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Cellular iron is inseparably related with the proper functionalities of mitochondria for its potential to readily donate and accept electrons. Though promising, the available endeavors of iron chelation antitumor therapies have tended to be adjuvant therapies. Herein, we conceptualized and fabricated an "iron-phagy" nanoparticle (Dp44mT@HTH) capable of inducing the absolute devastation of mitochondria via inhibiting the autophagy-removal of impaired ones for promoting cancer cell death. The Dp44mT@HTH with hyaluronic acid (HA) as hydrophilic shell can specifically target the highly expressed CD44 receptors on the surface of 4T1 tumor cells. After internalization and lysosomal escape, the nanoparticle disassembles in response to the reactive oxygen species (ROS), subsequently releasing the iron chelator Dp44mT and autophagy-inhibitory drug hydroxychloroquine (HCQ). Dp44mT can then seize cellular Fe2+ to trigger mitochondrial dysfunction via respiratory chain disturbance, while HCQ not only lessens Fe2+ intake, but also impedes fusions of autophagosomes and lysosomes. Consequentially, Dp44mT@HTH induces irreversible mitochondrial impairments, in this respect creating a substantial toxic stack state that induces apoptosis and cell death. Initiating from the perspective of endogenous substances, this strategy illuminates the promise of iron depletion therapy via irreversible mitochondrial damage induction for anticancer treatment. Our research applied nanotechnology for constructing an autophagy-inhibition prodrug micelle (HTH)-based nano-delivery system (Dp44mT@HTH), for targeted and controlled release of Dp44mT (an iron chelator), in study of the iron chelation antitumor therapy. We advanced this "iron-phagy" strategy to induce irreversible mitochondrial impairments and toxic stacks via disrupting respiratory chain and inhibiting the autophagy-removal of impaired mitochondria, thus leading to tumor cell death. [Display omitted] [ABSTRACT FROM AUTHOR]

Systematic transfusions coupled with iron chelation therapy have substantially improved the life expectancy of thalassemia patients in developed nations. As the human organism does not have a protective mechanism to remove excess iron, iron overload is a significant concern in thalassemia, leading to organ damage, especially in the heart and liver. Thus, iron chelation therapy is crucial to prevent or reverse organ iron overload. There are three widely used iron chelators, either as monotherapy or in combination. The choice of iron chelator depends on several factors, including local guidelines, drug availability, and the individual clinical scenario. Despite treatment advancements, challenges persist, especially in resource-limited settings, highlighting the need for improved global healthcare access. This review discusses clinical management, current treatments, and future directions for thalassemia, focusing on iron overload and its complications. Furthermore, it underscores the progress in transforming thalassemia into a manageable chronic condition and the potential of novel therapies to further enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Arsenic (As) poisoning has become a global public problem threatening human health. Chelation therapy (CT) is the preferred treatment for arsenic poisoning. Nevertheless, efficient and safe arsenic removal in vivo remains a daunting challenge due to the limitations of chelators, including weak affinity, poor cell membrane penetration, and short half-life. Herein, a mercapto-functionalized and size-tunable hierarchical porous Zr-MOF (UiO-66-TC-SH) is developed, which possesses abundant arsenic chemisorption sites, effective cell uptake ability, and long half-life, thereby efficiently removing toxic arsenic in vivo. Moreover, the strong binding affinity of UiO-66-TC-SH for arsenic reduces systemic toxicity caused by off-target effects. In animal trials, UiO-66-TC-SH decreases the blood arsenic levels of acute arsenic poisoning mice to a normal value within 48 h, and the efficacy is superior to clinical drugs 2,3-dimercaptopropanesulfonic acid sodium salt (DMPS). Meanwhile, UiO-66-TC-SH also significantly mitigates the arsenic accumulation in the metabolic organs of chronic arsenic poisoning mice. Surprisingly, UiO-66-TC-SH also accelerates the metabolism of arsenic in organs of tumor-bearing mice and alleviates the side effects of arsenic drugs antitumor therapy. Arsenic (As) contamination has become a global problem threatening public health. The present clinical chelation therapy (CT) still has some limitations, including the weak affinity, poor cell membrane permeability and short half-life of hydrophilic chelators. Herein, a metal−organic framework (MOF)-based multieffective arsenic removal strategy in vivo is proposed for the first time. Mercapto-functionalized and size-tunable hierarchical porous Zr-MOF nanoantidote (denoted as UiO-66-TC-SH) is accordingly designed and synthesized. After injection, UiO-66-TC-SH can form Zr− O −As bonds and As− S bonds with arsenic, thus enhancing arsenic adsorption capacity, cycling stability and systemic safety simultaneously. The acute arsenic poisoning model results indicate that UiO-66-TC-SH shows superior efficacy to the clinical drug sodium dimercaptopropanesulfonate (DMPS). More meaningfully, we find that UiO-66-TC-SH also accelerates the metabolism of arsenic in organs of tumor-bearing mice and alleviates side effects of arsenic drugs anti-tumor therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. A total of 42 adult TDT patients (18 male, 24 female; age range: 41–55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients. [ABSTRACT FROM AUTHOR]

• Currently available conventional treatment modalities in β-thalassemia have posed many challenges and limitations. • There is a need for therapies that reduce patient reliance on RBC transfusions and iron chelation therapy. • Many novel therapies for β-thalassemia are now being tested in clinical trials. • These can be classified into three major categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the α/β globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. β-thalassemias are genetic disorders causing an imbalance in hemoglobin production, leading to varying degrees of anemia, with two clinical phenotypes: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Red blood cell transfusions and iron chelation therapy are the conventional treatment options for the management of β-thalassemia. Currently available conventional therapies in thalassemia have many challenges and limitations. Accordingly, multiple novel therapeutic approaches are currently being developed for the treatment of β-thalassemias. These strategies can be classified into three categories based on their efforts to address different aspects of the underlying pathophysiology of β-thalassemia: correction of the α/β globin chain imbalance, addressing ineffective erythropoiesis, and targeting iron dysregulation. Managing β- thalassemia presents challenges due to the many complications that can manifest, limited access and availability of blood products, and lack of compliance/adherence to treatment. Novel therapies targeting ineffective erythropoiesis and thus improving anemia and reducing the need for chronic blood transfusions seem promising. However, the complex nature of the disease itself requires personalized treatment plans for each patient. Collaborations and partnerships between thalassemia centers can also help share knowledge and resources, particularly in regions with higher prevalence and limited resources. This review will explore the different conventional treatment modalities available today for the management of β-thalassemia, discuss the unmet needs and challenges associated with them in addition to exploring the role of some novel therapeutic agents in the field. [ABSTRACT FROM AUTHOR]

A 23-year-old previously healthy woman presented with headache, generalized seizures, ataxia, encephalopathy, abdominal pain, nausea, and vomiting culminating in a 40-pound weight loss. A contrasted magnetic resonance imaging scan of the brain showed T2/FLAIR hyperintensities in the sulci of the occipital and parietal lobes, a punctate focus of restricted diffusion along the inferior aspect of the left caudate head and an empty sella. A lumbar puncture showed an opening pressure of 55 cm H2O, and kidney, ureter, and bladder X ray showed a radiopaque particle in the colon. Serum lead level was 85 mcg/dL (< 3.5). Blood smear showed foreign bodies identified as lead particles in the blood with basophilic stippling of RBCs. She was treated with chelation therapy and bowel irrigation and eventually recovered. Further investigation indicated that she was being slowly poisoned by her husband, a chiropractor who had access to lead. [ABSTRACT FROM AUTHOR]

Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy. [Display omitted] • Neurological worsening in Wilson disease occurs at two peaks. • Early neurological worsening is observed within 3 months after treatment initiation. • Late neurological worsening is observed after 12 months of treatment initiation. • Late neurological worsening is associated with non-adherence. • Early "paradoxical" neurologic worsening was not observed in patients without preexisting neurologic symptoms. [ABSTRACT FROM AUTHOR]

Metal ions play a pivotal role in maintaining optimal brain function within the human body. Nevertheless, the accumulation of these ions can result in irregularities that lead to brain damage and dysfunction. Disruptions of metal ion homeostasis can result in various pathologies, including inflammation, redox dysregulation, and blood-brain barrier disruption. While research on metal ions has chiefly focused on neurodegenerative diseases, little attention has been given to their involvement in the onset and progression of stroke. Recent studies have identified cuproptosis and confirmed ferroptosis as significant factors in stroke pathology, underscoring the importance of metal ions in stroke pathology, including abnormal ion transport, neurotoxicity, blood-brain barrier damage, and cell death. Additionally, it provides an overview of contemporary metal ion chelators and detection techniques, which may offer novel approaches to stroke treatment. • The transport of metal ions in the normal brain and changes during a stroke. • The relationship between metal ion imbalance and the blood-brain barrier disruption after stroke. • The various pathways of cell death related to metal ions, with a focus on the role of these ions in these processes. • Different methods of detecting metal ions. • Current strategies for metal ion chelation therapy. [ABSTRACT FROM AUTHOR]

In this work, fluorescent carbon dots with high quantum yield were effectively prepared for the sensitive detection of deferasirox utilizing the controllable chelation of Cu2+ and deferasirox with the new absorbance peak at 334 nm through simple mixing operation. [Display omitted] • Carbon dots (CDs) with excellent fluorescent quantum yield were effectively prepared. • The coordination effect of deferasirox and Cu2+ exhibited a new absorption peak at 334 nm. • The absorption peak at 334 nm played an internal filtration effect on CDs. • Deferasirox was efficiently monitored with good performance. As an iron chelation therapy, deferasirox (DEF) is commonly used as the primary treatment drug to prevent intracellular iron overload in patients with thalassemia who require long-term and large blood transfusions. However, due to the toxic side effects of long-term use, building a convenient and sensitive DEF detection method remains an important task. This study developed a simple and effective fluorescence detection strategy for DEF based on the coordination effect of DEF and Cu2+ (DEF-Cu). The high quantum yield N-doped blue emission carbon dots (CDs) synthesized by a simple one-step hydrothermal method were applied as the fluorescent probe. The DEF-Cu exhibited a new absorption peak centered at 334 nm, overlapping with the absorption wavelength of CDs, resulting in an internal filtration effect (IFE) for quenching the fluorescence of CDs. The quenching degrees of CDs caused by DEF-Cu showed a good linear relationship in the range of 0.5–20 μg/mL, with a detection limit (LOD) as low as 0.12 μg/mL. The accurate detections of DEF in dispersible tablets and plasma were also achieved. This strategy not only enriched the understanding of the properties of target drugs but also provided valuable insights for designing CDs with specific luminescent properties and applying them to distinctive methods for drug analysis. [ABSTRACT FROM AUTHOR]

The design of novel chelators for therapeutic applications has been the subject of extensive research to address various diseases. Many chelators can manipulate the levels of metal ions within cells and effectively modulate the metal excess. In some cases, chelators show significant toxicity to cells. We investigated polyimidazole ligands by potentiometry and UV–Vis spectroscopy for their ability to form copper(II) complexes. We also compared the antiproliferative activity of the polyimidazole ligands and their copper(II) complexes with polypyridine ligands in CaCo-2 (colorectal adenocarcinoma), SH-SY5Y (neuroblastoma) and K562 (chronic myelogenous leukemia) cells and normal HaCaT (keratinocyte) cells. Polyimidazole ligands are less cytotoxic than their analogous polypyridine ligands. All polyimidazole ligands, except the tetraimidazole ligand for K562 cells, did not show any significant effect on the viability of cancer and normal cells. In contrast, the cytotoxic activity of polypiridine ligands was also observed in normal cells with IC 50 values similar to those of cancer cells. Tetraimidazole ligand, the only ligand active on the leukemic K562 cell line, induced caspase-dependent apoptosis and increased intracellular reactive oxygen species production with mitochondrial damage. The low cytotoxicity of the polyimidazole ligands, even if it limits their use as anticancer agents, could make them useful in other medical applications, such as in the treatment of metal overload, microbial infections, inflammation or neurodegenerative disorders. The low cytotoxicity of imidazole ligands makes them promising for medical applications, including the treatment of metal overload. [Display omitted] • Chelators can modulate the metal ion homeostasis inside cells. • Imidazole is a binding site in biological systems. • Polyimidazole ligands can bind copper(II). • Imidazole ligands show a low antiproliferative effect. • The low cytotoxicity could make them promising for a variety of medical applications. [ABSTRACT FROM AUTHOR]

The dyshomeostasis of metal ions in the brain leads to the accumulation of excess metals in extracellular and inter-neuronal locations and the Amyloid β peptide (Aβ) binds these transition metals, which ultimately cause the Aβ aggregation and severe oxidative stress in the brain. The aggregation of Aβ and oxidative stress are important factors to trigger Alzheimer's disease (AD). Metal chelation therapy is a promising approach to removing metals from Aβ-M species and relieve the oxidative stress. Therefore, 4 tetrahydrosalens containing benzothiazole moiety were designed and synthesized. Their biological activities for Alzheimer's disease therapy in vitro were determined by Turbidity assay, BCA protein assay, MTT assay and fluorescent probe of DCFH-DA. The results were comparing with that of non-specific chelator (cliquinol, CQ) and non-benzothiazole functionalized tetrahydrosalens, the results demonstrated that benzothiazole functionalized chelators had more efficient bio-activities in preventing Cu2+-induced Aβ aggregation, attenuating cytotoxicity mediated by Aβ-Cu2+ species and decrease the level of reactive oxygen species (ROS) in Cu2+-Aβ treated PC12 cells than that of cliquinol and non-benzothiazole functionalized analogues. 4 benzothiazole functionalized Tetrahedrosalens were synthesized. Their bioactivities for Alzheimer's disease therapy in vitro were investigated. The results show that these chelators can effectively inhibit Cu2+-induced Aβ aggregation, decrease the level of reactive oxygen species (ROS) in Cu2+-Aβ treated PC12 cells and attenuate neurotoxicity mediated by Aβ-Cu2+ species. [Display omitted] • Development of the synthesis of benzothiozole functionalized tetrahydroSalen. • The bifunctional tetrahydrosalens effectively inhibit the Cu2+-induced Aβ aggregation. • The bifunctional chelators effectively remove the ROS in Aβ-Cu2+ treated PC12 cells. • The bifunctional chelators effectively increase the viability of Aβ-Cu2+ treated PC12 cells. [ABSTRACT FROM AUTHOR]

Mitochondria-targeted metal chelators accumulate in mitochondria due to the mitochondrial membrane potential and affect the availability of metals and their redox stability. [Display omitted] Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson's disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism – the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator's intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator–metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation. [ABSTRACT FROM AUTHOR]

The T2* technique, used for quantifying myocardial iron content (MIC), has limitations in detecting early myocardial iron overload (MIO). The in vivo mapping of the myocardial T1 relaxation time is a promising alternative for the early detection and management of MIO. 32 β-thalassemia major (βTM) patients aged 11.5 ± 4 years and 32 healthy controls were recruited and underwent thorough clinical and laboratory assessments. The mid-level septal iron overload was measured through T1 mapping using a modified Look-Locker inversion recovery sequence with a 3 (3 s) 3 (3 s) 5 scheme. Septum was divided at the mentioned level into 3 zones corresponding to segments 8 and 9 in the cardiac segmentation model. 21.9 % of βTM had clinical cardiac morbidity. The cut-off of T1 mapping of hepatic and myocardium to differentiate between the patients and control groups was ≤466 and ≥ 923 ms respectively. The T1 technique was able to detect 4 patients with high MIC, two of them were not detected by the T2* technique. There was a statistically significant correlation between the average T1 values of the studied zones in patients with βTM and the liver iron content (LIC), the T1 values within segment 8 of the liver, age of patients, the age at first transfusion, age of splenectomy and serum ferritin value. The addition of the T1 mapping sequence to the conventional T2* technique was able to increase the efficacy of the MIC detection protocol by earlier detection of MIO. This would guide chelation therapy to decrease myocardial morbidity. [ABSTRACT FROM AUTHOR]

Iron is an essential micronutrient for maintaining physiological activities, especially for highly active cardiomyocytes. Inappropriate iron overload or deficiency has a significant impact on the incidence and severity of cardiovascular diseases (CVD). Iron overload exerts potentially deleterious effects on doxorubicin (DOX) cardiomyopathy, atherosclerosis, and myocardial ischemia-reperfusion injury (MI/RI) by participating in lipid peroxides production. Notably, iron overload-associated cell death has been defined as a possible mechanism for ferroptosis. At present, some traditional herbal medicines and extracts have been included in the study of regulating iron overload and the subsequent therapeutic effect on CVD. To give an outline of iron metabolism and ferroptosis in cardiomyocytes and to focus on herbal medicines and extracts to prevent iron overload in CVD. Literature information was systematically collected from ScienceDirect, PubMed, Google Scholar, Web of Science, China National Knowledge Infrastructure, WanFang data, as well as classic books and clinical reports. After understanding the mechanism of iron overload on CVD, this paper reviews the therapeutic function of various herbal medicines in eliminating iron overload in CVD. These include Chinese herbal compound prescriptions (Salvia miltiorrhiza injection, Gegen Qinlian decoction, Tongxinluo, Banxia-Houpu decoction), plant extracts, phenylpropanoids, flavonoids, terpenoids, and polyphenols. Among them, flavonoids are considered to be the most promising compounds because of their prominent iron chelation. Mechanically, these herbal medicines act on the Nrf2 signaling pathway, AMPK signaling pathway, and KAT5/GPX4 signaling pathway, thereby attenuating iron overload and lipid peroxidation in CVD. Our review provides up-to-date information on herbal medicines that exert cardiovascular protective effects by modulating iron overload and ferroptosis. These herbal medicines hold promise as a template for preventing iron overload in CVD. [Display omitted] • Iron overload exerts potentially deleterious effects in cardiovascular diseases. • The protective effects of various herbal medicines on eliminating iron overload in cardiovascular diseases. • Flavonoids have prominent iron chelates and are considered to be the most promising compounds. [ABSTRACT FROM AUTHOR]

Background: The Trial to Assess Chelation Therapy (TACT) found that chelation therapy significantly reduced clinical events in patients with a history of myocardial infarction (MI). The initial report of TACT included the observation of an interaction between edetate disodium infusions and MI location, as well as diabetes. Thus, we examined in greater detail the effect of edetate disodium chelation therapy as a function of MI location and diabetes.Methods: Patients (n = 1708) at least 6 weeks post-MI and age ≥ 50 were randomized to receive 40 infusions of a 500 mL chelation solution or placebo (median follow-up 55 months). The effect of edetate disodium on the primary outcome (all-cause mortality, MI, stroke, hospitalization for angina, or coronary revascularization) was assessed as a function of MI location using log-rank test and Cox regression model, adjusting for other prognostic variables.Results: Among patients with post anterior MI (n = 674), chelation was associated with a lower risk of the primary endpoint (HR 0.63, 95% CI 0.47-0.86, p = 0.003) among anterior MI patients, but not in post non-anterior MI (n = 1034) patients (HR 0.96, 95% CI 0.77-1.20, p = 0.702) (p-for-interaction = 0.032). The point estimates for each component of the primary endpoint favored chelation therapy. The differing treatment effect in patients with post anterior vs. non-anterior MI was consistent among patients with or without diabetes and remained significant after adjusting for other prognostic variables (p < 0.01).Conclusions: Edetate disodium infusions reduced the risk of cardiovascular events among patients with a prior anterior MI. Future studies should focus on replicating these results and understanding the mechanisms of benefit. [ABSTRACT FROM AUTHOR]

Lead toxicity (plumbism) secondary to retained lead missiles in synovial joint spaces is a rare complication after gunshot injuries. Management of lead missiles in the intradiscal space regarding potential lead toxicity is less certain. We reviewed the literature regarding lead toxicity secondary to intradiscal bullets particularly concerning incidence, management, and outcomes. A lack of high-quality published data precludes a meta-analysis from taking place. Only four reports of lead toxicity secondary to missiles in the intradiscal space have been published. Including an additional case presented in this report, our review of the literature has led us to make several management recommendations, largely based on both the available literature and our current report. First, there is insufficient evidence for removing retained lead missiles solely to mitigate the risk of lead toxicity. Second, chelation therapy in addition to surgical removal of the lead source is a valuable adjunct in the perioperative period and should be undertaken with the assistance of medical toxicology. Third, a retained missile does not mandate a simultaneous stabilization procedure in lieu of other indications based on the data available at this time. [ABSTRACT FROM AUTHOR]

Aceruloplasminemia (ACP) is a rare autosomal recessive disorder characterized by intracranial and visceral iron overload. With R2*-based imaging or quantitative susceptibility mapping (QSM), it is feasible to measure iron in the brain quantitatively, although to date this has not yet been done for patients with ACP. The aim of this study was to provide quantitative iron measurements for each affected brain region in an ACP patient with the potential to do so in all future ACP patients. This may shed light on the link between brain iron metabolism and the territories affected by ceruloplasmin function. We imaged a patient with ACP using a 3T magnetic resonance imaging scanner with a fifteen-channel head coil. We manually demarcated gray matter and white matter on the Strategically Acquired Gradient Echo (STAGE) images, and calculated values for susceptibility and R2* in these regions. Correlation analysis was performed between the R2* values and the susceptibility values. Besides the usual territories affected in ACP, we also discovered that the mammillary bodies and the lateral habenulae had significant increases in iron, and the hippocampus was severely affected both in terms of iron content and abnormal tissue signal. We also noted that the iron in the cortical gray matter appeared to be deposited in the inner layers. Moreover, several pathways between the superior colliculus and the pulvinar thalamus, between the caudate and putamen anteriorly and between the caudate and pulvinar thalamus posteriorly were also evident. Finally, R2* correlated strongly with the QSM data (R2 = 0.67, t = 6.78, p < 0.001). QSM and R2* have proven to be sensitive and quantitative means by which to measure iron content in the brain. Our findings included several newly noted affected brain regions of iron overload and provided some new aspects of iron metabolism in ACP that may be further applicable to other pathologic conditions. Furthermore, our study may pave the way for assessing efficacy of iron chelation therapy in these patients and for other common iron related neurodegenerative disorders. • With R2*-based imaging or quantitative susceptibility mapping, it is feasible to measure iron in the brain quantitatively. • Several newly noted affected brain regions of iron overload are observed in aceruloplasminemia. • Some new aspects of iron metabolism in aceruloplasminemia that may be further applicable to other pathologic conditions. [ABSTRACT FROM AUTHOR]

CuSO4 (Copper sulphate) poisoning though rare, is associated with high mortality. It involves multiple organ systems and if not dealt with promptly can lead to death. Supportive care and chelation therapy along with TPE (therapeutic plasma exchange), whole blood exchange or red cell exchange can be employed in management. We report such a case where swift clinical improvement was seen after TPE. [ABSTRACT FROM AUTHOR]

Lead (Pb) is highly toxic to human body and can induce oxidative stress, causing irreversible hepato-renal and intestinal injury. Once accumulated, it is difficult to fully eliminate it from the body. However, the chelation therapy most widely used in the clinical against lead poisoning has severe side effects, such as oral dimethylaminosulfanilid will cause gastrointestinal symptoms, rash, and excessive deficiency of essential trace elements in the human body and prolonged treatment with it even has the disadvantage of causing kidney failure. Here we developed a multifunctional oral hydrogel system, BBR-CV@ALG, which composed of biocompatible carrier, Chlorella vulgaris (CV), anti-inflammation drug molecules, berberine (BBR), and stabilizer, carboxymethyl chitosan/sodium alginate complex, to adsorb and remove Pb in the living body, and alleviate lead poisoning-related diseases. In acute, subacute, and chronic models of lead poisoning, our microalgal gel has contributed to longer retention in the gastrointestinal tract to function the use of microalga in biosorption, effectively removing lead in the liver, kidney, and bone. Also, the BBR can be released to further reduce tissue damage caused by oxidative stress under lead exposure. Meanwhile, BBR-CV@ALG can also repair the intestinal barrier, significantly increase the abundance of Akkermansia muciniphila and Lactobacillus taiwanensis, and maintain intestinal homeostasis. In addition, this system exhibits many advantages such as biodegradability, low cost, and high biosafety, demonstrating a potential for clinical application. [Display omitted] • Microalga-based oral hydrogel BBR-CV@ALG could treat acute/subacute/chronic lead poisoning detoxification. • BBR-CV@ALG demonstrated enhanced stability within the gastric barrier and biodegradability in the gut, leading to less gut toxicity. • The combined therapeutic strategy of BBR-CV@ALG was based on chelation therapy, antioxidant therapy, and modulating gut microbiota therapy. • BBR-CV@ALG could improve the diversity of the microbiota, protect intestinal barriers, and maintain healthy intestinal microenvironment. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a highly mortal disease in which anemia is unresponsive to treatment. In this study, the effect of basal ferritin values on prognosis and survival was investigated in MDS patients without history of transfusion. Data were retrospectively analyzed for 62 MDS cases. The cases were divided into two groups according to ferritin values. The mean survival time was 61.1 ± 4.8 months. During the follow-up period, 34 (54.8%) patients deceased. Median ferritin level was 358 ng/mL. The serum ferritin (SF) level associated with mortality was determined as 400 ng/mL (ROC area for SF was 0.731 with a cutoff value of 400; sensitivity and specificity were 70.7% and 68.2%, respectively) (P = 0.002). There were 29 (46.8%) patients with serum ferritin levels of ≥ 400 ng/mL. Patients with serum ferritin levels ≥ 400 ng/mL had low survival rates. Ferritin ≥ 400 ng/mL was associated with six times increased mortality (P = 0.001). Although the acceptable ferritin level at the start of chelation therapy is 1000 ng/mL, the fact that 400 ng/mL value is associated with survival in our study suggests that it may be useful to start chelation therapy in the early period. Further case studies on the subject are required. [ABSTRACT FROM AUTHOR]

• MDS are clonal stem cell disorders often requiring red blood cell (RBC) transfusion. • RBC transfusion results in iron overload, which portends inferior clinical outcomes. • Studies of iron chelation in MDS show hematologic improvement (HI) in some patients. • We review clinical data on hematologic improvement with iron chelation therapy in MDS. • We review mechanisms by which HI may occur & identify areas for future investigation. Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation. [ABSTRACT FROM AUTHOR]

Objective: Approximately 1 in 7 US adults have diabetes; and over 60% of deaths in patients with diabetes have cardiac disease as a principal or contributing cause. Both coronary and peripheral artery disease (PAD) identify high-risk cohorts among patients with diabetes. We have previously demonstrated improved cardiovascular outcomes with edetate disodium-based chelation in post-MI patients with diabetes, enrolled in the Trial to Assess Chelation Therapy (TACT). In these analyses we further studied the effect size of patients with diabetes and severe disease in 2 vascular beds; coronaries, and lower extremity arteries. We questioned whether greater atherosclerotic burden would attenuate the observed beneficial effect of edetate disodium infusions.Research Design and Methods: The multicenter TACT used a double blind, placebo controlled, 2 × 2 factorial design with 1708 participants, randomly assigned to receive edetate disodium-based chelation, or placebo and high dose oral vitamins or placebo. There were 162 (9.5% of 1708) post-MI patients with a diagnosis of diabetes mellitus and PAD for this post hoc analysis. Patients received up to 40 double-blind intravenous infusions of edetate disodium-based chelation, or placebo. The composite primary endpoint of TACT consisted of death from any cause, myocardial infarction, stroke, coronary revascularization and hospitalization for angina.Results: The median age was 66 years, 15% female, 5% non-Caucasian, and BMI was 31. Insulin was used by 32% of patients. Active infusions significantly reduced the primary endpoint compared with placebo infusions (HR, 0.52; 95% CI, 0.30-0.92; P = 0.0069), with a 30% absolute risk reduction in the primary endpoint. There was a marked reduction in total mortality from 24% to 11%, although of borderline significance (P = 0.052).Conclusion: Atherosclerotic disease in multiple vascular beds did not attenuate the beneficial effect of edetate disodium infusions in post MI patients with diabetes. Studies now in progress will prospectively test this post hoc finding. [ABSTRACT FROM AUTHOR]

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Sickle cell disease (SCD) is a frequent indication for chronic transfusion, which can cause iron overload. Excess iron often affects the liver, but not the heart in SCD. Magnetic resonance (MR) is recommended to detect myocardial iron overload (MIO) but its elevated cost requires optimized indication. We aimed to compile all published data on MIO in SCD upon the description of a fatal case of severe MIO in our institution, and to determine associated risk factors. We performed a systematic review using the PRISMA guidelines in two databases (PubMed and Web of Science). Inclusion criteria were publication in English, patients diagnosed with SCD, and reporting ferritin and MIO by MR. Twenty publications reported on 865 SCD adult and pediatric patients, with at least 10 other cases of MIO. The prevalence of MIO in chronically transfused SCD patients can be estimated to be 3% or less, and is associated with high transfusion burden, top-up transfusions, and low adherence to iron chelation. Cardiac siderosis in SCD is rarely reported, and increased awareness with better use of the available screening tools are necessary. Prospective studies should define the recommended chelation regimens depending on the severity of MIO. • Chronic transfusions can lead to liver and heart iron overload. • Myocardial iron overload is rare, but can be fatal in sickle cell disease. • Transfusion burden and low compliance to chelation are possible risk factors. • Increased awareness and better screening for iron overload are necessary. [ABSTRACT FROM AUTHOR]

This review illustrates heavy metals toxicity, currently available therapies and the role and efficacy of chelation therapy for its management. Heavy metals are necessary for various biological processes, but they become harmful in excess. Specifically, they induce oxidative stress by generating free radicals and reducing antioxidant levels. Heavy metals also alter the confirmation of protein and DNA and inhibit their function. Chelation therapy is commonly used to treat metals toxicity. Chelation is a chemical process that occurs when interaction between a central metal atom/ion and ligand leads to formation of a complex ring-like structure. The ligand has a donor ion/molecule, which has a lone pair of electrons and may be monodentate to polydentate. Each metal has a different reactivity with a ligand, so a specific chelation agent is required for each metal. Combination therapy with a chelating agent and an antioxidant led to improved outcome. Heavy metal poisoning is a common health problem because of mining, smelting, industrial, agricultural and sewage waste. Heavy metals can be efficiently excreted from the body following treatment with proper chelation agents. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD), in contrast to many neurogenetic metabolic diseases, can be very effectively treated in acute and chronic stages of the disease. However, early recognition is paramount because delays in treatments have much higher risk of unfavorable clinical outcomes. Identification of WD remains challenging because it is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Initial neurologic problems can be seen in approximately 40%-50% of patients and the rest has either hepatic or primarily psychiatric manifestations. Neurologic and neuropsychiatric problems in WD are quite nonspecific and we discuss the most common clinical problems associated with early and late stages of the disease. Many patients with neurologic symptoms do not have any obvious hepatic symptoms. Most common neurologic abnormalities include dysarthria, dystonia, tremor and Parkinsonism. In spite of its phenotypic heterogeneity, laboratory abnormalities, reflecting abnormal copper homeostasis, are very specific and the diagnosis of WD remains laboratory based. We review most important challenges and pitfalls in laboratory evaluation of WD, including emerging role of genetic testing. Pharmacologic treatments need to be life-long and are focused on restoration of negative copper balance without inducing iatrogenic copper deficiency. The gold standard of therapy is chelation of excessive copper. Chelators may induce further clinical deterioration in some treated patients. We also review most promising novel therapeutic approaches that appear to better control non-ceruloplasmin or free copper because elevation of free copper may be responsible for paradoxical neurologic worsening. [ABSTRACT FROM AUTHOR]

Abstract Organic compounds with a caffeoyl moiety (e.g. caffeic acid, rosmarinic acid, chicoric acid, etc.) have antiviral properties towards herpes simplex (HSV), influenza and immunodeficiency viruses (HIV). This study evaluated the HSV antiviral properties of caffeic acid when paired with a variety of metal and other inorganic ions. The results demonstrated that the antiviral activity of caffeic acid increased upwards of 100-fold by the addition of cations, such as Fe3+, and anionic molecules, such as molybdate and phosphate. Cellular toxicity tests of the caffeic acid chelates showed that they have low toxicities with selectivity indices (TD 50 /EC 50) for Fe3+, MoO 4 2−, and PO 4 3− chelates being 1700, >540, and >30, respectively. Caffeic acid paired with Fe3+ was tested against eight strains of viruses, including those from different families. The caffeic acid chelates were mostly effective against HSV1 and HSV2, but they also had moderate activity against vaccinia virus and a VSV-Ebola pseudotyped virus. All the viruses that were strongly impacted by the caffeic chelates require heparan sulfate proteoglycans for cellular attachment, so it is likely that caffeic chelates target and interfere with this mechanism. Since the caffeic acid chelates target an extra-cellular process, they might be able to be combined with existing medications, such as acyclovir, that target an intracellular process to achieve greater viral control. Graphical abstract Image 1 Highlights • Antiviral properties of caffeic acid and related compounds are increased with the addition of chelated inorganic ions. • Antiviral activity increased upwards of 100 fold with the addition of iron(III) ions. • The mechanism of action for the caffeic acid chelates occurs early in the virus replication cycle. • The caffeic acid chelates have low cellular toxicities. • These compounds were antiviral towards HSV1, HSV2, vaccinia and VSV-Ebola pseudotyped viruses. [ABSTRACT FROM AUTHOR]

Abstract N,N' - Bis [(1,2-didehydro-1-hydroxy-2-thioxopyrid-4-yl)-carbonyl]- L-lysine (HTPL) is a novel newly synthesized compound intended to be used for the chelation of lead in intoxicated animals. Subchronic lead intoxication experiments were carried out on Wistar male rats; these rats were intoxicated with lead and then treated with HTPL. Results were compared with those obtained with known compounds used for lead chelation therapy, such as disodium ethylnediaminetetraacetic acid (CaNa 2 EDTA) and meso -2,3-dimercaptosuccininc acid (DMSA), using different routes of administration. Biological samples of whole blood and urine were collected and analyzed for urinary proporphyrins, δ -aminolevulinic acid dehydratase, and zinc protoporphyrin. Results revealed that HTPL can remarkably reverse the toxic effects of lead intoxication at biochemical levels. Additionally, results showed that this agent is as good or even more potent than calcium disodium ethylnediaminetetraacetic acid (CaNa 2 EDTA) and meso -2,3-dimercaptosuccininc acid (DMSA) in reversing the toxic effect of lead. More importantly, HTPL was found effective when administrated intraperitoneally and orally. [ABSTRACT FROM AUTHOR]

The supporting tissues of dental implants can be affected by peri -implant disease, which encompasses mucositis and peri -implantitis. Mucositis is localized in the soft tissues around dental implants and is reversible. Meanwhile, peri -implantitis is irreversible, presents peri -implant bone loss, and can lead to implant failure. The causes of peri -implantitis are multifactorial, including biofilms, genetics, history of periodontal disease, smoking, obesity, incorrect prosthetic designs, and metal particles and ions. The current strategies for treating peri -implantitis (decontamination of the implant surface, treatment of the infection, regeneration of the lost bone, and modification of risk factors) have obtained inconsistent outcomes, and relapse occurs. In recent years new histological, immunological, and clinical data shows a strong relationship between metallic ions and particles (nano- or micron-sized) and peri -implantitis. In which the metal ions and particles can produce foreign body reactions, diminished cellular response, increased DNA methylation, alteration of the microbiome, and dysbiosis. Therefore, current therapies for oral peri -implantitis do not consider the deposits of metal particles and ions, and this could explain why the peri -implant disease is not entirely under control with conventional treatments. We hypothesize that chelation therapy used to treat oral peri -implantitis could reduce the excess metal ions present in the surrounding peri -implant tissues improving the outcomes of the current treatments against peri -implantitis. Represented by reduced metal ions, lowered inflammatory markers, reduced bone loss and increased implant survival. [ABSTRACT FROM AUTHOR]

A novel optically active (E)-N’-(5-allyl-2-hydroxy-3-methoxybenzylidene) nicotinohydrazide (receptor 3) was synthesized by simple Schiff base condensation of 5-allyl-2-hydroxy-3-methoxybenzaldehyde with nicotinohydrazide. The ability of receptor 3 was investigated for the selective sensing of cations by chromogenic and fluorogenic technique. Receptor 3 showed highly selective response for Zn 2+ ions in the binary mixture of acetonitrile/water (50:50, v/v) and possessed no interference from any of the potentially competing cations. Upon additions of Zn 2+ , the fluorescence intensity of the receptor 3 showed significant enhancement at 517 nm due to the chelation-enhanced fluorescence (CHEF) effect. The receptor 3 showed a good linearity for Zn 2+ ion with the detection limit down to 4.35 nM. With negligible toxicity towards live cells, the receptor 3 could be successfully employed to monitor the Zn 2+ ions in live A549 cells. [ABSTRACT FROM AUTHOR]

Wilson disease (WD) is a rare genetic disorder of the copper metabolism leading to systemic copper accumulation, predominantly in the liver. The therapeutic approach in WD patients is the generation of a negative copper balance and the maintenance of copper homeostasis, currently by the use of copper chelators such as D-penicillamine (D-PA). However, in circumstances of delayed diagnosis, poor treatment compliance, or treatment failure, mortality is almost certain without hepatic transplantation. Moreover, even after years of D-PA treatment, high liver copper levels are present in WD patients. We have recently suggested the use of the bacterial peptide Methanobactin (MB), which has an outstanding binding affinity for copper, as potentially efficient and patient-friendly remedy against copper damage in WD. Here we substantiate these findings considerably, by demonstrating a significant removal of copper from liver samples of WD rats upon short, one week only, MB treatments. Using laser ablation-inductively coupled plasma-mass spectrometry with a spatial resolution down to 4 μm, we demonstrate that only small copper hotspots remain in MB treated animal livers. We further demonstrate in WD rat liver, seven weeks after the stopped MB treatment, a lower liver copper concentration as compared to untreated control animals. Thus, MB highly efficiently depletes liver copper overload with a sustained therapeutic effect. [ABSTRACT FROM AUTHOR]

Nowadays, 3-hydroxypyridine-4-ones (HPOs) as orally active iron chelators have been introduced for the treatment of disorders associated with iron such as iron overload in thalassemia patients. In this work, a density functional theory (DFT) study was performed on a series of HPOs constituted of the different substitutions at the different positions. Structural analysis indicates that all of the HPO derivatives bind to Fe 3+ as a two-dentate mode through the oxygen atoms of the C = O groups. It is confirmed that the HPO derivative composed of three methyl groups at the different positions (3-hydroxy-1,2,5-trimethyl-4(1H) pyridinone) forms the most stable complex with Fe 3+ . Therefore, this HPO derivative acts as a better iron chelator than other ones. The vibrational frequency analysis reveals a correlation between the iron affinity constant and C = O vibrational frequency of the HPOs. Donor-acceptor interactions show an effective charge transfer from the oxygen atoms of the HPOs towards Fe 3+ . Quantum theory of atoms in molecules analysis shows the non-covalent interactions, mainly, electrostatic interactions play an important role in the complex formation of the HPOs and Fe 3+ . Finally, some linear correlations between the electron densities of the Fe − O chemical bond and interaction energy values, the vibrational frequency of the C = O bonds and electron densities of the Fe − O chemical bond were obtained and analyzed. [ABSTRACT FROM AUTHOR]

Iron-mediated generation of highly toxic Reactive Oxygen Species (ROS) plays a major role in the process leading to iron overload-related diseases. The long-term subcutaneous administration of Deferoxamine (DFO) is currently clinically-approved to improve patient symptoms and survival. However, non-specific toxicity and short circulation times of the drug in humans often leads to poor patient compliance. Herein, thioketal-based ROS-responsive polymeric nanogels containing DFO moieties (rNG-DFO) were designed to chelate iron and to degrade under oxidative stimuli into fragments <10 nm to enhance excretion of iron-bound chelates. Serum ferritin levels and iron concentrations in major organs of IO mice decreased following treatment with rNG-DFO, and fecal elimination of iron-bound chelates increased compared to free DFO. Furthermore, rNG-DFO decreased iron mediated oxidative stress levels in vitro and reduced iron-mediated inflammation in the liver of IO mice. The study confirms that ROS-responsive nanogels may serve as a promising alternative to DFO for safer and more efficient iron chelation therapy. [ABSTRACT FROM AUTHOR]

Introduction Trithiol chelates are suitable for labeling radioarsenic ( 72 As: 2.49 MeV β + , 26 h; 77 As: 0.683 MeV β − , 38.8 h) to form potential theranostic radiopharmaceuticals for PET imaging and therapy. To investigate the in vivo stability of trithiol chelates complexed with no carrier added (nca) radioarsenic, a bifunctional trithiol chelate was developed, and conjugated to bombesin(7–14)NH 2 as a model peptide. Methods A trithiol-BBN(7–14)NH 2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol-BBN(7–14)NH 2 conjugate was radiolabeled with 77 As, its in vitro stability assessed, and biodistribution studies were performed in CF-1 normal mice of free [ 77 As]arsenate and 77 As-trithiol- BBN(7–14)NH 2 . Results The trithiol-BBN(7–14)NH 2 conjugate, its precursors and its As-trithiol-BBN(7–14)NH 2 complex were fully characterized. Radiolabeling studies with nca 77 As resulted in over 90% radiochemical yield of 77 As-trithiol-BBN, which was stable for over 48 h. Biodistribution studies were performed with both free [ 77 As]arsenate and Sep-Pak® purified 77 As-trithiol-BBN(7–14)NH 2 . Compared to the fast renal clearance of free [ 77 As]arsenate, 77 As-trithiol-BBN(7–14)NH 2 demonstrated increased retention with clearance mainly through the hepatobiliary system, consistent with the lipophilicity of the 77 As-trithiol-BBN(714)NH 2 complex. Conclusion The combined in vitro stability of 77 As-trithiol-BBN(7–14)NH 2 and the biodistribution results demonstrate its high in vivo stability, making the trithiol a promising platform for developing radioarsenic-based theranostic radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

Introduction: Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients.Methods: Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols.Results: Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron.Conclusion: Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy. [ABSTRACT FROM AUTHOR]

In this investigation, the capacity of citric acid as copper scavenger is analyzed. For the copper scavenger capacity, the formation of the chelate complexes is studied using the Gibbs free energies. The chelates may be formed since the formation reactions are all exergonic. The free radical scavenger ability of chelate complexes is investigated using the single electron transfer mechanism with the Full Electron Donor-Acceptor Map (FEDAM). Different acid-base species of citric acid are also studied as OH inactivating ligands (OIL). The conclusion of this investigation is that metal chelation is viable for citric acid species and also that the formed chelates are efficient OH scavengers. Therefore, it is possible to conclude that citric acid is promising for copper chelation therapy (metal scavenger). These results may be useful for further investigations concerning citric acid and can give ideas about the benefits of citric acid as an additive in food. [ABSTRACT FROM AUTHOR]

Chelation therapy is the mainstream treatment for heavy metal poisoning. Apart from this, therapy using antioxidant/herbal extracts are the other strategies now commonly being tried for the treatment. We have previously reported individual beneficial efficacy of nanoparticle mediated administration of an antioxidant like ‘curcumin’ and an arsenic chelator ‘monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)’ for the treatment of arsenic toxicity compared to bulk drugs. The present paper investigates our hypothesis that a combination drug delivery therapy employing two nanosystems, a chelator and a strong antioxidant, may produce more pronounced therapeutic effects compared to individual effects in the treatment of arsenic toxicity. An in-vivo study was conducted wherein arsenic as sodium arsenite (100 ppm) was administered in drinking water for 5 months to Swiss albino mice. This was followed by a treatment protocol comprising of curcumin encapsulated chitosan nanoparticles ( nano-curcumin , 15 mg/kg, orally for 1 month) either alone or in combination with MiADMSA encapsulated polymeric nanoparticles ( nano-MiADMSA , 50 mg/kg for last 5 days) to evaluate the therapeutic potential of the combination treatment. Our results demonstrated that co-treatment with nano-curcumin and nano-MiADMSA provided beneficial effects in a synergistic way on the adverse changes in oxidative stress parameters and metal status induced by arsenic. [ABSTRACT FROM AUTHOR]

Dysfunctional accumulation of amyloid-β (Aβ) protein stimulated by Cu 2+ is considered as a key process in the pathogenesis of Alzheimer's disease (AD). Thus, bifunctional substances capable of chelating Cu 2+ and inhibiting Aβ aggregation are promising therapeutic agents against AD. Herein, a novel bifunctional decapeptide RTHLVFFARK-NH 2 (RK10) was developed by integrating a metal chelating tripeptide (RTH) and an Aβ aggregation inhibitor Ac-LVFFARK-NH 2 (LK7). The high selectivity of RK10 for Cu 2+ over other biologically relevant metal ions was demonstrated by isothermal titration calorimetry. RK10 bound Cu 2+ with a dissociation constant of 0.02 μM. This enabled RK10 to sequester Cu 2+ from Aβ 40 -Cu 2+ species and to arrest the production of reactive oxygen species (ROS) catalyzed by Cu 2+ or Aβ 40 -Cu 2+ species. Extensive physical, biophysical and biological studies indicate that RK10 targeted free and Cu 2+ -bound Aβ 40 species, suppressed Aβ 40 aggregation, and diminished the cytotoxicity induced by Aβ 40 and Cu 2+ -mediated Aβ 40 in cultured SH-SY5Y cells. Taken together, the results proved the excellent selective roles of RK10 in inhibiting Cu 2+ -mediated Aβ 40 aggregation and eliminating ROS generation catalyzed by Cu 2+ /Aβ 40 -Cu 2+ species. Thus, this work provided new insight into the design and development of potent bifunctional inhibitors against Aβ aggregation and cytotoxicity. [ABSTRACT FROM AUTHOR]

The extraction of Periploca polysaccharides (PAPS) was optimized using the response surface methodology. The influence of solvent, liquid-solid ratio and extraction time on polysaccharide yield was evaluated using a full factorial design (2 3 ). Also, PAPS extract did not induce a cytotoxic effect on HepG2 cells within the range of tested concentrations (0–250 μg mL −1 ). Herein, the pre-treatment with PAPS extract (100 μg mL −1 ) reduced cell mortality. Furthermore, the in vivo antioxidant activity of PAPS extract was investigated in rats. The oral administration of 250 mg kg −1 body weight of PAPS extract administered above a period of 10 weeks to cadmium chloride (CdCl 2 ) induced toxicity in male Wistar rats, markedly decreased the content of MDA and protein damage in liver tissue, and enhanced liver function parameters (ALAT, ASAT and bilirubin), as well as the activities of hepatic antioxidant status (SOD, CAT, GPx and GSH). Finally, the examination of liver histopathology confirmed that PAPS ameliorate the alteration of liver tissue caused by exposition to cadmium. [ABSTRACT FROM AUTHOR]

Patients with hemochromatosis require regular surveillance of liver and cardiac iron concentration with liver and cardiac MRI. However, cardiac MRI includes a part of the liver in the field of view. The purpose of this retrospective and prospective study is to determine if liver T2* measured on cardiac MRI may be used as a surrogate for T2* obtained on standard liver MRI. Liver iron concentrations were measured on cardiac and liver MRI in 21 patients. Although statistically significant, the difference may be clinically insignificant as the same patients merited chelation therapy when relying on either the cardiac or liver MRI. [ABSTRACT FROM AUTHOR]

Background Analyses suggest MDS patients with higher serum ferritin levels (SF) have inferior overall survival (OS), in one study across MDS subtypes. Multiple analyses suggest those with high SF receiving iron chelation therapy (ICT) have superior OS, but which MDS subtypes benefit from ICT remains undefined. Methods We performed survival analyses of MDS subtypes by receipt of ICT. Results 182 MDS were lower IPSS risk and received red blood cell (RBC) transfusions; 63 received ICT. For the entire cohort, receiving ICT independently predicted superior OS in a multivariate analysis (hazard ratio for death 0.3, p = 0.01). Features differing for ICT and non-ICT patients, respectively, were: age; IPSS risk group; number of RBC units transfused; and SF, p ≤ 0.03 for all. At a median follow up of 76.5 and 28.4 months, 65.1% and 63.0% were alive. Median OS (months) for ICT and non-ICT patients was: RA, 140.9 and 36.3, p = 0.0008; RARS/RARS-t, 133.4 and 73.3, p = 0.02. For RCMD/RCMD-RS, p = NS, however, 3 (20%) had significant erythroid improvement with ICT; other subtypes had small numbers. Discussion In this retrospective analysis, RA and RARS/RARS-t patients receiving ICT had superior OS to non-ICT patients. These findings should be verified and other MDS subtypes examined in larger prospective analyses. [ABSTRACT FROM AUTHOR]

Aims Chelation therapy and antioxidant supplements have been demonstrated to be useful in ameliorating aluminum (Al) induced neurotoxicity. Oleracein E (OE) is a phenolic antioxidant alkaloid which possesses a rare tetrahydroisoquinoline/pyrrolidone tricyclic skeleton and a catechol moiety. The aim of this study was to investigate whether OE can chelate with Al and alleviate AlCl 3 -induced oxidative stress and neurotoxicity. Main methods Kunming mice were administered AlCl 3 (40 mg/kg/d, i.p., 28 days), with co-administration of OE (3 mg/kg/d, 15 mg/kg/d, i.g.) and the positive control piracetam (PA, 400 mg/kg/d, i.g.). The Al contents in the brain and plasma were determined using ICP-MS. Al chelating ability of OE was assayed using UV spectroscopy. MDA, GSH, SOD or CAT, in the brain or plasma were determined. HE staining was used to examine hippocampal morphology alterations. IHC staining was employed to measure the expression of apoptotic-related proteins Bax, Bcl-2 and Caspase-3. Key findings AlCl 3 remarkably increased the brain and plasma Al contents, increased lipid peroxidation and induced hippocampal neuronal damage. OE chelated with Al to form a stable complex. An increase in brain Al content by OE (15 mg/kg) likely occurred through chelating with Al, which reduced the toxicity of free Al ion in the brain. OE significantly decreased MDA by regulating some antioxidant biomarkers. Furthermore, OE significantly ameliorated the protein expression changes in some apoptotic indices induced by AlCl 3 . Significance The phenolic alkaloid OE, as an antioxidant, Al chelator and apoptosis inhibitor, alleviates oxidative stress and neurotoxicity induced by AlCl 3 . [ABSTRACT FROM AUTHOR]

A number of new mono- and dihydroxypyridinethione ligands have been synthesized via reaction of dimethylamine and amino acid esters with the active amide obtained from the reaction of 1-hydroxy-2-pyridinethione-4-carboxylic acid ( 1 ) and 1,1′-carbonyldiimidazole in DMF. Moreover, the lead complexes of these new ligands were also prepared. Structures of the newly synthesized compounds have been confirmed by different spectroscopic methods such as IR, 1 H NMR, and 13 C NMR, and by elemental analysis. The effect of these synthesized ligands on the excretion of lead, iron, and zinc, and their distribution in kidneys, liver, and bones in acutely intoxicated rats was investigated and results, for lead, were compared with those of the known drug meso -2,3-dimercaptosuccinic acid (DMSA). Results obtained revealed that compound 5 exhibits remarkable ability in total fecal and urinary excretion of lead and was superior to DMSA. In addition, results show that the concentration of lead in soft tissues and bones was lower in rats treated with HTPL than those treated with DMSA. Furthermore, the concentration of lead in liver tissues obtained from sub-chronic lead-intoxicated rats treated with HTPL was lower than those treated with DMSA and calcium disodium ethylenediaminetetraacetic acid (CaNa 2 EDTA). [ABSTRACT FROM AUTHOR]

Gastrointestinal tract perforations are relatively rare in children. Patients who receive repeated blood transfusions are susceptible to iron overload with its own associated complications. To obviate these complications, iron chelation therapy with deferasirox is the treatment of choice. One of the rare complications of chronic treatment with deferasirox is gastrointestinal perforations. The aim of this report is to outline aspects of diagnosis, management, and the role of minimal invasive surgery in the management of this rare complication. This report describes a case of duodenal perforation in a 5-year-old patient with beta-thalassemia receiving multiple blood transfusions and on chronic chelation with deferasirox. She presented to the emergency department with vomiting and diarrhea of 5 days duration and diagnosed to have acute viral gastroenteritis. She was admitted to the pediatric medical ward and later on the same day she developed severe abdominal pain, mostly in the epigastric region. On physical examination, she was initially afebrile but later developed fever (38.9 °C). She was also tachycardic (a heart rate of 130 beats/min), and tachypneic (a breathing rate of 24–28 breaths per minute). Her blood pressure was 115/76 mmHg. Her abdominal examination revealed generalized abdominal tenderness with guarding and mildly reduced bowel sounds. An erect abdominal x-ray revealed free intraabdominal air which was confirmed by an abdominal CT scan. The diagnosis of gastrointestinal perforation was made, and the patient was prepared for an emergent diagnostic laparoscopy which revealed a duodenal perforation in the anterior aspect of the first part of the duodenum. Primary repair of the perforation was done, followed by reinforcement with a Graham patch and peritoneal lavage. Postoperatively she did well and was discharged home on the 8th postoperative day. Deferasirox induced duodenal perforation is very rare. Duodenal perforation should be suspected in patients with severe gastrointestinal symptoms and abdominal tenderness while on Deferasirox, especially at high doses (30+ mg/kg). Awareness of this rare complication is important to avoid delay in diagnosis and treatment with its known sequalae. Once suspected the diagnosis can be confirmed and managed laparoscopically. [ABSTRACT FROM AUTHOR]

Drug-induced nephrolithiasis can arise from insoluble components within medications or crystallization of metabolites due to changes in metabolism and urinary pH. The connection between drugs utilized for iron chelation therapy (ICT) and nephrolithiasis is not well understood. In this report, we describe two pediatric patients diagnosed with nephrolithiasis while undergoing treatment with the chelating agents deferasirox, deferiprone, and deferoxamine for iron overload secondary to repeat blood transfusion. [ABSTRACT FROM AUTHOR]

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. • LiHOPO is more effective than DTPA in limiting systemic plutonium deposits. • Early inhalation of LiHOPO is the best strategy to limit lung retention of plutonium. • The superiority of 3,4,3-Li(1,2-HOPO) over DTPA decreases when treatment is delayed. • Orally administered 3,4,3-Li(1,2-HOPO) fails to mobilize pulmonary plutonium. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a group of clonally-acquired blood disorders characterized by ineffective hematopoiesis leading to cytopenias. Red blood cell transfusions are an important component of supportive care in patients with MDS. Prolonged exposure to transfusions can lead to iron overload, which results in iron-induced toxicity caused by the production of reactive oxygen species (ROS). ROS accumulation has detrimental effects also on hematopoietic stem cells and may contribute to MDS progression. The observation that iron chelation improves hematologic parameters and reduces transfusion dependence further indicates that iron overload impairs hematopoiesis. Over the past decade, the mechanisms regulating iron homeostasis and the complex interplay between iron overload and toxicity, ineffective hematopoiesis, and transformation to leukemia have become clearer. In this narrative review, we provide an overview of recent findings pertaining to iron overload in patients with MDS and its effects on hematopoiesis. We also briefly discuss the position of chelation therapy in the context of the new developments. [ABSTRACT FROM AUTHOR]

The CaNa 2 EDTA chelation therapy is often practiced with antioxidant supplementation. Dry olive leaf extract (DOLE) is natural product with antioxidant and DNA protective properties. The effects of DOLE on the levels of DNA damage were investigated ex vivo in peripheral blood lymphocytes (PBLs) of 19 workers occupationally exposed to lead (Pb), before and after CaNa 2 EDTA chelation therapy. DOLE demonstrated pronounced radical scavenging activity in concentrations ≥1 mg/mL, and showed no genotoxicity per se , in concentrations 0.125–1 mg/mL. The level of DNA damage in PBLs of workers before chelation therapy was elevated (24.21 ± 14.26) compared to controls (6.0 ± 3.37). The incubation of PBLs before chelation therapy with selected concentration of DOLE lead to a severe increase of DNA damage (64.03 ± 20.96), exhibiting prooxidant rather than antioxidant effect. After the five-day CaNa 2 EDTA chelation regimen, DNA damage in PBLs of workers decreased (8.26 ± 4.62) significantly compared to baseline. Treatment of PBLs with DOLE after chelation, again produced high level of damage (41.82 ± 23.17) and the acute prooxidant effects of DOLE remained, but, DNA damage was less severe than before chelation. The DOLE exhibits prooxidant effect in presence of Pb in lymphocytes of exposed workers, and its effect is less pronounced following the removal of Pb after standard chelation therapy. [ABSTRACT FROM AUTHOR]

Leishmaniasis is an infection caused by protozoa of the genus Leishmania and transmitted by sandflies. Current treatments are expensive and time-consuming, involving Sb(V)-based compounds, lipossomal amphotericin B and miltefosine. Recent studies suggest that inhibition of trypanothione reductase (TR) could be a specific target in the development of new drugs because it is essential and exclusive to trypanosomatids. This work presents the synthesis and characterization of new iminodibenzyl derivatives ( dado ) with ethylenediamine ( ea ), ethanolamine ( en ) and diethylenetriamine ( dien ) and their copper(II) complexes. Computational methods indicated that the complexes were highly lipophilic. Pro-oxidant activity assays by oxidation of the dihydrorhodamine (DHR) fluorimetric probe showed that [Cu( dado-ea )] 2 + has the highest rate of oxidation, independent of H 2 O 2 concentration. The toxicity to L. amazonensis promastigotes and RAW 264,7 macrophages was assessed, showing that dado-en was the most active new compound. Complexation to copper did not have an appreciable effect on the toxicity of the compounds. [ABSTRACT FROM AUTHOR]