Alarming use of chelation therapy

Chelation therapy is a consolidated medical procedure used primarily to hinder the effects of toxic metal ions on human tissues. Its application spans a broad spectrum of disorders, ranging from acute metal intoxication to genetic metal-overload. The use of chelating agents is compromised by a number of serious side effects, mainly attributable to perturbed equilibrium of essential metal ion homeostasis and dislocation of complexed metal ions to dangerous body sites. For this reason, chelation therapy has been limited to specific critical and otherwise untreatable conditions and needs to be monitored within an appropriate clinical context. An alarming issue today is that fraudsters use the term “chelation therapy” to take advantage of and make profit from people with tragic health problems. We believe that scientists working in this field have the corollary obligation to deter these frauds and to inform the scientific community of the possible side effects and complications of chelation therapy. This duty is all the more important if we consider the detrimental and even life threatening consequences that can occur in subjects with no clear clinical and laboratory evidence of metal intoxication. The aim of this communication is to present how this “false chelation therapy” developed and in which diseases it is currently applied

Chelation therapy: evaluation of the coordination ability of bis-kojic and hydroxypyridinone derivative ligands towards Cd^II ions <i>via</i> NMR spectroscopy

The soft acid CdII is an accumulative toxic metal ion which is able to substitute for the essential borderline ZnII ion in many zinc enzymes. Nuclear magnetic resonance (NMR) spectroscopy was used to assess the coordination ability of two ligands, an amine-bearing bis-kojic acid: 6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) [1,2] and a hydroxypiridinone derivative: 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one [3], for their use as potential chelating molecules towards CdII ions in detoxification treatments. A combination of 1D, 2D total correlation spectroscopy (TOCSY), heteronuclear single quantum coherence spectroscopy (HSQC) and rotating-frame Overhauser effect spectroscopy (ROESY) experiments was used to assign the signals of both free and metal-bound ligands, as previously reported for similar systems [4-6]. The metal-ligand system was studied at physiological pH and different temperature values. Competition experiments with essential ZnII ions were also performed

Comparison of selectivity of a family of chelating agents for trivalent (Al³⁺, Fe³⁺) and bivalent (Cu²⁺, Zn²⁺) metal ions

Chelation therapy is used for the treatment of metal intoxication in humans. Selectivity towards the target metal ion is one important characteristic of the chelating agent. In the frame of our research of chelating agents for iron and aluminium, we synthesized five new ligands (Figure 1), and studied their behavior toward the trivalent metal ions. L4, L5, L6 and L8 were found to be excellent ligands for the coordination of Fe3+ and Al3+. We are presenting here a study on the same ligands with the two essential bivalent metal ions, Zn2+ and Cu2+. The results of spectrophotometric, potentiometric, and NMR measurements performed to determine the equilibrium formation constants will be presented. The speciation of the complexes with the trivalent metal ions in presence of endogenous zinc and copper will be discussed

Undercover Toxic Ménage à Trois of Amylin, Copper (II) and Metformin in Human Embryonic Kidney Cells

In recent decades, type 2 diabetes complications have been correlated with amylin aggregation, copper homeostasis and metformin side effects. However, each factor was analyzed separately, and only in some rare cases copper/amylin or copper/metformin complexes were considered. We demonstrate for the first time that binary metformin/amylin and tertiary copper (II)/amylin/metformin complexes of high cellular toxicity are formed and lead to the formation of aggregated multi-level lamellar structures on the cell membrane. Considering the increased concentration of amylin, copper (II) and metformin in kidneys of T2DM patients, our findings on the toxicity of amylin and its adducts may be correlated with diabetic nephropathy development

Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis

Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron2+ and iron3+ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.Financial support from FIR 2019 and from Regione Autonoma della Sardegna (grant RASSR79857) is gratefully acknowledged

A New hydroxypyrone powerful chelator: from synthesis to Al^III, Fe^III, Cu^II and Zn^II complex formation equilibria, and structural characterization

In the frame of our research interest on kojic acid derivatives as powerful chelators for the trivalent iron and aluminium cations [1-4], we have designed, synthesized, and characterized the new ligand 6,6'-(((2-(diethylamino)ethyl)azanediyl)bis(methylene))bis(5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one), L9. In this communication will be present the study on protonation constants and on the complex formation equilibria with iron and aluminium and with the bivalent essential metal ions, zinc and copper. X-ray structures of the ligand and of some of its metal complexes will be also presented

Iron Chelation for Iron Overload in Thalassemia

This chapter is devoted to the chelation treatment of transfusion-dependent thalassemia patients. After a brief overview on the pathophysiology of iron overload and on the methods to quantify it in different organs, the chelation therapy is discussed, giving particular attention to the chemical and biomedical requisites. The main tasks of an iron chelator should be the scavenging of excess iron, allowing an equilibrium between iron supplied by transfusions and that removed with chelation, and protection of the individual from the poisonous effects of circulating iron. The chelating agents in clinical use are presented, illustrating the main chemical and pharmacological features, together with a comparative cost analysis of their treatments. As a final section, an overview is provided on chelators undergoing clinical trials, and on research in progress

Nickel Binding Sites in Histone Proteins: Spectroscopic and Structural Characterization

Nickel compounds influence carcinogenesis by interfering with a variety of cellular targets. It has been found that nickel is a potent inhibitor in vivo of histone H4 acetylation, in both yeast and mammalian cells. It has preference to specific lysine residues in the H4 N-terminal - S(1)GRGK(5)GGK(8)GLGK(12)GGAK(16)RH(18)RKVL(22) tail, in which the sites of acetylation are clustered. About the nature of the structural changes induced by histone acetylation on H4, it has been recently demonstrated that acetylation promotes an increase in a-helical conformation of the acetylated N-terminal tail of H4. This causes a shortening of the tail and such an effect may have an important structural and functional implication as a mechanism of transcriptional regulation. Here we report a study on the conformational changes induced by carcinogenic nickel compounds on the histone H4 protein. From a circular dichroism study we found that nickel is able to induce a secondary structure in the protein. In particular, nickel has the same effect as acetylation: it induces an increase in a-helical conformation of the non-acetylated histone H4. The a-helical increase occurring upon nickel interaction with histone H4 should decrease the ability of histone acetyl transferase to recognize and bind the histone tail, thus affecting the ability of the enzyme to further modify the lysine residues. The shortening of the distance between adjacent amino acids, caused by the translation from an extended to a helical conformation, could disrupt the histone recognition motif; this may eventually compromise the entire "histone code"

Silver coordination compounds: A new horizon in medicine

Silver coordination compounds with a number of different ligands (N-heterocyclic carbenes, phosphines, N-heterocycles and others) possess several properties, ranging from antibacterial, anti-inflammatory and antiseptic to antineoplastic activity. They also promise to be agents capable of overcoming drug resistance and beating antibiotic-resistant bacteria, fungi and parasites. In spite of the large volume of research undertaken in this area and the synthesis of several new silver complexes, most of them still remain in an academic research context and few have actually been approved for medical treatment of human diseases.In this review we present an overview of this noble metal's active derivatives, properties, mode of action and potential uses with the aim of stimulating further evaluation of their potential clinical applications and therapeutic uses