Vitamin C-Conjugated Nanoparticle Protects Cells from Oxidative Stress at Low Doses but Induces Oxidative Stress and Cell Death at High Doses

Cadmium is a common transition metal that entails an extremely wide range of toxic effects in humans and animals. The cytotoxicity of cadmium ions and its compounds is due to various genotoxic effects, including both DNA damage and chromosomal aberrations. Some bone diseases, kidney and digestive system diseases are determined as pathologies that are closely associated with cadmium intoxication. In addition, cadmium is included in the list of carcinogens because of its ability to initiate the development of tumors of several forms of cancer under conditions of chronic or acute intoxication. Despite many studies of the effects of cadmium in animal models and cohorts of patients, in which cadmium effects has occurred, its molecular mechanisms of action are not fully understood. The genotoxic effects of cadmium and the induction of programmed cell death have attracted the attention of researchers in the last decade. In recent years, the results obtained for in vivo and in vitro experimental models have shown extremely high cytotoxicity of sublethal concentrations of cadmium and its compounds in various tissues. One of the most studied causes of cadmium cytotoxicity is the development of oxidative stress and associated oxidative damage to macromolecules of lipids, proteins and nucleic acids. Brain cells are most sensitive to oxidative damage and can be a critical target of cadmium cytotoxicity. Thus, oxidative damage caused by cadmium can initiate genotoxicity, programmed cell death and inhibit their viability in the human and animal brains. To test our hypothesis, cadmium cytotoxicity was assessed in vivo in U251 glioma cells through viability determinants and markers of oxidative stress and apoptosis. The result of the cell viability analysis showed the dose-dependent action of cadmium chloride in glioma cells, as well as the generation of oxidative stress (p <0.05). Calculated for 48 hours of exposure, the LD50 was 3.1 μg×ml-1. The rates of apoptotic death of glioma cells also progressively increased depending on the dose of cadmium ions. A high correlation between cadmium concentration and apoptotic response (p <0.01) was found for cells exposed to 3–4 μg×ml-1 cadmium chloride. Moreover, a significant correlation was found between oxidative stress (lipid peroxidation) and induction of apoptosis. The results indicate a strong relationship between the generation of oxidative damage by macromolecules and the initiation of programmed cell death in glial cells under conditions of low doses of cadmium chloride. The presented results show that cadmium ions can induce oxidative damage in brain cells and inhibit their viability through the induction of programmed death. Such effects of cadmium intoxication can be considered as a model of the impact of heavy metal pollution on vertebrates.

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Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress-mediated cell death pathways

Molecular Medicine Reports ◽

10.3892/mmr.2015.4167 ◽

2015 ◽

Vol 12 (4) ◽

pp. 6086-6092 ◽

Cited By ~ 12

Author(s):

TSAI-KUN WU ◽

CHYOU-WEI WEI ◽

YING-RU PAN ◽

SHUR-HUEIH CHERNG ◽

WEI-JUNG CHANG ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Vitamin C ◽

Toxic Effect ◽

Aristolochic Acid ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Cell Death Pathways ◽

Renal Tubular

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Low-DoseAronia melanocarpaConcentrate Attenuates Paraquat-Induced Neurotoxicity

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/5296271 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

A. J. Case ◽

D. Agraz ◽

I. M. Ahmad ◽

M. C. Zimmerman

Keyword(s):

Reactive Oxygen Species ◽

Hydrogen Peroxide ◽

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Reactive Oxygen ◽

High Dose ◽

Low Doses ◽

Oxygen Species ◽

High Doses

Herbicides containing paraquat may contribute to the pathogenesis of neurodegenerative disorders such as Parkinson’s disease. Paraquat induces reactive oxygen species-mediated apoptosis in neurons, which is a primary mechanism behind its toxicity. We sought to test the effectiveness of a commercially available polyphenol-richAronia melanocarpa(aronia berry) concentrate in the amelioration of paraquat-induced neurotoxicity. Considering the abundance of antioxidants in aronia berries, we hypothesized that aronia berry concentrate attenuates the paraquat-induced increase in reactive oxygen species and protects against paraquat-mediated neuronal cell death. Using a neuronal cell culture model, we observed that low doses of aronia berry concentrate protected against paraquat-mediated neurotoxicity. Additionally, low doses of the concentrate attenuated the paraquat-induced increase in superoxide, hydrogen peroxide, and oxidized glutathione levels. Interestingly, high doses of aronia berry concentrate increased neuronal superoxide levels independent of paraquat, while at the same time decreasing hydrogen peroxide. Moreover, high-dose aronia berry concentrate potentiated paraquat-induced superoxide production and neuronal cell death. In summary, aronia berry concentrate at low doses restores the homeostatic redox environment of neurons treated with paraquat, while high doses exacerbate the imbalance leading to further cell death. Our findings support that moderate levels of aronia berry concentrate may prevent reactive oxygen species-mediated neurotoxicity.

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Hippocampal Dysfunction Provoked by Mercury Chloride Exposure: Evaluation of Cognitive Impairment, Oxidative Stress, Tissue Injury and Nature of Cell Death

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/7878050 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Walessa Alana Bragança Aragão ◽

Francisco Bruno Teixeira ◽

Nathalia Carolina Fernandes Fagundes ◽

Rafael Monteiro Fernandes ◽

Luanna Melo Pereira Fernandes ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Cognitive Impairment ◽

Chronic Exposure ◽

Tissue Injury ◽

Cognitive Test ◽

Exposure Model ◽

Mercury Chloride ◽

Low Doses ◽

Hippocampal Dysfunction

Mercury (Hg) is a highly toxic metal, which can be found in its inorganic form in the environment. This form presents lower liposolubility and lower absorption in the body. In order to elucidate the possible toxicity of inorganic Hg in the hippocampus, we investigated the potential of low doses of mercury chloride (HgCl2) to promote hippocampal dysfunction by employing a chronic exposure model. For this, 56 rats were exposed to HgCl2 (0.375 mg/kg/day) via the oral route for 45 days. After the exposure period, the animals were submitted to the cognitive test of fear memory. The hippocampus was collected for the measurement of total Hg levels, analysis of oxidative stress, and evaluation of cytotoxicity, apoptosis, and tissue injury. It was observed that chronic exposure to inorganic Hg promotes an increase in mercury levels in this region and damage to short- and long-term memory. Furthermore, we found that this exposure model provoked oxidative stress, which led to cytotoxicity and cell death by apoptosis, affecting astrocytes and neurons in the hippocampus. Our study demonstrated that inorganic Hg, even with its low liposolubility, is able to produce deleterious effects in the central nervous system, resulting in cognitive impairment and hippocampal damage when administered for a long time at low doses in rats.

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Effects of Low-Dose versus High-Doseγ-Tocotrienol on the Bone Cells Exposed to the Hydrogen Peroxide-Induced Oxidative Stress and Apoptosis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/680834 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Nizar Abd Manan ◽

Norazlina Mohamed ◽

Ahmad Nazrun Shuid

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Antioxidant Enzymes ◽

Low Dose ◽

Bone Cells ◽

Dependent Manner ◽

Low Doses ◽

Antioxidant Enzymes Activities ◽

High Doses ◽

Dose Dependent

Oxidative stress and apoptosis can disrupt the bone formation activity of osteoblasts which can lead to osteoporosis. This study was conducted to investigate the effects ofγ-tocotrienol on lipid peroxidation, antioxidant enzymes activities, and apoptosis of osteoblast exposed to hydrogen peroxide (H2O2). Osteoblasts were treated with 1, 10, and 100 μM ofγ-tocotrienol for 24 hours before being exposed to 490 μM (IC50) H2O2for 2 hours. Results showed thatγ-tocotrienol prevented the malondialdehyde (MDA) elevation induced by H2O2in a dose-dependent manner. As for the antioxidant enzymes assays, all doses ofγ-tocotrienol were able to prevent the reduction in SOD and CAT activities, but only the dose of 1 μM of GTT was able to prevent the reduction in GPx. As for the apoptosis assays,γ-tocotrienol was able to reduce apoptosis at the dose of 1 and 10 μM. However, the dose of 100 μM ofγ-tocotrienol induced an even higher apoptosis than H2O2. In conclusion, low doses ofγ-tocotrienol offered protection for osteoblasts against H2O2toxicity, but itself caused toxicity at the high doses.

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Alleviating Effects of Vitamins C and E Supplementation on Oxidative Stress, Hematobiochemical and Histopathological Alterations Caused by Copper Toxicity in Broiler Chickens

Animals ◽

10.3390/ani11061739 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1739

Author(s):

Mohamed A. Hashem ◽

Sahar S. Abd El Hamied ◽

Eman M. A. Ahmed ◽

Shimaa A. Amer ◽

Aziza M. Hassan

Keyword(s):

Oxidative Stress ◽

Vitamin E ◽

Vitamin C ◽

Broiler Chickens ◽

Copper Toxicity ◽

Basal Diet ◽

High Serum ◽

Control Group ◽

Broiler Chicks ◽

High Doses

The current investigation evaluated the alleviating effects of vitamin C and vitamin E on oxidative stress, hematobiochemical, and histopathological changes in the kidney induced by copper sulfate (CuSO4) toxicity in chickens. Two hundred and fifty-one-day-old male broiler chicks were randomly allotted into five experimental groups (five replicates/group, ten chicks/replicate): 1st group—basal diet with no additives (control group), 2nd group—basal diet complemented with CuSO4 (300 mg/kg diet), 3rd group—basal diet with CuSO4 (300 mg/kg diet) + vitamin C (250 mg/kg diet), 4th group—basal diet with CuSO4 (300 mg/kg diet) + vitamin E (250 mg/kg diet), and 5th group—basal diet with CuSO4 (300 mg/kg diet) + vitamin C (250 mg/kg diet) + vitamin E (250 mg/kg diet) for a 42 day feeding period. The results showed a significant reduction in red blood cells (RBCs), hemoglobin (Hb) concentration, and hematocrit values as well as total leukocyte counts (WBCs), lymphocyte, heterophil, and monocyte counts in the CuSO4-intoxicated birds (2.42 × 106/µL, 9.54 g/dL, 26.02%, 15.80 × 103/µL, 7.86 × 103/µL, 5.26 × 103/µL, and 1.18 × 103/µL, respectively, at the 6th week) compared to (2.79 × 106/µL, 10.98 g/dL, 28.46%, 21.07 × 103/µL, 10.84 × 103/µL, 7.12 × 103/µL, and 1.60 × 103/µL, respectively) in the control group. Moreover, CuSO4-intoxicated birds showed hypoglycemia with a rise in serum uric acid and creatinine levels (122.68, 5.18, and 0.78 mg/dL at the 6th week) compared to (159.46, 4.41, and 0.61 mg/dL) in the control group. The CuSO4 toxicity in birds induced oxidative stress, indicated by a high serum malondialdehyde level (MDA) and diminished activity of the antioxidant enzymes (glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD)) (2.01 nmol/mL, 37.66 U/mL, and 2.91 U/mL, respectively, at the 6th week) compared to (1.34 nmol/mL, 57.00 U/mL, 4.99 U/mL, respectively) in the control group. High doses of Cu exposure caused severe microscopic alterations in kidney architecture. The addition of vitamins C and E, singularly or in combination, displayed a beneficial effect in alleviating these harmful effects of Cu toxicity. These findings showed the possible mitigating impacts of dietary antioxidants on the hematobiochemical alterations, oxidative stress, and kidney damage induced by CuSO4 toxicity.

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Melatonin prevents cytosolic calcium overload, mitochondrial damage and cell death due to toxically high doses of dexamethasone-induced oxidative stress in human neuroblastoma SH-SY5Y cells

Neurochemistry International ◽

10.1016/j.neuint.2016.05.003 ◽

2016 ◽

Vol 97 ◽

pp. 34-41 ◽

Cited By ~ 37

Author(s):

Wilasinee Suwanjang ◽

Andrey Y. Abramov ◽

Komgrid Charngkaew ◽

Piyarat Govitrapong ◽

Banthit Chetsawang

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Cytosolic Calcium ◽

Mitochondrial Damage ◽

Calcium Overload ◽

Human Neuroblastoma ◽

High Doses

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Effect of Co Enzyme Q10 Alone or in Combination with Vitamin C on Lipopolysaccharide-Induced Brain Injury in Rats

Biomedical & Pharmacology Journal ◽

10.13005/bpj/1483 ◽

2018 ◽

Vol 11 (3) ◽

pp. 1215-1226

Author(s):

Nabila A. El-Laithy ◽

Elsayed M.E. Mahdy ◽

Eman R. Youness ◽

Nermeen Shafee ◽

Mohamed S.S. Mowafy ◽

...

Keyword(s):

Oxidative Stress ◽

Vitamin C ◽

Brain Tissue ◽

Paraoxonase 1 ◽

Intraperitoneal Dose ◽

High Doses ◽

C 50 ◽

Histopathological Results ◽

The Impact

Our was to determine the impact of CoenzymeQ10 (Co Q10) and vitamin C alone or in combination on oxidative stress in brain tissue of rats during endotoxemia induced by single intraperitoneal dose of Lipopolysaccharide (LPS), 500µg/kg. Both CoQ10&vitamin C were given orally to rats with doses (200&100 mg/kg) respectively for 7successive days prior induction of endotoxemia .LPS injected, with Co Q10 with doses (100 &200 mg/kg) &vit. C (50&100 mg/kg).In addition CoQ10 and vitamin C together in doses (100&50 mg/kg) & (200&100 mg/kg) respectively were added to LPS-treated rats. Then euthanized 4 hours later. Histopathological assessment of brain tissue was done. Results: LPS injection induced oxidative stress in brain tissue, resulting in marked increase in malondiadehyde (MDA), nitrite (NO) and Amyloid beta (Aβ), while decreasing reduced glutathione (GSH), paraoxonase-1 (PON1) and brain derived neurotrophic factor (BDNF).CoQ10 and vit.C administration with doses(200&100 mg/ kg) before endotoxemia result in reduction of brain MDA, NO and Aβ, while increasing levels of GSH, PON1 and BDNF compared to controls. The addition of both Co Q10 &vit.C to LPS- treated rats lead to decrease of brain NO, MDA and Aβ, also increase of GSH, PON1 and BDNF. This effect was more obviouswith high doses, this due to the ameliorating effect of both CoQ10 and vit.C on oxidative stress of brain tissue during endotoxemia.This consisted with the histopathological results. Conclusion: this work focuses on the possible role of CoQ10 &vit.C as antioxidants in protecting brain tissue.

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Alzheimer ’s Disease: Possible Mechanisms Behind Neurohormesis Induced by Exposure to Low Doses of Ionizing Radiation

Journal of Biomedical Physics and Engineering ◽

10.31661/jbpe.v8i2.919 ◽

2018 ◽

Vol 8 (2) ◽

Cited By ~ 9

Author(s):

J J Bevelacqua ◽

S M J Mortazavi

Keyword(s):

Oxidative Stress ◽

Ionizing Radiation ◽

Cellular Therapy ◽

Antioxidant Defenses ◽

Low Doses ◽

Proliferation And Differentiation ◽

Ros Formation ◽

Neuro Inflammation ◽

High Doses ◽

Focal Demyelination

In 2016, scientists reported that human exposure to low doses of ionizing radiation (CT scans of the brain) might relieve symptoms of both Alzheimer’s disease (AD) and Parkinson disease (PD). The findings were unbelievable for those who were not familiar with neurohormesis. X-ray stimulation of the patient’s adaptive protection systems against neurodegenerative diseases was the mechanism proposed by those authors. Now, some more recent studies performed in the field of neurobiological research confirm that low levels of stress can produce protective responses against the pathogenic processes. This paper outlines possible protective consequences of LDR in preventing the pathogenesis of AD through mechanisms such as restoring the myelin sheath and preventing neurodegeneration caused by oxidative stress. Focal demyelination is frequently reported in the proximity of beta-amyloid plaques within neocortex. Extracellular accumulation of amyloid is among well-characterized pathological changes in AD. It should be noted that LDR has been shown to contribute to the regeneration and functional recovery after transverse peripheral nerve injury (through inducing increased production of VEGF and GAP-43), which advances both the axonal regeneration and myelination. Another mechanism which is possibly involved is preventing neurodegeneration caused by oxidative stress. While high doses can induce reactive oxygen species (ROS) formation, oxidative stress and neuro-inflammation, substantial evidence now indicates that LDR can mitigate tissue damage through antioxidant defenses. Although adult neurogenesis has been reported to be beneficial for the regeneration of nervous system, some studies demonstrate that neurogenesis increases in AD brains. In spite of these reports, cellular therapy is introduced as a promising strategy for AD, and hence, LDR can affect the proliferation and differentiation of neural stem cells. Although such mechanisms are not fully known yet, it is hoped that this paper would foster further investigation into the mechanisms of this phenomenon, which accordingly improves human health.

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Dual functional roles of Tie-2/angiopoietin in TNF-α-mediated angiogenesis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01058.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. H187-H195 ◽

Cited By ~ 50

Author(s):

Jian-Xiong Chen ◽

Ying Chen ◽

Laura DeBusk ◽

Wenyu Lin ◽

Pengnain Charles Lin

Keyword(s):

Endothelial Cells ◽

Cell Death ◽

Low Doses ◽

Functional Roles ◽

Akt Phosphorylation ◽

Dual Functional ◽

Tnf Α ◽

Corneal Angiogenesis ◽

High Doses ◽

Induced Apoptosis

Inflammation and angiogenesis are associated with pathological disorders. TNF-α is a major inflammatory cytokine that also regulates angiogenesis. TNF-α has been shown to regulate Tie-2 and angiopoietin (Ang) expression, but the functional significance is less clear. In this study, we showed that TNF-α induced a weak angiogenic response in a mouse cornea assay. Systemic overexpression of Ang-1 or Ang-2 dramatically increased corneal angiogenesis induced by TNF-α. In the absence of TNF-α, neither Ang-1 nor Ang-2 promoted corneal angiogenesis. Low doses (0–25 ng/ml) of TNF-α increased vascular branch formation of cultured endothelial cells. Overexpression of Ang-1 or Ang-2 enhanced the effects of TNF-α. These data suggest that Tie-2 signaling synergistically amplifies and participates in TNF-α-mediated angiogenesis. In addition, high doses (≥50 ng/ml) of TNF-α induced apoptosis in endothelial cells, but addition of Ang-1 or Ang-2 significantly reduced cell death. Enhanced endothelial cell survival was correlated with Akt phosphorylation. Collectively, our data reveal dual functional roles of Tie-2: low doses enhance TNF-α-induced angiogenesis, and high doses attenuate TNF-α-induced cell death. The study provides evidence supporting a role for Tie-2 in inflammatory angiogenesis.

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