification that may explain the beneficial effects of zinc observed in the treatment of age-related macular degeneration (AMD).
Abstract: Purpose To determine the molecular mechanisms underlying the protective effects of zinc against oxidative stress in cultured retinal pigment epithelial (RPE) cells. Methods Cultured ARPE-19 cells were treated with different concentrations of zinc for various times. Cellular glutathione (GSH) and glutathione disulfide (GSSG) levels were measured by high-performance liquid chromatography (HPLC). Glutamate-cysteine ligase (GCL) expression was measured by quantitative reverse transcription-PCR (RT-PCR). Nuclear factor erythroid2-related factor (Nrf2) activity was measured in a dual luciferase assay after transfection of reporter plasmids containing the antioxidant response element (ARE). The small interference (si)RNA approach was used to knock down the expression of Nrf2. Results Zinc significantly increased GSH levels in ARPE-19 cells through induction of the de novo synthesis pathway. At 150 microM, zinc increased the GSH level by 70%. At similar concentrations, zinc upregulated the mRNA level of GCL and activated the ARE-Nrf2 pathway. The effects of zinc on ARE activation and GSH synthesis were inhibited by knockdown of Nrf2 expression using the siRNA approach. Conclusions Induction of the ARE-Nrf2 pathway by zinc provides powerful and prolonged antioxidation and detoxification that may explain the beneficial effects of zinc observed in the treatment of age-related macular degeneration (AMD).
141 citations
TL;DR: The importance of designing Zn-containing bioactive glasses without cytotoxic effects is highlighted and supplementary information about the prooxidant role of zinc in living systems is given.
134 citations
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TL;DR: A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation and is used to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
50,114 citations
TL;DR: People older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD and those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye should consider taking a supplement of antioxidants plus zinc.
Abstract: BACKGROUND
Observational and experimental data suggest that antioxidant and/or zinc supplements may delay progression of age-related macular degeneration (AMD) and vision loss.
OBJECTIVE
To evaluate the effect of high-dose vitamins C and E, beta carotene, and zinc supplements on AMD progression and visual acuity.
DESIGN
The Age-Related Eye Disease Study, an 11-center double-masked clinical trial, enrolled participants in an AMD trial if they had extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye. At least 1 eye had best-corrected visual acuity of 20/32 or better. Participants were randomly assigned to receive daily oral tablets containing: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide; (3) antioxidants plus zinc; or (4) placebo.
MAIN OUTCOME MEASURES
(1) Photographic assessment of progression to or treatment for advanced AMD and (2) at least moderate visual acuity loss from baseline (> or =15 letters). Primary analyses used repeated-measures logistic regression with a significance level of.01, unadjusted for covariates. Serum level measurements, medical histories, and mortality rates were used for safety monitoring.
RESULTS
Average follow-up of the 3640 enrolled study participants, aged 55-80 years, was 6.3 years, with 2.4% lost to follow-up. Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71; 99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in this higher-risk group. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations.
CONCLUSIONS
Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.
2,898 citations
TL;DR: Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people.
Abstract: Objective. —To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. Design. —The multicenter Eye Disease Case-Control Study. Setting. —Five ophthalmology centers in the United States. Patients. —A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. Main Outcome Measures. —The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. Results. —A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92;Pfor trend=.02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (Pfor trend=.001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (Pfor trend Conclusion. —Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship. (JAMA. 1994;272:1413-1420)
1,411 citations
TL;DR: There is still much work to be done to characterize the properties of the different MCT isoforms and their regulation, which may have wide-ranging implications for health and disease.
Abstract: Monocarboxylates such as lactate and pyruvate play a central role in cellular metabolism and metabolic communication between tissues. Essential to these roles is their rapid transport across the plasma membrane, which is catalysed by a recently identified family of proton-linked monocarboxylate transporters (MCTs). Nine MCT-related sequences have so far been identified in mammals, each having a different tissue distribution, whereas six related proteins can be recognized in Caenorhabditis elegans and 4 in Saccharomyces cerevisiae. Direct demonstration of proton-linked lactate and pyruvate transport has been demonstrated for mammalian MCT1-MCT4, but only for MCT1 and MCT2 have detailed analyses of substrate and inhibitor kinetics been described following heterologous expression in Xenopus oocytes. MCT1 is ubiquitously expressed, but is especially prominent in heart and red muscle, where it is up-regulated in response to increased work, suggesting a special role in lactic acid oxidation. By contrast, MCT4 is most evident in white muscle and other cells with a high glycolytic rate, such as tumour cells and white blood cells, suggesting it is expressed where lactic acid efflux predominates. MCT2 has a ten-fold higher affinity for substrates than MCT1 and MCT4 and is found in cells where rapid uptake at low substrate concentrations may be required, including the proximal kidney tubules, neurons and sperm tails. MCT3 is uniquely expressed in the retinal pigment epithelium. The mechanisms involved in regulating the expression of different MCT isoforms remain to be established. However, there is evidence for alternative splicing of the 5'- and 3'-untranslated regions and the use of alternative promoters for some isoforms. In addition, MCT1 and MCT4 have been shown to interact specifically with OX-47 (CD147), a member of the immunoglobulin superfamily with a single transmembrane helix. This interaction appears to assist MCT expression at the cell surface. There is still much work to be done to characterize the properties of the different isoforms and their regulation, which may have wide-ranging implications for health and disease. In the future it will be interesting to explore the linkage of genetic diseases to particular MCTs through their chromosomal location.
1,298 citations
"Zinc and energy requirements in ind..." refers background in this paper
...Pyruvate is transported into cells by specific monocarboxylate transporters (29), and 4-CIN is a potent inhibitor of these transporters....
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TL;DR: Manipulations aimed at reducing extracellular zinc accumulation, or cellular vulnerability to toxic zinc exposure, may provide a novel therapeutic approach toward ameliorating pathological neuronal death in these settings.
Abstract: Zinc is an essential catalytic or structural element of many proteins, and a signaling messenger that is released by neural activity at many central excitatory synapses. Growing evidence suggests that zinc may also be a key mediator and modulator of the neuronal death associated with transient global ischemia and sustained seizures, as well as perhaps other neurological disease states. Manipulations aimed at reducing extracellular zinc accumulation, or cellular vulnerability to toxic zinc exposure, may provide a novel therapeutic approach toward ameliorating pathological neuronal death in these settings.
750 citations
"Zinc and energy requirements in ind..." refers background in this paper
...It is also possible for zinc itself to enter cells through such receptors (41)....
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...It is known that zinc has the potential to alter the behavior of multiple membrane channels and neurotransmitter receptors (41)....
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...Human RPE cells are also known to express GABAA-receptors (43) and the disturbance of these receptors by zinc may, in part, explain the detrimental effects of this ion at elevated concentrations....
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...Zinc can also modulate GABAA-receptors (41), altering inward ion fluxes....
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