Kiran Kalia

Strategies for Safe and Effective Therapeutic Measures for Chronic Arsenic and Lead Poisoning

Strategies for Safe and Effective Therapeutic Measures for Arsenic and Lead Poisoning: Kiran Kalia, et al. Department of Biosciences, Sardar Patel University, India— Exposure to toxic metals remains a widespread occupational and environmental problem in world. There have been a number of reports in the recent past suggesting an incidence of childhood lead poisoning and chronic arsenic poisoning due to contaminated drinking water in many areas of West Bengal in India and Bangladesh has become a national calamity. Low level metal exposure in humans is caused by air, food and water intake. Lead and arsenic generally interferes with a number of body functions such as the central nervous system (CNS), the haematopoietic system, liver and kidneys. Over the past few decades there has been growing awareness and concern that the toxic biochemical and functional effects are occurring at a lower level of metal exposure than those that produce overt clinical and pathological signs and symptoms. Despite many years of research, we are still far from an effective treatment of chronic plumbism and arsenicosis. Medical treatment of acute and chronic lead and arsenic toxicity is furnished by chelating agents. Chelating agents are organic compounds capable of linking together metal ions to form complex ring‐like structures called chelates. They have been used clinically as antidotes for acute and chronic poisoning. 2, 3‐dimercaprol (BAL) has long been the mainstay of chelation therapy for lead or arsenic poisoning. Meso 2, 3, ‐dimercaptosuccinic acid (DMSA) has been tried successfully in animals as well as in a few cases of human lead and arsenic poisoning. DMSA could be a safe and effective method for treating lead or arsenic poisoning, but one of the major disadvantages of chelation with DMSA has been its inability to remove lead from the intracellular sites because of its lipophobic nature. Further, it does not provide protection in terms of clinical/ biochemical recovery. A new trend in chelation therapy is to use combined treatment. This includes the use of structurally different chelators or a combination of an adjuvant and a chelator to provide better clinical/ biochemical recovery in addition to lead mobilization. The present review article attempts to provide update information about the current strategies being adopted for a safe, effective and specific treatment for two major toxic metals or metalloid.

Arsenate detoxification in a Pseudomonad hypertolerant to arsenic

Pseudomonas sp. strain As-1, obtained from an electroplating industrial effluent, was capable of growing aerobically in growth medium supplemented with up to 65xa0mM arsenate (As (V)), significantly higher concentrations than those tolerated by other reference arsenic resistant bacteria. The majority of the arsenic was detected in culture supernatants as arsenite (As (III)) and X-ray absorbance spectroscopy suggested that 30% of this cell-bound arsenic was As (V), 65% As (III) and 5% of arsenic was associated with sulphur. PCR analysis using primers designed against arsenic resistance genes of other Gram-negative bacteria confirmed the presence of an arsenic resistance operon comprising of three genes, arsR, arsB and arsC in order of predicted transcription, and consistent with a role in intracellular reduction of As (V) and efflux of As (III). In addition to this classical arsenic resistance mechanism, other biochemical responses to arsenic were implicated. Novel arsenic-binding proteins were purified from cellular fractions, while proteomic analysis of arsenic-induced cultures identified the upregulation of additional proteins not normally associated with the metabolism of arsenic. Cross-talk with a network of proteins involved in phosphate metabolism was suggested by these studies, consistent with the similarity between the phosphate and arsenate anions.

Manganese Accumulates Primarily in Nuclei of Cultured Brain Cells

Manganese (Mn) is known to pass across the blood-brain barrier and interact with dopaminergic neurons. However, the knowledge on the subcellular distribution of Mn in these cell types upon exposure to Mn remained incomplete. This study was designed to investigate the subcellular distribution of Mn in blood-brain barrier endothelial RBE4 cells, blood-cerebrospinal fluid barrier choroidal epithelial Z310 cells, mesencephalic dopaminergic neuronal N27 cells, and pheochromocytoma dopaminergic PC12 cells. The cells were incubated with 100 microM MnCl(2) with radioactive tracer (54)Mn in the culture media for 24h. The subcellular organelles, i.e., nuclei, mitochondria, microsomes, and cytoplasm, were isolated by centrifugation and verified for their authenticity by determining the markers specific to cellular organelles. Data indicated that maximum Mn accumulation was observed in PC12 cells, which was 2.8, 5.2- and 5.9-fold higher than that in N27, Z310 and RBE4 cells, respectively. Within cells, about 92%, 72%, and 52% of intracellular (54)Mn were found to be present in nuclei of RBE4, Z310, and N27 cells, respectively. The recovery of (54)Mn in nuclei and cytoplasm of PC12 cells were 27% and 69%, respectively. Surprisingly, less than 0.5% and 2.5% of cellular (54)Mn was found in mitochondrial and microsomal fractions, respectively. This study suggests that the nuclei may serve as the primary pool for intracellular Mn; mitochondria and microsomes may play an insignificant role in Mn subcellular distribution.

Arsenic antagonism studies with monoisoamyl DMSA and zinc in male mice

Administration of zinc either alone or in combination with monoisoamyl dimercaptosuccinic acid (DMSA) during and post-arsenic exposure was investigated in male mice. The animals were administered 2mgkg(-1) arsenic as sodium arsenite, intraperitoneally, once daily for 5 days either alone or in combination with 10mgkg(-1), zinc (as zinc acetate, orally), 50mgkg(-1) monoisoamyl dimercaptosuccinic acid (MiADMSA) given orally (p.o.), 2h after arsenic administration. Another group of arsenic treated animals was given both zinc (10mgkg(-1)) and MiADMSA (50mgkg(-1), p.o.). Animals were sacrificed 24h after the last dose. In another set of experimentation, arsenic pre-exposed mice (2mgkg(-1), i.p. for 5 days) were treated with saline, zinc, MiADMSA or zinc plus MiADMSA for next 3 days and sacrificed thereafter. Exposure to arsenic led to a significant inhibition of blood δ-aminolevulinic acid dehydratase (ALAD), depletion of glutathione (GSH) level and marginal elevations of zinc protoporphyrin (ZPP). Arsenic exposure caused a significant decrease in hepatic and renal GSH level and an increase in liver oxidized glutathione (GSSG) and liver and kidney thiobarbituric acid reactive substance (TBARS) levels. Concomitant administration of zinc with arsenic provided significant protection to blood ALAD activity while, GSH and ZPP levels remained unaltered. Co-administration of MiADMSA with arsenic significantly prevented accumulation of arsenic in blood, liver and kidney while, zinc had no effect on tissue arsenic concentration. Combined administration of zinc and MiADMSA had no major additional beneficial effects over their individual effects. Interestingly, post-arsenic exposure treatment with MiADMSA provided significant recovery in blood ALAD activity while, zinc supplementation alone had no effect. The best results however, were obtained when MiADMSA was administered along-with zinc. Most of the biochemical variables indicative of hepatic oxidative stress responded favorably to MiADMSA treatment while, zinc administration had no effect. Administration of MiADMSA significantly depleted arsenic concentration from the soft tissues while, combined zinc and MiADMSA had no additional beneficial effect over the individual effect of MiADMSA. The results thus lead us to conclude that in order to achieve best effects of chelation therapy, co-administration of zinc with chelator might be preferred. However, detailed experimental studies with variable doses and after chronic arsenic exposure are required.

Diabetic nephropathy and associated risk factors for renal deterioration

Predominantly diabetic nephropathy starts with glomerulosclerosis, when plasma molecules cross the dismantled glomerular basement membrane (GBM) and subsequently appear in urine. Therefore proteinuria is a sensitive criterion to diagnose progressive renal impairment and the presence of immunoglobulin like large molecules is potentially able to predict severity of nephropathy. Directly, or indirectly hyperglycemia induces proteinuria and high urinary excretion of IgG appears with progression of glomerular injury. This is an observational study of 683 patients with type 2 diabetes mellitus. Patients with varying degree of proteinuria were enrolled and classified into three groups according to the urinary albumin creatinine ratio (UACR, <29, 30–299, >300xa0mg/g creatinine.) and each group was further sub-classified into the low and high urinary IgG creatinine ratio (UIgGCR) based on the median value. Biochemical parameters were analyzed by standard laboratory methods. The association of proteinuria and odds ratio for risk factors of diabetic nephropathy was estimated using multinomial logistic regression models. The normoalbuminuric and microalbuminuric patients with high UIgGCR had shown lower eGFR (pu2009<u20090.05). There was no interaction observed between higher UIgGCR and lower eGFR in regression model analysis. Multinomial logistic regression model estimated the odds ratio for the AGEs, AOPP, lipid hydroperoxides and lipid peroxidation products were increased; 5.64 (95% CI 3.52–9.04), 1.03 (95% CI 1.02–1.04), 2.71 (95% CI 2.05–3.57) and 13.72 (95% CI 6.98–26.95) respectively with high UIgGCR in diabetic patients. High UIgGCR has shown a significant association with decreased eGFR and increased odds for potential hazardous factors. The current study has shown UIgGCR as an increased relative risk, and threat for rapid progression of diabetic nephropathy, possibly because GBM is the primary vulnerable site for deterioration by several hazardous metabolites. In conclusion, association between fractional clearance of IgG and relative risk of GBM threatening factors should be useful for prediction of progressive nature of diabetic nephropathy.

Detoxification of Arsenic

Publisher Summary Arsenic, which is ubiquitous in the environment, has become a worldwide public health problem. It has become evident that increasing use of arsenic-containing insecticides, herbicides, fungicides, pesticides, and wood preservatives, and through the mining and burning of coal has modified the global cycle of arsenic. Arsenic enters to biosphere primarily by leaching from geological formations. Its ubiquity in the environment has led to the evolution of arsenic defense mechanisms in every organism studied, from Escherichia coli to humans. Arsenic ranks 20th in natural abundance, consisting about 0.00005% of the earths crust, 14th in seawater, and 12th in the human body. The relative ubiquity of arsenic operon and the processes involved in arsenic detoxification and resistance, indicate that there have been important selective factors in microbial evolution. These taxonomically diverse and metabolically versatile microorganisms have evolved a number of mechanisms to gain energy for their growth from this toxic element in their environment, and developed detoxification mechanisms including oxidation, reduction, and methylation for increased tolerance and resistance to high levels of arsenic in their environment. Through a variety of detoxification and respiratory mechanisms, microorganisms have the ability to greatly influence the speciation of arsenic within the environment, and thus play a significant role in the arsenic cycle and impact of arsenic toxicity.

Grafting of Vinyl Monomers onto Sodium Salt of Partially Carboxymethylated Guar Gum: Comparison of Their Reactivity

Abstract: The optimum reaction conditions for affording maximum percentage of grafting have been established in the case of grafting of acrylonitrile (AN), methyl acrylate (MA), methyl methacrylate (MMA), and ethyl methacrylate (EMA) onto sodium salt of partially carboxymethylated guar gum (Na-PCMGG, ) using ceric ammonium nitrate (CAN) as a redox initiator in an aqueous medium by using different reaction parameters. Under the optimized reaction conditions, the following reactivity order of monomers was observed: AN > MA > MMA > EMA. The plausible explanation for this observed order of reactivity has been furnished. The thermal behavior of different graft copolymers of Na-PCMGG ( ) has been studied at four different heating rates by thermogravimetric analysis (TGA) and the results obtained have been analyzed by employing Osawa as well as Freeman-Carroll (multiple heating rate) methods for the evaluation of activation energy (E). The values of E calculated at various constant conversions as well as the average activation energy values (for both the steps of thermal degradation) calculated according to Osawa as well as Freeman-Carroll methods, for all the four different graft copolymers of Na-PCMGG ( ), have been found to be in good agreement with each other. The evidence of grafting has been ascertained by spectral (IR/1H-NMR) and scanning electron microscopic (SEM) methods.

Association Between Urinary IgG and Relative Risk for Factors Affecting Proteinuria in Type 2 Diabetic Patients

Abnormal glomerular permeability is the primary step towards the glomerulosclerosis. The progression rate of glomerulosclerosis is proportionate to abundance and severity of lesions created at incipient stage, which is reflected as proteinuria even though eGFR remains in the normal range. Therefore, there is a current need to find out the association between relative risks for the factors leading to proteinuria. The relations could be more informative, if it is with respect to the macromolecules like “IgG” excretion in urine. Type 2 diabetic patients were selected for this study with eGFRxa0>xa075xa0ml/min/1.73xa0m2 and grouped into four quartiles based on UIgGCR. The markers of key factors affecting progression of proteinuria were estimated through biochemical tests. The impact of these markers on proteinuria was accessed by applying multinomial logistic regression. The adjusted odds ratio for the UGAGCR was 1.186 (95xa0% CI: 1.061–1.327) Pxa0<xa00.003 in highest quartiles of UIgGCR, followed by odds ratio for markers of collagen catabolism 1.051 (95xa0% CI: 1.025–1.079) Pxa0<xa00.001, and USACR 1.044 (95xa0% CI: 1.013–1.077) Pxa0<xa00.006 respectively. The marker of glycation, i.e., glycated hemoglobin showed the highest odds ratio 5.449 (95xa0% CI: 1.132–26.236) Pxa0<xa00.035. In addition, odds for the systolic blood pressure was observed 1.387 (95xa0% CI: 1.124–1.712) Pxa0<xa00.002. The higher odds inform and could help to discriminate the diabetic patients with fast progressive diabetic nephropathy. The study describes critical relationship between the urinary excretion of IgG and factors leading to proteinuria in type 2 diabetic patients.

Age dependent distribution and retention of 109cadmium in the selected organs of rat

A single intraperitoneal injection of 10 μCi/kg of carrier free 109CdCl2 was administered to 1-day, 21-day and 180-day old rats to study the distribution of Cd in selected organs at 4 hrs and 14 days post injection. 109Cd uptake was detected in all the body tissues. The chief site of storage was the liver, where approximately 50% of the injected dose accumulated in all the age groups of animals. The percent of the 109Cd dose accumulated in most of the organs at 4 hrs either increased or did not change significantly by 14 days. The results also demonstrated a faster uptake of 109Cd by the liver, muscle and pancreas compared to a slower accumulation by other organs. Furthermore, the radio-labelled metal level in various organs particularly in brain, lungs and heart was significantly greater in the younger animals. This suggests that young animals may be more susceptible to the neurotoxic, pulmotoxic and cardiotoxic effects of Cd than older animals. An inefficient excretory system and underdeveloped blood-organ barrier may be responsible for the higher tissue levels of 109Cd observed in the growing animals.

Modification of sodium salt of partially carboxymethylated guar gum by graft copolymerization with methyl acrylate

Grafting of methyl acrylate onto sodium salt of partially carboxymethylated guar gum (backbone) was carried out using ceric ammonium nitrate as a redox initiator in an aqueous medium. The reaction variables including concentrations of initiator, nitric acid, monomer and amount of the backbone as well as time and temperature were varied for establishing the optimized reaction conditions for grafting. The influence of these reaction parameters on the grafting yields and the rates of polymerization, graft copolymerization and homopolymerization was also studied and the results were discussed. The kinetic scheme of free radical graft copolymerization was proposed and the experimental results were found to agree very well with the proposed kinetic scheme. The graft copolymer sample was characterized by IR-spectroscopic, thermal and scanning electron microscopic techniques.