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Sustained rise in cytosolic Ca^sup 2+^ and cell shrinkage mainly caused by K^sup +^ and Cl^sup -^ efflux are known to be prerequisites to apoptotic cell death. Here, we investigated how the efflux of K^sup +^ and Cl^sup -^ as well as the rise in cytosolic Ca^sup 2+^ occur prior to caspase activation and are coupled to each other in apoptotic human epithelial HeLa cells. Caspase-3 activation and DNA laddering induced by staurosporine were abolished by blockers of K^sup +^ and Cl^sup -^ channels or cytosolic Ca^sup 2+^ chelation. Staurosporine induced decreases in the intracellular free K^sup +^ and Cl^sup -^ concentrations ([K^sup +^]^sub i^ and [Cl^sup -^]^sub i^) in an early stage prior to caspase-3 activation. Staurosporine also induced a long-lasting rise in the cytosolic free Ca^sup 2+^ concentration. The early-phase decreases in [K^sup +^]^sub i^ and [Cl^sup -^]^sub i^ were completely prevented by a blocker of K^sup +^ or Cl^sup -^ channel, but were not affected by cytosolic Ca^sup 2+^ chelation. By contrast, the Ca^sup 2+^ response was abolished by a blocker of K^sup +^ or Cl^sup -^ channel. Strong hypertonic stress promptly induced a cytosolic Ca^sup 2+^ increase lasting >50 min together with sustained shrinkage and thereafter caspase-3 activation after 4 h. The hypertonic stress induced slight increases in [K^sup +^]^sub i^ and [Cl^sup -^]^sub i^ in the first 50 min, but these increases were much less than the effect of shrinkage-induced condensation, indicating that K^sup +^ and Cl^sup -^ efflux took place. Hypertonicity induced caspase-3 activation that was prevented not only by cytosolic Ca^sup 2+^ chelation but also by K^sup +^ and Cl^sup -^ channel blockers. Thus, it is concluded that not only Ca^sup 2+^ mobilization but early-phase efflux of K^sup +^ and Cl^sup -^ are required for caspase activation, and Ca^sup 2+^ mobilization is a downstream and resultant event of cell shrinkage in both staurosporine- and hypertonicity-induced apoptosis.[PUBLICATION ABSTRACT]

Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer’s disease, AD), automaticity (Parkinson’s disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.

Thalassemia syndromes are characterized by the inability to produce normal hemoglobin. Ineffective erythropoiesis and red cell transfusions are sources of excess iron that the human organism is unable to remove. Iron that is not saturated by transferrin is a toxic agent that, in transfusion-dependent patients, leads to death from iron-induced cardiomyopathy in the second decade of life. The availability of effective iron chelators, advances in the understanding of the mechanism of iron toxicity and overloading, and the availability of noninvasive methods to monitor iron loading and unloading in the liver, heart, and pancreas have all significantly increased the survival of patients with thalassemia. Prolonged exposure to iron toxicity is involved in the development of endocrinopathy, osteoporosis, cirrhosis, renal failure, and malignant transformation. Now that survival has been dramatically improved, the challenge of iron chelation therapy is to prevent complications. The time has come to consider that the primary goal of chelation therapy is to avoid 24-h exposure to toxic iron and maintain body iron levels within the normal range, avoiding possible chelation-related damage. It is very important to minimize irreversible organ damage to prevent malignant transformation before complications set in and make patients ineligible for current and future curative therapies. In this clinical case-based review, we highlight particular aspects of the management of iron overload in patients with beta-thalassemia syndromes, focusing on our own experience in treating such patients. We review the pathophysiology of iron overload and the different ways to assess, quantify, and monitor it. We also discuss chelation strategies that can be used with currently available chelators, balancing the need to keep non-transferrin-bound iron levels to a minimum (zero) 24 h a day, 7 days a week and the risk of over-chelation.

Intravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design. TACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are followed for 2.5 to 5 years. The primary endpoint is time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial has >;85% power to detect a 30% relative reduction in the primary endpoint. TACT2 also includes a Trace Metals and Biorepository Core Lab, to test whether benefits of treatment, if present, are due to chelation of lead and cadmium from patients. Design features of TACT2 were chosen to replicate selected features of the first TACT, which demonstrated a significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. Results are expected in 2024. TACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants.

The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2’s participants. At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. ClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185

Effective iron chelation is crucial for preventing morbidity and mortality in transfusion-dependent beta-thalassemia major. While oral chelation is the preferred mode of administration, heavily iron-overloaded patients often require combination therapy. Although desferoxamine and deferiprone are commonly recommended, a combination of two oral chelators—deferasirox and deferiprone, offers a more convenient alternative. This study evaluates the efficacy and safety of combination oral chelation in pediatric patients with severe iron overload. Children with transfusion-dependent beta-thalassemia major and persistently high serum ferritin levels (> 2500 µg/dL) for more than six months despite maximum-dose deferasirox (40 mg/kg/day) were initiated on combination chelation with deferiprone. Serum ferritin levels were monitored at six-month intervals to assess treatment efficacy. Among 130 regularly followed patients, 27 met the criteria for combination chelation. A significant reduction in serum ferritin levels was observed, decreasing from 4277 ± 1885 µg/dL at baseline to 3242 ± 1110 µg/dL at six months ( p  = 0.003) and further to 2985 ± 1116 µg/dL at twelve months ( p  = 0.018). No significant adverse effects were noted during the study period. Combination chelation with deferasirox and deferiprone is an effective and well-tolerated strategy for managing severe iron overload in children with beta-thalassemia major. This approach provides a practical alternative to injectable therapies and may improve adherence and treatment outcomes.

Kidney transplant recipients (KTR) with high-normal lead have a higher risk of graft failure (GF). Clinically, chelation therapy using meso-2,3-dimercaptosuccinic acid (DMSA) removes lead. Despite the proposal that chelation therapy can prevent GF through lead removal, evidence is lacking. To guide research efforts, we conducted an early economic evaluation, aiming to explore the economic feasibility of screening for and implementing chelation therapy with oral DMSA for high-normal plasma lead concentrations in KTR (i.e., the intervention) compared to standard of care. A Markov model simulated the life course of 10,000 KTR in the Netherlands from a societal perspective. Transition probabilities were estimated using the data from TransplantLines Food and Nutrition Biobank and Cohort study. Costs and utilities were sourced from publications and public data. Model robustness was investigated through deterministic and probabilistic sensitivity analyses. Various administration strategies were tested. Five-year costs were calculated from a healthcare payer's perspective. Value of information was assessed. The intervention was cost-saving and improved health, leading to a dominant incremental cost-effectiveness ratio. The result was most sensitive to transition probabilities (led by GF, followed by death with functioning graft and after graft failure). The probability of the intervention being cost-effective was 60%. Chelation strategies did not affect the result. The intervention applied to the Dutch KTR population could save €27 million in the initial five years. Further research is desirable if the cost of obtaining perfect information on GF survival is approximately below €4,000/KTR (all uncertainties under €5,000/KTR). The cost-effectiveness of the intervention is robust in KTR, except when considering the uncertainties around (graft) survival probabilities. Applying chelation therapy in the new setting we studied holds significant potential. However, trials that systematically assess the efficacy, administration strategies, and impacts on survival are crucial in updating the current evaluation and informing policies.

Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator–metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.

Patients suffering from iron overload can experience serious complications. In such patients, various organs, such as endocrine glands and liver, can be damaged. Although iron is a crucial element for life, iron overload can be potentially toxic for human cells due to its role in generating free radicals. In the past few decades, there has been a major improvement in the survival of patients who suffer from iron overload due to the application of iron chelation therapy in clinical practice. In clinical use, deferoxamine, deferiprone, and deferasirox are the three United States Food and Drug Administration-approved iron chelators. Each of these iron chelators is well known for the treatment of iron overload in various clinical conditions. Based on several up-to-date studies, this study explained iron overload and its clinical symptoms, introduced each of the above-mentioned iron chelators, and evaluated their advantages and disadvantages with an emphasis on combination therapy, which in recent studies seems a promising approach. In numerous clinical conditions, due to the lack of accurate indicators, choosing a standard approach for iron chelation therapy can be difficult; therefore, further studies on the issue are still required. This study aimed to introduce each of these iron chelators, combination therapy, usage doses, specific clinical applications, and their advantages, toxicity, and side effects.

Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.