Cinnamic Acid: A Low-Toxicity Natural Bidentate Ligand for Uranium Decorporation.

Uranium accumulation in the kidneys and bones following internal contamination results in severe damage, emphasizing the pressing need for the discovery of actinide decorporation agents with efficient removal of uranium and low toxicity. In this work, cinnamic acid (3-phenyl-2-propenoic acid, CD), a natural aromatic carboxylic acid, is investigated as a potential uranium decorporation ligand. CD demonstrates markedly lower cytotoxicity than that of diethylenetriaminepentaacetic acid (DTPA), an actinide decorporation agent approved by the FDA, and effectively removes approximately 44.5% of uranyl from NRK-52E cells. More importantly, the results of the prompt administration of the CD solution remove 48.2 and 27.3% of uranyl from the kidneys and femurs of mice, respectively. Assessments of serum renal function reveal the potential of CD to ameliorate uranyl-induced renal injury. Furthermore, the single crystal of CD and uranyl compound (C9H7O2)2·UO2 (denoted as UO2-CD) reveals the formation of uranyl dimers as secondary building units. Thermodynamic analysis of the solution shows that CD coordinates with uranyl to form a 2:1 molar ratio complex at a physiological pH of 7.4. Density functional theory (DFT) calculations further show that CD exhibits a significant 7-fold heightened affinity for uranyl binding in comparison to DTPA.

A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans.

Candida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against C. albicans is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug's target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against a C. albicans clinical isolate and identified 17 molecules that inhibited C. albicans growth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicans Candida, including Candida auris and Candida glabrata, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mould Aspergillus fumigatus. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescued C. albicans growth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogen C. albicansIMPORTANCEThe worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogen Candida albicans is the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity against C. albicans. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species including Candida auris and Aspergillus fumigatus. Finally, we determined that these compounds inhibit the growth of C. albicans in culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens.

A critical review of a typical research system for food-derived metal-chelating peptides: Production, characterization, identification, digestion, and absorption.

In the past decade, food-derived metal-chelating peptides (MCPs) have attracted significant attention from researchers working towards the prevention of metal (viz., iron, zinc, and calcium) deficiency phenomenon by primarily inhibiting the precipitation of metals caused by the gastrointestinal environment and exogenous substances (including phytic and oxalic acids). However, for the improvement of limits of current knowledge foundations and future investigation directions of MCP or their derivatives, several review categories should be improved and emphasized. The species' uniqueness and differences in MCP productions highly contribute to the different values of chelating ability with particular metal ions, whereas comprehensive reviews of chelation characterization determined by various kinds of technique support different horizons for explaining the chelation and offer options for the selection of characterization methods. The reviews of chelation mechanism clearly demonstrate the involvement of potential groups and atoms in chelating metal ions. The discussions of digestive stability and absorption in various kinds of absorption model in vitro and in vivo as well as the theory of involved cellular absorption channels and pathways are systematically reviewed and highlighted compared with previous reports as well. Meanwhile, the chelation mechanism on the molecular docking level, the binding mechanism in amino acid identification level, the utilizations of everted rat gut sac model for absorption, and the involvement of cellular absorption channels and pathway are strongly recommended as novelty in this review. This review makes a novel contribution to the literature by the comprehensive prospects for the research and development of food-derived mineral supplements.

Exogenous chelating agents influence growth, physiological characteristics and cell ultrastructure of Robinia pseudoacacia seedlings under lead-cadmium stress.

Heavy metal pollution of soil, especially by lead (Pb) and cadmium (Cd), is a serious problem worldwide. The application of safe chelating agents, combined with the growing of tolerant trees, constitutes an approach for phytoremediation of heavy-metal-contaminated soil. This study aimed to determine whether the two safe chelators, tetrasodium glutamate diacetate (GLDA) and citric acid (CA), could improve the phytoremediation capacity of black locust (Robinia pseudoacacia L.) in a Pb-Cd-contaminated soil and to find the key factors affecting the biomass accumulation of stressed black locust. In Pb- and Cd-stressed black locust plants, medium- and high-concentration GLDA treatment inhibited the growth, chlorophyll synthesis and maximum photochemical efficiency (Fv/Fm), promoted the absorption of Pb and Cd ions and resulted in the shrinkage of chloroplasts and starch grains when compared with those in Pb- and Cd-stressed plants that were not treated with GLDA. The effects of CA on plant growth, ion absorption, chlorophyll content, chlorophyll fluorescence and organelle size were significantly weaker than those of GLDA. The effect of both agents on Cd absorption was greater than that on Pb absorption in all treatments. The levels of chlorophyll a and plant tissue Cd and rates of starch metabolism were identified as the key factors affecting plant biomass accumulation in GLDA and CA treatments. In the future, GLDA can be combined with functional bacteria and/or growth promoters to promote the growth of Pb- and Cd-stressed plants and to further improve the soil restoration efficiency following pollution by heavy metals. Application of CA combined with the growing of black locust plants has great potential for restoring the Cd-polluted soil. These findings also provide insights into the practical use of GLDA and CA in phytoremediation by R. pseudoacacia and the tolerant mechanisms of R. pseudoacacia to Pb-Cd-contaminated soil.

Perilla frutescens: A new strategy for uranium decorporation.

Radionuclide uranium is a great threat to human health, due to its high chemical toxicity and radioactivity. Finding suitable uranium decorporation to reduce damage caused by uranium internal contamination is an important aspect of nuclear emergency response. However, the poor selectivity and/or high toxicity of the only excretory promoter approved by Food and Drug Administration (FDA) is an obvious disadvantage. Herein, we choose an edible natural product, the traditional Chinese medicine called Perilla frutescens (PF), which has wide sources and can be used as an excellent and effective uranyl decorporation. In vivo uranium decorporation assays illustrate the removal efficiency of uranium in kidney were 68.87% and 43.26%, in femur were 56.66% and 54.53%, by the test of prophylactic and immediate administration, respectively. Cell level experiments confirmed that it had better biocompatibility than CaNa3-DTPA (CaNa3-diethylenetriamine pentaacetate, a commercial actinide excretion agent). In vitro static adsorption experiments exhibited that its excellent selectivity sorption for uranyl. All those results findings would provide new research insights about natural product for uranyl decorporation.

Chelation Modeling of a Plutonium-238 Inhalation Incident Treated with Delayed DTPA.

This work describes an analysis, using a previously established chelation model, of the bioassay data collected from a worker who received delayed chelation therapy following a plutonium-238 inhalation. The details of the case have already been described in two publications. The individual was treated with Ca-DTPA via multiple intravenous injections and then nebulizations beginning several months after the intake and continuing for four years. The exact date and circumstances of the intake are unknown. However, interviews with the worker suggested that the intake occurred via inhalation of a soluble plutonium compound. The worker provided daily urine and fecal bioassay samples throughout the chelation treatment protocol, including samples collected before, during, and after the administration of Ca-DTPA. Unlike the previous two publications presenting this case, the current analysis explicitly models the combined biokinetics of the plutonium-DTPA chelate. Using the previously established chelation model, it was possible to fit the data through optimizing only the intake (day and magnitude), solubility, and absorbed fraction of nebulized Ca-DTPA. This work supports the hypothesis that the efficacy of the delayed chelation treatment observed in this case results mainly from chelation of cell-internalized plutonium by Ca-DTPA (intracellular chelation). It also demonstrates the validity of the previously established chelation model. As the bioassay data were modified to ensure data anonymization, the calculation of the "true" committed effective dose was not possible. However, the treatment-induced dose inhibition (in percentage) was calculated.

Understanding Alzheimer's Disease and its Metal Chelation Therapeutics: A Narrative Review.

The neurodegenerative disorders are age-related illnesses that cause the morphology or activity of neurons to deteriorate over time. Alzheimer's disease is the most frequent neurodegenerative illness in the long run. The rate of advancement might vary, even though it is a progressive neurological illness. Various explanations have been proposed, however the true etiology of Alzheimer's disease remains unclear. Most pharmacological interventions are based on the cholinergic theory, that is earliest idea. In accordance with the amyloid hypothesis, the buildup of beta-amyloid in brain regions is the primitive cause of illness. There is no proof that any one strategy is useful in avoiding Alzheimer's disease, though some epidemiological studies have suggested links within various modifiable variables, such as cardiovascular risk, diet and so on. Different metals like zinc, iron, and copper are naturally present in our bodies. In metal chelation therapy drugs are used to jam the metal ions from combining with other molecules in the body. Clioquinol is one of the metal chelation drugs used by researchers. Research on metal chelation is still ongoing. In the present review, we go over the latest developments in prevalence, incidence, etiology, or pathophysiology of our understanding of Alzheimer's disease. Additionally, a brief discussion on the development of therapeutic chelating agents and their viability as Alzheimer's disease medication candidates is presented. We also assess the effect of clioquinol as a potential metal chelator.

Chelation therapy with 3,4,3-Li(1,2-HOPO) after pulmonary exposure to plutonium in rats.

Internal exposure to plutonium can occur through inhalation for the nuclear worker, but also for the public if the radionuclide was released into the atmosphere in the context of a nuclear accident or terrorist attack. DieThylenetriaminePentaAcetic acid (DTPA) is currently still the only authorized chelator that can be used to decorporate internalized plutonium. The Linear HydrOxyPyridinOne-based ligand named 3,4,3-Li(1,2-HOPO) remains the most promising drug candidate to replace it in the hopes of improving chelating treatment. This study aimed to assess the efficacy of 3,4,3-Li(1,2-HOPO) in removing plutonium from rats exposed to the lungs, depending on the timing and route of treatment, and almost always compared to DTPA at a ten-fold higher dose used as a reference chelator. First, early intravenous injection or inhalation of 3,4,3-Li(1,2-HOPO) demonstrated superior efficacy over DTPA in preventing plutonium accumulation in liver and bone in rats exposed by injection or lung intubation. However, this superiority of 3,4,3-Li(1,2-HOPO) was much less pronounced with delayed treatment. In rats given plutonium in the lungs, the experiments also showed that 3,4,3-Li-HOPO reduced pulmonary retention of plutonium more effectively than DTPA only when the chelators were injected early but not at delayed times, while it was always the better of the two chelators when they were inhaled. Under our experimental conditions, the rapid oral administration of 3,4,3-Li(1,2-HOPO) was successful in preventing systemic accumulation of plutonium, but not in decreasing lung retention. Thus, after exposure to plutonium by inhalation, the best emergency treatment would be the rapid inhalation of a 3,4,3-Li(1,2-HOPO) aerosol to limit pulmonary retention of plutonium and prevent extrapulmonary deposition of plutonium in target systemic tissues.

A conserved zinc-binding site in Acinetobacter baumannii PBP2 required for elongasome-directed bacterial cell shape.

Acinetobacter baumannii is a gram-negative bacterial pathogen that causes challenging nosocomial infections. ß-lactam targeting of penicillin-binding protein (PBP)-mediated cell wall peptidoglycan (PG) formation is a well-established antimicrobial strategy. Exposure to carbapenems or zinc (Zn)-deprived growth conditions leads to a rod-to-sphere morphological transition in A. baumannii, an effect resembling that caused by deficiency in the RodA-PBP2 PG synthesis complex required for cell wall elongation. While it is recognized that carbapenems preferentially acylate PBP2 in A. baumannii and therefore block the transpeptidase function of the RodA-PBP2 system, the molecular details underpinning cell wall elongation inhibition upon Zn starvation remain undefined. Here, we report the X-ray crystal structure of A. baumannii PBP2, revealing an unexpected Zn coordination site in the transpeptidase domain required for protein stability. Mutations in the Zn-binding site of PBP2 cause a loss of bacterial rod shape and increase susceptibility to ß-lactams, therefore providing a direct rationale for cell wall shape maintenance and Zn homeostasis in A. baumannii. Furthermore, the Zn-coordinating residues are conserved in various ß- and γ-proteobacterial PBP2 orthologs, consistent with a widespread Zn-binding requirement for function that has been previously unknown. Due to the emergence of resistance to virtually all marketed antibiotic classes, alternative or complementary antimicrobial strategies need to be explored. These findings offer a perspective for dual inhibition of Zn-dependent PG synthases and metallo-ß-lactamases by metal chelating agents, considered the most sought-after adjuvants to restore ß-lactam potency against gram-negative bacteria.

A novel calcium-binding peptide from bovine bone collagen hydrolysate and chelation mechanism and calcium absorption activity of peptide-calcium chelate.

A novel calcium-binding peptide from bovine bone collagen hydrolysate was screened based on a new target-the calcium-sensing receptor (CaSR), and its chelation mechanism and calcium absorption activity were investigated. Glu-Tyr-Gly exhibited superior binding affinities to CaSR because of its interaction with the active sites of the CaSR Venus Flytrap (VFT) domain. Glu-Tyr-Gly-Ca may exist in five potential chelation modes and its potential chelation mechanism was that calcium ions were located in the center and surrounded by ionic bonds (carboxyl group) and coordination bonds (carbonyl, amino, and carboxyl group). Glu-Tyr-Gly-Ca was slightly damaged in the intestinal fluid and at different temperatures, whereas it was severely damaged in the gastric fluid and acidic conditions. The results of the calcium dialysis percentage and Caco-2 cells experiments showed that Glu-Tyr-Gly-Ca possessed good calcium transport activity and bioavailability. The findings provided theoretical basis for Glu-Tyr-Gly-Ca as potential calcium supplement to improve intestinal calcium absorption.

Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid ß (Aß) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer's disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM), via intraperitoneal (IP) administration for 6 months to determine if it could lower copper content in vascular amyloid deposits and modify CAA pathology. Results showed that TTM treatment led to elevated Aß load in the hippocampus of the rTg-DI rats and increased microbleeds in the wild type (WT) animals. X-ray fluorescence microscopy was performed to image the distribution of copper and revealed a surprising increase in copper colocalized with Aß aggregates in TTM-treated rTg-DI rats. Unexpectedly, we also found an increase in the copper content in unaffected vessels of both rTg-DI and WT animals. These results show that IP administration of TTM was ineffective in removing copper from vascular Aß aggregates in vivo and increased the development of disease pathology in CAA.

Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimer's Disease.

Essential trace metals like zinc (Zn), iron (Fe), and copper (Cu) play an important physiological role in the metabolomics and healthy functioning of body organs, including the brain. However, abnormal accumulation of trace metals in the brain and dyshomeostasis in the different regions of the brain have emerged as contributing factors in neuronal degeneration, Aß aggregation, and Tau formation. The link between these essential trace metal ions and the risk of AD has been widely studied, although the conclusions have been ambiguous. Despite the absence of evidence for any clinical benefit, therapeutic chelation is still hypothesized to be a therapeutic option for AD. Furthermore, the parameters like bioavailability, ability to cross the BBB, and chelation specificity must be taken into consideration while selecting a suitable chelation therapy. The data in this review summarizes that the primary intervention in AD is brain metal homeostasis along with brain metal scavenging. This review evaluates the impact of different trace metals (Cu, Zn, Fe) on normal brain functioning and their association with neurodegeneration in AD. Also, it investigates the therapeutic potential of metal chelators in the management of AD. An extensive literature search was carried out on the "Web of Science, PubMed, Science Direct, and Google Scholar" to investigate the effect of trace elements in neurological impairment and the role of metal chelators in AD. In addition, the current review highlights the advantages and limitations of chelation therapies and the difficulties involved in developing selective metal chelation therapy in AD patients.

Quantum-mechanical characteristics of apigenin: Antiradical, metal chelation and inhibitory properties in physiologically relevant media.

Density functional theory was used to examine the antioxidant activity of apigenin. All protonated species that are present in a non-negligible population at physiological pH were considered in the study. The ability to scavenge the hydroperoxide radical was evaluated in lipid and aqueous environments. The capacity to halt the Fenton reaction by chelating Fe(III) and Cu(II) ions was also investigated, as was the ability to inhibit xanthine oxidase. The results indicate that these activities may be particularly important in describing the beneficial effects of apigenin, especially because of its lower anti-•OOH potential than Trolox or vitamin C. The findings underscore the significant role of dianion in the antiradical and chelating properties, despite its presence in much lower molar fractions than other ions.

Metal ion chelation of poly(aspartic acid): From scale inhibition to therapeutic potentials.

Poly(aspartic acid) (PASP) is a biodegradable, biocompatible water-soluble synthetic anionic polypeptide. PASP has shown a strong affinity and thus robust complexation with heavy and alkaline earth metal ions, from which several applications are currently benefiting, and several more could also originate. This paper discusses different areas where the ion chelation ability of PASP has thus far been exploited. Due to its calcium chelation ability, PASP prevents precipitation of calcium salts and hence is widely used as an effective scale inhibitor in industry. Due to potassium chelation, PASP prevents precipitation of potassium tartrate and is employed as an efficient and edible stabilizer for wine preservation. Due to iron chelation, PASP inhibits corrosion of steel surfaces in harsh environments. Due to chelation, PASP can also enhance stability of various colloidal systems that contain metal ions. The chelation ability of PASP alleviated the toxicity of heavy metals in Zebrafish, inhibited the formation of kidney stones and dissolved calcium phosphate which is the main mineral of the calcified vasculature. These findings and beyond, along with the biocompatibility and biodegradability of the polymer could direct future investigations towards chelation therapy by PASP and other novel and undiscovered areas where metal ions play a key role.

Comparison of synthetic and organic biodegradable chelants in augmenting cadmium phytoextraction in Solanum nigrum.

This study focused to enhance the cadmium (Cd) phytoextraction efficiency in Solanum nigrum by applying four biodegradable chelants (10 mM)-ethylene glycol tetraacetic acid (EGTA), ethylenediamine disuccinate (EDDS), nitrilotriacetic acid (NTA), and citric acid (CA), when grown in Cd-spiked soil (12 and 48 mg kg-1). Plant height, dry biomass, photosynthetic traits, and metal accumulation varied significantly with Cd and chelant treatments. Cadmium-toxicity resulted in reduction of plant growth and photosynthetic physiology, whereas chelant supplementation alleviated the toxic effect of Cd and increased its accumulation. Tolerance index value increased with addition of chelants in the order: EGTA (1.57-1.63) >EDDS (1.39-1.58) >NTA (1.14-1.50) >CA (1-1.22) compared with Cd (0.46-1.08). Transfer coefficient of root increased with supplementation of EGTA (3.40-3.85), EDDS (3.10-3.40), NTA (2.60-2.90), and CA (1.85-2.29), over Cd-alone (1.61-1.63). Similarly, translocation factor was also increased upon addition of EGTA (0.52-0.73), EDDS (0.35-0.81), NTA (0.38-0.75), and CA (0.53-0.54), compared with Cd-alone (0.36-0.59). Maximum Cd removal (67.67% at Cd12 and 36.05% at Cd48) was observed with supplementation of EGTA. The study concludes that the supplementation of EGTA and EDDS with S. nigrum can be employed as an efficient and environmentally safe technique for reclamation of Cd-contaminated soils.

Apart from the selection of a good hyperaccumulator, the choice of chelant (biodegradable/non-biodegradable) is an important aspect for the successful phytoextraction of metals from contaminated soil. We reported for the first time the potential of ethylene glycol tetraacetic acid (EGTA; a biodegradable chelant) in enhancing Cd phytoextraction by Solanum nigrum. Comparative appraisal of metal extraction efficiency of biodegradable chelants at low (12 mg kg⁻¹) and high (48 mg kg⁻¹) Cd dose depicted that EGTA performed better than EDDS, NTA, and CA (other biodegradable chelants). EGTA supplementation did not induce toxicity in plants; rather it improved metal accumulation, morphology, and photosynthetic physiology.

Effect of Copper Chelators via the TGF-ß Signaling Pathway on Glioblastoma Cell Invasion.

Glioblastoma multiforme (GBM) is a fast-growing and aggressive type of brain cancer. Unlike normal brain cells, GBM cells exhibit epithelial-mesenchymal transition (EMT), which is a crucial biological process in embryonic development and cell metastasis, and are highly invasive. Copper reportedly plays a critical role in the progression of a variety of cancers, including brain, breast, and lung cancers. However, excessive copper is toxic to cells. D-penicillamine (DPA) and triethylenetetramine (TETA) are well-known copper chelators and are the mainstay of treatment for copper-associated diseases. Following treatment with copper sulfate and DPA, GBM cells showed inhibition of proliferation and suppression of EMT properties, including reduced expression levels of N-cadherin, E-cadherin, and Zeb, which are cell markers associated with EMT. In contrast, treatment with copper sulfate and TETA yielded the opposite effects in GBM. Genes, including TGF-ß, are associated with an increase in copper levels, implying their role in EMT. To analyze the invasion and spread of GBM, we used zebrafish embryos xenografted with the GBM cell line U87. The invasion of GBM cells into zebrafish embryos was markedly inhibited by copper treatment with DPA. Our findings suggest that treatment with copper and DPA inhibits proliferation and EMT through a mechanism involving TGF-ß/Smad signaling in GBM. Therefore, DPA, but not TETA, could be used as adjuvant therapy for GBM with high copper concentrations.

Chelation Combination-A Strategy to Mitigate the Neurotoxicity of Manganese, Iron, and Copper?

The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to the central nervous system (CNS). Strategies for mobilization of metals such as manganese (Mn), iron (Fe), and Cu from brain deposits may require the combined use of two agents: one water-soluble agent to remove circulating metal into urine, in addition to an adjuvant shuttler to facilitate the brain-to-blood mobilization. The present review discusses the chemical basis of metal chelation and the ligand exchange of metal ions. To obtain increased excretion of Mn, Cu, and Fe, early experiences showed promising results for CaEDTA, PSH, and DFOA, respectively. Recent experiments have indicated that p-amino salicylate (PAS) plus CaEDTA may be a useful combination to remove Mn from binding sites in CNS, while the deferasirox-DFOA and the tetrathiomolybdate-DMSA combinations may be preferable to promote mobilization of Fe and Cu, respectively, from the CNS. Further research is requested to explore benefits of chelator combinations.

Adansonia digitata L. fruit shell extract alleviates lead-induced neurotoxicity in mice via modulation of oxidative stress and a possible chelating activity.

BACKGROUND: Lead is a ubiquitous environmental heavy metal known to induce neurotoxicity. It has been postulated that substance with high antioxidant capacity could alleviate lead-induced neurotoxicity. Adansonia digitata fruit shell extract (ADFS) has been reported to have high phenolic contents and exerts antioxidant activity. This study investigated the effects of Adansonia digitata fruit shell extract on lead-induced neurotoxicity in mice. METHODS: Male balb/c mice (n = 7) were administered with Pb-acetate (50 mg/kg) 30 mins before ADFS (250 mg/kg and 500 mg/kg) or succimer (50 mg/kg) per orally for 28 days. Motor activities were evaluated on days 29 and 30 through horizontal bar and open field tests respectively. Further, spectrophotometry, atomic absorption spectrophotometry and haematoxylin and eosin staining were carried-out to determine the expression of oxidative stress biomarkers, level of lead concentration in the brain and histology of the cerebellum respectively. RESULTS: Lead acetate exposure significantly (p < 0.05) induced motor deficits in horizontal bar test and open field test, caused oxidative stress, high concentration of lead in the brain as well as histological aberration in the cerebellum. ADFS significantly (p < 0.05) reversed the motor deficits evident by increased muscle strength and number of lines crossed. Further, ADFS significantly reversed oxidative stress evident by increased levels of SOD, CAT and GSH and decreased level of MDA. There was also significant (p < 0.05) decrease in brain lead concentration as well as reduced cerebellar cells death. CONCLUSION: Findings suggest that ADFS attenuated motor deficits via inhibition of oxidative stress and chelating activity which is comparable to succimer. Hence, ADFS should be explored for possible development of chelating agent against lead and other heavy metals toxicity.

Actinide Decorporation: A Review on Chelation Chemistry and Nanocarriers for Pulmonary Administration.

Chelation is considered the best method for detoxification by promoting excretion of actinides (Am, Np, Pu, Th, U) from the human body after internal contamination. Chemical agents that possess carboxylic acid or hydroxypyridinonate groups play a vital role in actinide decorporation. In this review article, we provide considerable background details on the chelation chemistry of actinides with an aim to formulate better decorporation agents. Nanocarriers for pulmonary delivery represent an exciting prospect in the development of novel therapies for actinide decorporation that both reduce toxic side effects of the agent and improve its retention in the body. Recent studies have demonstrated the benefits of using a nebulizer or an inhaler to administer chelating agents for the decorporation of actinides. Effective chelation therapy with large groups of internally contaminated people can be a challenge unless both the agent and the nanocarrier are readily available from strategic national stockpiles for radiological or nuclear emergencies. Sunflower lecithin is particularly adept at alleviating the burden of administration when used to form liposomes as a nanocarrier for pulmonary delivery of diethylenetriamine-pentaacetic acid (DTPA) or hydroxypyridinone (HOPO). Better physiologically-based pharmacokinetic models must be developed for each agent in order to minimize the frequency of multiple doses that can overload the emergency response operations.

Chemistry, Pharmacology, and Toxicology of Monoisoamyl Dimercaptosuccinic Acid: A Chelating Agent for Chronic Metal Poisoning.

Arsenic, a metalloid, is known to cause deleterious effects in various body organs, particularly the liver, urinary bladder, and brain, and these effects are primarily mediated through oxidative stress. Chelation therapy has been considered one of the promising medical treatments for arsenic poisoning. Meso 2,3- dimercaptosuccinic acid (DMSA) has been recognized as one of the most effective chelating drugs to treat arsenic poisoning. However, the drug is compromised with a number of shortcomings, including the inability to treat chronic arsenic poisoning due to its extracellular distribution. Monoisoamyl 2,3-dimercaptosuccinic acid, one of the analogues of meso 2,3-dimeraptosuccinic acid (DMSA), is a lipophilic chelator and has shown promise to be considered as a potential future chelating agent/antidote not only for arsenic but also for a few other heavy metals like lead, mercury, cadmium, and gallium arsenide. The results from numerous studies carried out in the recent past, mainly from our group, strongly support the clinical application of MiADMSA. This review paper summarizes most of the scientific details including the chemistry, pharmacology, and safety profile of MiADMSA. The efficacy of MiADMSA mainly against arsenic toxicity but also a few other heavy metals was also discussed. We also reviewed a few other strategies in order to achieve the optimum effects of MiADMSA, like combination therapy using two chelating agents or coadministration of a natural and synthetic antioxidant (including phytomedicine) along with MiADMSA for treatment of metal/metalloid poisoning. We also briefly discussed the use of nanotechnology (nano form of MiADMSA i.e. nano-MiADMSA) and compared it with bulk MiADMSA. All these strategies have been shown to be beneficial in getting more pronounced therapeutic efficacy of MiADMSA, as an adjuvant or as a complementary agent, by significantly increasing the chelating efficacy of MiADMSA.