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BMB Reports Feb 2023Particulate matter is an air pollutant composed of various components, and has adverse effects on the human body. Particulate matter is known to induce cell death by...
Particulate matter is an air pollutant composed of various components, and has adverse effects on the human body. Particulate matter is known to induce cell death by generating an imbalance in the antioxidant system; however, the underlying mechanism has not been elucidated. In the present study, we demonstrated the cytotoxic effects of the size and composition of particulate matter on small intestine cells. We found that particulate matter 2.5 (PM2.5) with extraction ion (EI) components (PM2.5 EI), is more cytotoxic than PM containing only polycyclic aromatic hydrocarbons (PAHs). Additionally, PM-induced cell death is characteristic of ferroptosis, and includes iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) generation. Furthermore, ferroptosis inhibitor as liproxstatin-1 and iron-chelator as deferiprone attenuated cell mortality, lipid peroxidation, iron accumulation, and ROS production after PM2.5 EI treatment in human small intestinal cells. These results suggest that PM2.5 EI may increase ferroptotic-cell death by iron accumulation and ROS generation, and offer a potential therapeutic clue for inflammatory bowel diseases in human small intestinal cells. [BMB Reports 2023; 56(2): 96-101].
Topics: Humans; Particulate Matter; Iron; Ferroptosis; Antioxidants; Reactive Oxygen Species; Antineoplastic Agents
PubMed: 36476270
DOI: 10.5483/BMBRep.2022-0139 -
Bioinorganic Chemistry and Applications 2022Free heme in plasma acts as a prooxidant; thus, it is bound to hemopexin and eliminated by the liver. High iron content in the liver can support growth and cause...
Free heme in plasma acts as a prooxidant; thus, it is bound to hemopexin and eliminated by the liver. High iron content in the liver can support growth and cause oxidative liver injury. Inversely, the withholding of excessive iron can inhibit this growth and protect the liver against malaria infection. This study examined the effects of a deferiprone-resveratrol (DFP-RVT) hybrid on malaria parasites and its relevant hepatoprotective properties. Mice were infected with , gavage DFP-RVT, deferiprone (DFP), and pyrimethamine (PYR) for 8 consecutive days. Blood and liver parameters were then evaluated. The presence of blood-stage parasites was determined using the microscopic Giemsa staining method. Subsequently, plasma liver enzymes, heme, and concentrations of thiobarbituric acid-reactive substances (TBARS) were determined. The liver tissue was examined pathologically and heme and TBARS concentrations were then quantified. The results indicate that the suppression potency against growth occurred as follows: PYR > DFP-RVT hybrid > DFP. Importantly, DFP-RVT significantly improved RBC size, restored alanine aminotransferase and alkaline activities, and increased heme and TBARS concentrations. The compound also reduced the liver weight index, heme, and TBARS concentrations significantly when compared to mice that were untreated. Our findings support the contention that the hepatoprotective effect of DFP-RVT is associated with parasite burden, iron depletion, and lipid peroxidation in the host.
PubMed: 36466999
DOI: 10.1155/2022/3869337 -
International Journal of Molecular... Nov 2022There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the... (Review)
Review
There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron-chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients.
Topics: Humans; Iron; Neoplasms; Iron Chelating Agents; Metabolic Networks and Pathways; Hypoxia
PubMed: 36430469
DOI: 10.3390/ijms232213990 -
Biomolecules Nov 2022The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead... (Review)
Review
The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to the central nervous system (CNS). Strategies for mobilization of metals such as manganese (Mn), iron (Fe), and Cu from brain deposits may require the combined use of two agents: one water-soluble agent to remove circulating metal into urine, in addition to an adjuvant shuttler to facilitate the brain-to-blood mobilization. The present review discusses the chemical basis of metal chelation and the ligand exchange of metal ions. To obtain increased excretion of Mn, Cu, and Fe, early experiences showed promising results for CaEDTA, PSH, and DFOA, respectively. Recent experiments have indicated that p-amino salicylate (PAS) plus CaEDTA may be a useful combination to remove Mn from binding sites in CNS, while the deferasirox-DFOA and the tetrathiomolybdate-DMSA combinations may be preferable to promote mobilization of Fe and Cu, respectively, from the CNS. Further research is requested to explore benefits of chelator combinations.
Topics: Humans; Manganese; Copper; Iron; Chelating Agents; Ions; Metals; Neurotoxicity Syndromes; Succimer; Water
PubMed: 36421727
DOI: 10.3390/biom12111713 -
Scientific Reports Nov 2022Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal demyelination in the brain and spinal cord. Studies showed that iron released during the...
Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal demyelination in the brain and spinal cord. Studies showed that iron released during the course of myelin breakdown exacerbates tissue damage, which is in agreement with the features of iron-dependent cell death, ferroptosis. Here, we aimed to investigate the possible contribution of ferroptosis in the demyelinated optic nerve, and to explore the effectiveness of ferroptosis inhibitor, deferiprone (DFP), on the extent of demyelination, inflammation and axonal damage. For this purpose, focal demyelination was induced by injection of lysolecithin (LPC), into the optic nerve of male C57BL/6J mice. Afterward, optic nerves were harvested at different time points from as early as 6 h up to 7 days post-LPC injection. Next, to evaluate the effectiveness of DFP two groups of animals received daily intraperitoneal injection of DFP for 3 or 7 continuous days. Vehicle groups received saline. Iron deposition was observed at different time points post-LPC injection from 6 h to 7 days post injection. Examining ferroptosis markers showed a significant reduction in glutathione content along with increased level of malondialdehyde and upregulated ferroptosis marker genes at early time points after injection. Besides, DFP treatment during the inflammatory phase of the model resulted in decreased microgliosis and inflammation. Reduced demyelination, microgliosis and astrogliosis was shown in mice that received DFP for 7 days. Moreover, DFP protected against axonal damage and retinal ganglion cells loss. Our results suggest the possible contribution of ferroptosis pathway in the process of demyelination. The therapeutic strategies targeting iron deposition, e.g. DFP treatment might thus represent a promising therapeutic target for patients with MS.
Topics: Animals; Male; Mice; Deferiprone; Ferroptosis; Inflammation; Iron; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Neuroprotection; Optic Nerve
PubMed: 36385152
DOI: 10.1038/s41598-022-24152-2 -
Neurobiology of Disease Dec 2022Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra... (Review)
Review
Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders.
Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors. This review analyzes the involvement of each of these pathways in dopamine neuron physiology and function, and discusses how disrupted interplay of dopamine, alpha-synuclein, and iron pathways may synergize to promote pathology and drive the unique vulnerability to disease states. We suggest that elucidating the interactions of dopamine with iron and alpha-synuclein, and the role of dopamine metabolism in driving pathogenic phenotypes will be critical for developing therapeutics to prevent progression in diseases that show degeneration of nigral dopamine neurons such as Parkinson's disease and the rare family of disorders known as Neurodegeneration with Brain Iron Accumulation.
Topics: Humans; alpha-Synuclein; Dopaminergic Neurons; Parkinson Disease; Dopamine; Iron; Substantia Nigra; Brain
PubMed: 36351559
DOI: 10.1016/j.nbd.2022.105920 -
RSC Medicinal Chemistry Oct 2022The versatile structural motif of hydroxypyrone is found in natural products and can be easily converted into hydroxypyridone and hydroxythiopyridone analogues. The... (Review)
Review
The versatile structural motif of hydroxypyrone is found in natural products and can be easily converted into hydroxypyridone and hydroxythiopyridone analogues. The favourable toxicity profile and ease of functionalization to access a vast library of compounds make them an ideal structural scaffold for drug design and discovery. This versatile scaffold possesses excellent metal chelating properties that can be exploited for chelation therapy in clinics. Deferiprone [1,2-dimethyl-3-hydroxy-4(1)-one] was the first orally active chelator to treat iron overload in thalassemia major. Metal complexes of hydroxy-(thio)pyr(id)ones have been investigated as magnetic resonance imaging contrast agents, and anticancer and antidiabetic agents. In recent years, this compound class has demonstrated potential in discovering and developing metalloenzyme inhibitors. This review article summarizes recent literature on hydroxy-(thio)pyr(id)ones as inhibitors for metalloenzymes such as histone deacetylases, tyrosinase and metallo-β-lactamase. Different approaches to the design of hydroxy-(thio)pyr(id)ones and their biological properties against selected metalloenzymes are discussed.
PubMed: 36325396
DOI: 10.1039/d2md00175f -
Acta Pharmacologica Sinica May 2023Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in...
Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg·d, ip) or DFP (100 mg·kg·d, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (Pparα, Scd1, Fasn, Hmgcr and Cpt1a), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.
Topics: Animals; Mice; Ferroptosis; Insulin Resistance; Lipids; Non-alcoholic Fatty Liver Disease
PubMed: 36323829
DOI: 10.1038/s41401-022-01010-5 -
Journal of Physiology and Pharmacology... Jun 2022Acute cardiac pathologies represent one of the leading causes of death, while iron metabolism is recognized to be implicated in reactive oxygen species production, lipid...
Acute cardiac pathologies represent one of the leading causes of death, while iron metabolism is recognized to be implicated in reactive oxygen species production, lipid peroxidation, and inflammation. The aim of the present study was to assess iron chelation effects in isoproterenol (ISO) induced acute cardiac stress. We divided male Wistar rats into preventive and secondary treatment groups, with the active arm consisting in deferiprone (DFP), a lipid permeable chelator. Mortality of ISO was 10-18.18% in both preventive and secondary groups. We analyzed serum and myocardial tissue parameters of inflammation, iron dynamics, and lipid peroxidation, accompanied by ultramicroscopy, histological, and ultrasound-derived parameters of left ventricular function. Results reveal that ISO-mediated lipid peroxidation and inflammation are alleviated by administration of DFP, with negligible effect on systemic ferroregulation dynamics and global ventricular function (as assessed by ultrasound). DFP administration after cardiovascular stress is associated with a decrease in lipid peroxidation and inflammation, without an improvement in gross left ventricular parameters.
Topics: Animals; Male; Rats; Inflammation; Iron; Iron Chelating Agents; Isoproterenol; Lipid Peroxidation; Myocardium; Oxidative Stress; Rats, Wistar
PubMed: 36302532
DOI: 10.26402/jpp.2022.3.04 -
Frontiers in Bioscience (Elite Edition) Jul 2022Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of... (Review)
Review
Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.
Topics: Benzoates; Deferasirox; Deferiprone; Deferoxamine; Humans; Iron; Iron Chelating Agents; Pyridones; Risk Assessment; Thalassemia; Triazoles
PubMed: 36137990
DOI: 10.31083/j.fbe1403018