Heavy Metal Toxicity in Chronic Renal Failure and Cardiovascular Disease: Possible Role for Chelation Therapy.

Exposure to heavy metals is common. This exposure is related to environmental contamination of air, water and soil, occupational exposure, accumulation in food, tobacco, and other factors. Cadmium and lead are notable for their widespread contamination, long-lasting effects in the body, and renal as well as cardiovascular toxicity. Acute toxicity due to high-level exposure, as well as chronic low-level exposure are now well-established pathogenic entities. Both chronic renal failure and ischemic heart disease patients have been treated separately in recent studies with ethylenediaminetetraacetic acid (EDTA) chelation therapy. In patients with chronic kidney disease (serum creatinine: 1.5-4.0 mg/dL) and increased body lead burden, weekly low-dose chelation with calcium EDTA slowed the rate of decline in renal function in patients with diabetes and in non-diabetic patients. In patients with a history of myocardial infarction, the Trial to Assess Chelation Therapy study showed that EDTA chelation decreased the likelihood of cardiovascular events, particularly in patients with diabetes. However, heavy metal levels were not measured in this study. It is clear that more research is needed in this area. There is also a need to more frequently consider and test for the possibility of cadmium and lead toxicity in patients with increased risk, such as those with hypertension, diabetes mellitus, and chronic renal disease.

Extracellular vesicles from human bone marrow mesenchymal stem cells repair organ damage caused by cadmium poisoning in a medaka model.

Treatment modalities for kidney disease caused by long-term exposure to heavy metals, such as cadmium (Cd), are limited. Often, chronic, long-term environmental exposure to heavy metal is not recognized in the early stages; therefore, chelation therapy is not an effective option. Extracellular vesicles (EVs) derived from stem cells have been demonstrated to reduce disease pathology in both acute and chronic kidney disease models. To test the ability of EVs derived from human bone marrow mesenchymal stem cells (hBM-MSCs) to treat Cd damage, we generated a Cd-exposed medaka model. This model develops heavy metal-induced cell damage in various organs and tissues, and shows decreased overall survival. Intravenous injection of highly purified EVs from hBM-MSCs repaired the damage to apical and basolateral membranes and mitochondria of kidney proximal tubules, glomerular podocytes, bone deformation, and improved survival. Our system also serves as a model with which to study age- and sex-dependent cell injuries of organs caused by various agents and diseases. The beneficial effects of EVs on the tissue repair process, as shown in our novel Cd-exposed medaka model, may open new broad avenues for interventional strategies.

[Recent research progress on natural medicines in treatment of cadmium toxicity].

Cadmium contamination of environment is a subject of serious international concern. Bioaccumulation of cadmium occurs primarily through ingestion of contaminated water and food. Cadmium poisoning came into prominence with the "itai-itai" disease event in Japan in the 1950s. It could also cause damages to liver, kidney, lung and other organs. Thus, the treatment of cadmium poisoning has become a research hotspot. Researchers are trying their best to explore prophylactic and therapeutic medicines for prevention and treatment of cadmium-induced poisoning. So far, chelation therapy, the conventional treatment for heavy metal toxicity, is reported to have a number of safety and efficacy issues. Natural medicines have a variety of advantages such as extensive sources, high safety, less adverse reactions, and thus have great potentials in treating cadmium poisoning. In this review, the progress in the antagonistic effects of natural drugs in cadmium poisoning and their therapeutic mechanisms were summarized in order to provide certain references for the future development and in-depth study of antagonistic substances.

Cadmium toxicity and treatment.

Cadmium is a heavy metal of considerable toxicity with destructive impact on most organ systems. It is widely distributed in humans, the chief sources of contamination being cigarette smoke, welding, and contaminated food and beverages. Toxic impacts are discussed and appear to be proportional to body burden of cadmium. Detoxification of cadmium with EDTA and other chelators is possible and has been shown to be therapeutically beneficial in humans and animals when done using established protocols.

Cadmium toxicity revisited: focus on oxidative stress induction and interactions with zinc and magnesium.

Discovered in late 1817, cadmium is currently one of the most important occupational and environmental pollutants. It is associated with renal, neurological, skeletal and other toxic effects, including reproductive toxicity, genotoxicity, and carcinogenicity. There is still much to find out about its mechanisms of action, biomarkers of critical effects, and ways to reduce health risks. At present, there is no clinically efficient agent to treat cadmium poisoning due to predominantly intracellular location of cadmium ions. This article gives a brief review of cadmium-induced oxidative stress and its interactions with essential elements zinc and magnesium as relevant mechanisms of cadmium toxicity. It draws on available literature data and our own results, which indicate that dietary supplementation of either essential element has beneficial effect under condition of cadmium exposure. We have also tackled the reasons why magnesium addition prevails over zinc and discussed the protective role of magnesium during cadmium exposure. These findings could help to solve the problem of prophylaxis and therapy of increased cadmium body burden.

Papel de la vía de Ras en un modelo de nefrotoxicidad inducida por cadmio. Efecto protector del antioxidante quercetina / Role of Ras signalling pathway in a model of cadmium-induced nephrotoxicity. Protective effect of the antioxidant quercetin

El cadmio (Cd) es un tóxico presente en el medio ambiente que afecta a los sistemas biológicos por varias rutas. Los mecanismos moleculares de su toxicidad no están bien definidos. Nosotros hemos demostrado recientemente en un modelo de administración crónica de Cd en ratas, que la quercetina, un potente “scavenger" de radicales libres de oxígeno, tiene un efecto protector sobre la nefrotoxicidad inducida por Cd. La potente actividad antioxidante de la quercetina pudiera ser la responsable de este efecto protector. Sin embargo, el Cd activa múltiples rutas de señalización relacionadas con respuestas celulares frente al estrés. Ras es un miembro de la familia de las pequeñas GTPasas, con una gran variedad de funciones que incluyen la regulación de genes de expresión y proliferación celular. Nuestro objetivo en este trabajo fue estudiar el efecto del cadmio y la quercetina en el proceso proliferativo relacionado con las vías de señalización mediadas por Ras. El estudio se realizó durante nueve semanas con ratas Wistar. Se dividieron en cuatro grupos: 1) Grupo control, 2) Grupo cadmio: 1,2 mg/Kg/día, s.c., 3) Grupo quercetina: 50 mg/Kg/día, i.p., 4) Grupo cadmio-quercetina: animales tratados con cadmio y quercetina a las dosis y vías de administración anteriormente descritas. Para valorar la toxicidad renal se determinó la excreción urinaria de proteínas y enzimas marcadoras de necrosis tubular, así como las concentraciones plasmáticas de creatinina y urea. La expresión y activación renal de Ras se evaluó mediante Western blot e inmunohistoquímica. La proliferación celular se determinó por detección del antígeno Ki-67. Los resultados mostraron que la co-administración de cadmio y quercetina mejoró la función renal alterada por la exposición a cadmio. Por otra parte, se observó una mayor activación de Ras y una mayor proliferación celular en los riñones de los animales tratados con cadmio. El tratamiento con quercetina redujo la activación renal de Ras y el número de células en proliferación. Nuestros resultados sugieren que el efecto protector de la quercetina sobre la nefrotoxicidad inducida por cadmio pudiera deberse a la inhibición de esta ruta de señalización (AU)

Cadmium (Cd) is an ubiquitous environmental toxicant that affects biological systems in various ways. The molecular mechanisms of its toxicity are not yet well defined. We have recently reported in an experimental model of chronic cadmium administration in rats, that quercetin, a potent oxygen free radical scavenger, has a protective effect on cadmium-induced nephrotoxicity. Quercetin´s strong antioxidant activity could be responsible for the protective effect. However, Cd activates multiple signal transduction pathways related to cellular responses to stress. Ras is a member of a family of small GTPases with a great variety of functions including regulation of gene expression and cell proliferation. Our aim in this work was to study the effect of Cd and quercetin on the proliferation related to Ras-mediated signal transduction pathways. Experiments were carried out in male Wistar rats during nine weeks. Rats were distributed in four experimental groups: 1) control rats; 2) cadmium group (1,2 mg Cd/Kg/day s.c.); 3) quercetin group (50 mg/Kg/day, i.p.) and 4) cadmium-quercetin group (Cd and quercetin at the same doses as in the groups 2 and 3 respectively). Renal toxicity was evaluated by measuring urinary excretion of proteins and enzyme markers of tubular necrosis, as well as plasma concentrations of creatinine and urea. Renal expression of Ras and Ras activation was assessed by Western blot and inmuhistochemistry. Assessment of cell proliferation was evaluated by detection of the Ki-67 antigen. Animals that received both Cd and quercetin showed a better renal function than those receiving Cd alone. On the other hand, Cd increased renal Ras activation and cell proliferation. Quercetin treatment reduced Ras activation and the number of cells in proliferation. Our results suggest that the protective effect of quercetin on cadmium-induced nephrotoxicity could be associated with the inhibition of Ras signal transduction pathway (AU)

Environnement, homeopathie et toxicologie / Environment, homeopathy and toxicology

Les polluants atmospheriques, les toxiques industriels (metaux lourds) et les medicaments sont a l'origine d'un certain nombre de pathogenesies accidentelles et de maladies iatrogenes. L'utilisation de tres faibles doses, voire des dilutions "non materielles"de l'agent inducteur peut etre une alternative therapeutique efficace et non toxique a ces maladies de l'environnement. Les... (AU)

Extracorporeal complexation and haemodialysis for the treatment of cadmium poisoning. I. Effects of four chelators on the in vitro elimination of cadmium from human blood.

The effect of ethylenediamine tetraacetic acid (EDTA), glutathione (GSH), citrate and 2,3-dimercaptosuccinic acid (DMSA) on the elimination of cadmium (Cd) from human blood, by complexing haemodialysis, was investigated in vitro. A significant increase in elimination rate was observed with all four chelators compared to that observed without chelators. EDTA was found to be the most effective agent, which at a level of 0.01M in the dialysate facilitated elimination of 80% of the blood Cd originally present.

Quelaçäo de metais pesados, radicais livres e doenças humanas / Heavy metals chelation free radicals and human diseases

É sugerida uma nova abordagem para o entendimento das causas da doença aterosclerótica, baseando-se nas recentes investigaçöes da Biologia Molecular sobre a açäo dos radicais livres. Com a quelaçäo de metais pesados, eliminando uma importante fonte geradora de radicais livres, observam-se melhoras sintomáticas e funcionais näo usuais no caso de doença vascular oclusiva, bem como resultados animadores nas doenças relacionadas à intoxicaçäo subclínica por metais pesados