Nikhat J. Siddiqi

Biomedical Implications of Heavy Metals Induced Imbalances in Redox Systems

Several workers have extensively worked out the metal induced toxicity and have reported the toxic and carcinogenic effects of metals in human and animals. It is well known that these metals play a crucial role in facilitating normal biological functions of cells as well. One of the major mechanisms associated with heavy metal toxicity has been attributed to generation of reactive oxygen and nitrogen species, which develops imbalance between the prooxidant elements and the antioxidants (reducing elements) in the body. In this process, a shift to the former is termed as oxidative stress. The oxidative stress mediated toxicity of heavy metals involves damage primarily to liver (hepatotoxicity), central nervous system (neurotoxicity), DNA (genotoxicity), and kidney (nephrotoxicity) in animals and humans. Heavy metals are reported to impact signaling cascade and associated factors leading to apoptosis. The present review illustrates an account of the current knowledge about the effects of heavy metals (mainly arsenic, lead, mercury, and cadmium) induced oxidative stress as well as the possible remedies of metal(s) toxicity through natural/synthetic antioxidants, which may render their effects by reducing the concentration of toxic metal(s). This paper primarily concerns the clinicopathological and biomedical implications of heavy metals induced oxidative stress and their toxicity management in mammals.

Identification of potential biomarkers of gold nanoparticle toxicity in rat brains

BackgroundGold nanoparticles (AuNPs) are finding increased use in therapeutics and imaging. However, their toxic effects still remain to be elucidated. Therefore this study was undertaken to study the biochemical effects of AuNPs on rat brain and identify potential biomarkers of AuNP toxicity.MethodsMale Wister rats weighing 150–200 g were injected with 20 μg/kg body weight of 20-nm gold nanoparticles for 3 days through the intraperitoneal route. The rats were killed by carbon dioxide asphyxiation 24 h after the last dose of gold nanoparticle injection. The parameters studied included lipid peroxidation, glutathione peroxidase, 8- hydroxydeoxyguanosine, caspase-3, heat shock protein70, serotonin, dopamine, gamma amino-butyric acid and interferon-γ.ResultsIn this study AuNPs caused generation of oxidative stress and a decrease of antioxidant enzyme, viz., glutathione peroxidase activity in rat brain. This was accompanied by an increase in 8-hydroxydeoxyguanosine, caspase-3 and heat shock protein70, which might lead to DNA damage and cell death. Gold nanoparticles also caused a significant decrease in the levels of neurotransmitters like dopamine and serotonin, indicating a possible change in the behavior of the treated animals. There was a significant increase in the cerebral levels of IFN-γ in treated animals.ConclusionThis study concludes that AuNPs cause generation of oxidative stress and an impairment of the antioxidant enzyme glutathione peroxidase in rat brain. AuNPs also cause generation of 8-hydroxydeoxyguanosine (8OHdG), caspase-3 and heat shock protein70 (Hsp70), and IFN-γ, which may lead to inflammation and DNA damage/cell death.

Effects of docosahexaenoic Acid on neurotransmission.

Docosahexaenoic acid (DHA) is the major polyunsaturated fatty acid (PUFA) in the brain and a structural component of neuronal membranes. Changes in DHA content of neuronal membranes lead to functional changes in the activity of receptors and other proteins which might be associated with synaptic function. Accumulating evidence suggests the beneficial effects of dietary DHA supplementation on neurotransmission. This article reviews the beneficial effects of DHA on the brain; uptake, incorporation and release of DHA at synapses, effects of DHA on synapses, effects of DHA on neurotransmitters, DHA metabolites, and changes in DHA with age. Further studies to better understand the metabolome of DHA could result in more effective use of this molecule for treatment of neurodegenerative or neuropsychiatric diseases.

Pesticides-induced biochemical alterations in occupational North Indian suburban population

Pesticides are used in agriculture to protect crops from insects–pests. Most of the field workers of North Indian population are exposed to commonly used insecticides. In the present study, pesticides induced oxidative stress as well as alterations in the level of acetylcholinesterase (AChE) in a total of 70 male healthy agricultural sprayers, exposed to pesticides for about 5 years, were studied and the results were compared with 70 controls. The levels of antioxidant enzymes (superoxide dismutase, CAT, glutathione-S-transferase and glutathione peroxidase), AChE, lipid peroxidation and glutathione (GSH) contents were determined in their blood erythrocytes (red blood cells (RBCs)). The results indicated significant increase in the levels of malondialdehyde as well as the activities of antioxidant enzymes in pesticide-exposed individuals. The levels of GSH, RBC-AChE activity and plasma antioxidant potential were sharply decreased when compared with control subjects. The ferric-reducing ability of plasma (FRAP) assay was carried out to evaluate the antioxidant potential of pesticide in exposed as well as healthy controls. A significant positive correlation was observed between plasma FRAP value and the activity of AChE from RBCs in pesticides sprayers. Furthermore, these results were supported by enhanced messenger RNA expressions of cytochrome P450 isoform 2E1 (CYP2E1) and gutathione-S-transferase isoform pi (GST-pi) in the white blood cells of the randomly selected pesticide-exposed individuals. The decreased GSH level in human red blood cells accompanied by increase in the levels of the activities of antioxidative enzymes and over expressions of CYP2E1 and GST-pi is an indicative of oxidative stress in pesticides-exposed individuals. The reduced activity of AChE indicates possible occurrence of perturbations in blood as well as neurotoxicity in pesticide sprayers.

Carbofuran Induced Oxidative Stress Mediated Alterations in Na + -K + -ATPase Activity in Rat Brain: Amelioration by Vitamin E

Pesticides cause oxidative stress and adversely influence Na+‐K+‐ATPase activity in animals. Since impact of carbofuran has not been properly studied in the mammalian brain, the ability of carbofuran to induce oxidative stress and modulation in Na+‐K+‐ATPase activity and its amelioration by vitamin E was performed. The rats divided into six groups received two different doses of carbofuran (15% and 30% LD50) for 15 days. The results suggested that the carbofuran treatment caused a significant elevation in levels of malonaldehyde and reduced glutathione and sharp inhibition in the activities of super oxide dismutase, catalase, and glutathione‐S‐transferase; the effect being dose dependent. Carbofuran at different doses also caused sharp reduction in the activity of Na+‐K+‐ATPase. The pretreatment of vitamin E, however, showed a significant recovery in these indices. The pretreatment of rats with vitamin E offered protection from carbofuran‐induced oxidative stress.

Short- and long-term changes in blood miRNA levels after nanogold injection in rats—potential biomarkers of nanoparticle exposure

Context: Increased use of engineered nanoparticles may result in exposure of workers and consumers, making them a health concern. Objective: To identify potential blood miRNA biomarkers after intravenous gold nanoparticle (AuNP) exposure. Materials and methods: miRNA microarray analysis was carried out on blood of rats at 1 week and 2 months after injection. Results: Many up- and downregulated miRNAs were detected. Of these, rno-miR-298 was confirmed to be increased at 1 week postinjection by reverse transcription-PCR (RT-PCR). Discussion and conclusion: Blood miRNAs could be useful as biomarkers for exposure to nanoparticles. miR-298 regulates β-amyloid (Aβ) precursor protein-converting enzyme-1 (BACE1) in Alzheimer’s disease.

Protective effects of quercetin on cadmium fluoride induced oxidative stress at different intervals of time in mouse liver

Quercetin, a member of the flavonoid family is a major antioxidant acquired in humans by food consumption, while Cadmium fluoride (CdF2) is one of the naturally occurring chemicals having adverse effects. The protective effect of quercetin on time dependent oxidative damage induced in mice liver by CdF2 was studied in the following groups of mice consisting of six mice each: (i) control group; (ii) mice treated with single i.p injection of 2 mg/kg bw CdF2 for 24 h; (iii) mice treated with single i.p injection of 2 mg/kg bw CdF2 for 48 h; (iv) mice treated with single i.p injection of quercetin (100 mg/kg bw); (v) mice treated with i.p injection of 100 mg/kg bw of quercetin followed by i.p injection of CdF2 (2 mg/kg bw) for 24 h; and (vi) mice treated with i.p injection of 100mg/kg bw of quercetin followed by CdF2 (2 mg/kg bw) for 48 h. Administration of quercetin two hours before CdF2 significantly reduced the biochemical alterations in reduced glutathione, ascorbic acid, lipid peroxidation, super oxide dismutase, catalase and total protein (p<0.05). Histopathology also showed the protective effect of quercetin. The livers treated with CdF2 were atrophic, markedly nodular, inflamed and necrotic. However, this effect was reduced to a minimum in the mice pre-treated for two hours with quercetin.

Acetylcholinesterase from Human Erythrocytes as a Surrogate Biomarker of Lead Induced Neurotoxicity

Lead induced neurotoxicity in the people engaged in different occupations has received wide attention but very little studies have been carried out to monitor occupational neurotoxicity directly due to lead exposure using biochemical methods. In the present paper an endeavour has been made in order to assess the lead mediated neurotoxicity by in vitro assay of the activity of acetylcholinesterase (AChE) from human erythrocytes in presence of different concentrations of lead. The results suggested that the activity of this enzyme was localized in membrane bound fraction and it was found to be highly stable up to 30 days when stored at −20°C in phosphate buffer (50 mM, pH 7.4) containing 0.2% Triton X-100. The erythrocytes AChE exhibited K m for acetylcholinesterase to be 0.1 mM. Lead caused sharp inhibition of the enzyme and its IC50 value was computed to be 1.34 mM. The inhibition of the enzyme by lead was found to be of uncompetitive type (K i value, 3.6 mM) which negatively influenced both the V max and the enzyme-substrate binding affinity. Taken together, these results indicate that AChE from human erythrocytes could be exploited as a surrogate biomarker of lead induced neurotoxicity particularly in the people occupationally exposed to lead.

Carbofuran Induced Oxidative Stress in Rat Heart: Ameliorative Effect of Vitamin C

The aim of this study was to evaluate the effect of carbofuran on the levels of certain biomarkers in heart of rat exposed to sublethal concentrations of pesticide for 30 days after each interval of 24 h. The ameliorative effect of vitamin C by pretreatment of rats was also monitored. The results indicated that the activities of acetylcholinesterase and lactate dehydrogenase (LDH) decreased significantly in rat heart tissues, the extent of inhibition being concentration dependent. In contrast, the level of LDH increased in serum. The levels of malondialdehyde, total thiols, and glutathione were significantly elevated whereas the activities of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione-S-transferase were remarkably decreased in rat heart tissues. The serum concentrations of cholesterol increased by 47 and 77% and high density lipids decreased by 35 and 64%, respectively, due to exposure to 5 and 10% LD50 of carbofuran. The prior treatment of rats with vitamin C (100 mg kg−1 body weight) exerted significant ameliorative effect. The recovery was higher at low carbofuran concentration (5%) tested. The results indicated that carbofuran induced oxidative stress and caused damage to cardiac tissues, which could be recovered by prior application of vitamin C.

Renal Toxicity of Mercuric Chloride at Different Time Intervals in Rats

This study was undertaken to study the renal toxicity of mercuric chloride in rats at different periods of time. The following groups of rats were studied: i) control, ii) placebo, iii) rats injected with a single ip dose of 100 mg/kg body weight of 2, 3 dimercapto-1-propanesulfonic acid, iv) rats injected with a single ip dose of 100 mg/kg body weight of 2, 3 dimercapto-1-propanesulfonic acid (DMPS) followed by a single dose ip of 2.0 mg HgCl2/kg body weight one hour after DMPS injection v) rats injected with a single ip dose of 2.0 mg HgCl2/kg body weight. Results indicate that mercuric chloride was more toxic after 48 hours of its administration when compared to 24 hours. Mercuric chloride administration caused an impairment of renal function which was evident from a significant decrease in urine volume, urinary excretion of urea, creatinine and glomerular filteration rate (P < 0.001) when compared to other treated groups. There was an increased excretion of protein, albumin and γ–-glutamyltransferase in the urine of mercuric chloride treated rats. Administration of 2, 3 dimercapto-1-propanesulfonic acid before mercuric chloride treatment caused the altered indices to return to near normal levels.