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1.
MnDPDP: Contrast Agent for Imaging and Protection of Viable Tissue.
Jynge, P, Skjold, AM, Falkmer, U, Andersson, RGG, Seland, JG, Bruvold, M, Blomlie, V, Eidsaunet, W, Karlsson, JOG
Contrast media & molecular imaging. 2020;:3262835
Abstract
The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan™, GE Healthcare) for Mn-ion-enhanced MRI (MEMRI), should be reappraised for clinical use but now as a diagnostic drug with cytoprotective properties. Approved for imaging of the liver and pancreas, MnDPDP enhances contrast also in other targets such as the heart, kidney, glandular tissue, and potentially retina and brain. Transmetallation releases paramagnetic Mn2+ for cellular uptake in competition with calcium (Ca2+), and intracellular (IC) macromolecular Mn2+ adducts lower myocardial T 1 to midway between native values and values obtained with gadolinium (Gd3+). What is essential is that T 1 mapping and, to a lesser degree, T 1 weighted imaging enable quantification of viability at a cellular or even molecular level. IC Mn2+ retention for hours provides delayed imaging as another advantage. Examples in humans include quantitative imaging of cardiomyocyte remodeling and of Ca2+ channel activity, capabilities beyond the scope of Gd3+ based or native MRI. In addition, MnDPDP and the metabolite Mn dipyridoxyl diethyl-diamine (MnPLED) act as catalytic antioxidants enabling prevention and treatment of oxidative stress caused by tissue injury and inflammation. Tested applications in humans include protection of normal cells during chemotherapy of cancer and, potentially, of ischemic tissues during reperfusion. Theragnostic use combining therapy with delayed imaging remains to be explored. This review updates MnDPDP and its clinical potential with emphasis on the working mode of an exquisite chelate in the diagnosis of heart disease and in the treatment of oxidative stress.
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2.
Manganese Exposure and Neurologic Outcomes in Adult Populations.
Martin, KV, Edmondson, D, Cecil, KM, Bezi, C, Vance, ML, McBride, D, Haynes, EN
Neurologic clinics. 2020;(4):913-936
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Abstract
A review of published articles examining the effects of manganese exposure to workers and community residents shows adverse neurologic outcomes. Innovative biomarkers, including those from neuroimaging, were incorporated into many of these studies to assess both manganese exposure and neurologic outcomes. A variety of health effects were evaluated, including cognitive and motor impairments. Studies of community participants residing near manganese point sources show variability in outcomes, reflecting the complexities of exposure measurement, individual absorption, and assessment of neurologic effects. The aging population provides insight into the impacts of chronic exposure in younger populations.
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3.
Manganese-induced neurodegenerative diseases and possible therapeutic approaches.
Martins, AC, Gubert, P, Villas Boas, GR, Meirelles Paes, M, Santamaría, A, Lee, E, Tinkov, AA, Bowman, AB, Aschner, M
Expert review of neurotherapeutics. 2020;(11):1109-1121
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INTRODUCTION Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion disease represent important public health concerns. Exposure to high levels of heavy metals such as manganese (Mn) may contribute to their development. AREAS COVERED In this critical review, we address the role of Mn in the etiology of neurodegenerative diseases and discuss emerging treatments of Mn overload, such as chelation therapy. In addition, we discuss natural and synthetic compounds under development as prospective therapeutics. Moreover, bioinformatic approaches to identify new potential targets and therapeutic substances to reverse the neurodegenerative diseases are discussed. EXPERT OPINION Here, the authors highlight the importance of better understanding the molecular mechanisms of toxicity associated with neurodegenerative diseases, and the role of Mn in these diseases. Additional emphasis should be directed to the discovery of new agents to treat Mn-induced diseases, since present day chelator therapies have limited bioavailability. Furthermore, the authors encourage the scientific community to develop research using libraries of compounds to screen those compounds that show efficacy in regulating brain Mn levels. In addition, bioinformatics may provide novel insight for pathways and clinical treatments associated with Mn-induced neurodegeneration, leading to a new direction in Mn toxicological research.
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4.
Implications of Manganese in Chronic Acquired Hepatocerebral Degeneration.
Rajoriya, N, Brahmania, M, J Feld, J
Annals of hepatology. 2019;(1):274-278
Abstract
Neurological symptoms can be one of the over-riding symptoms in patients with liver cirrhosis. Patients can present with subtle changes in mood or neurological function due to hepatic encephalopathy (HE), to more severe presentations including stupor and coma. While HE, in its severe form, can be clinically easy to diagnose, more subtle forms may be more difficult to recognize. Other neurological diseases may indeed be overlooked in the context of cirrhosis or confuse the physician regarding the diagnosis. Chronic acquired hepatocerebral degeneration (CAHD) is an uncommon problem occurring in patients with cirrhosis characterised by a Parkinsonian-like neurological presentation with damage to the brain secondary to manganese (Mn) deposition. Here we describe a case of a patient with a neurological presentation of liver disease with a review of the current CAHD literature. In conclusion, CAHD is a rare condition occurring in liver cirrhosis that should always be considered in patients with neurological manifestations of chronic liver disease.
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5.
Genetic Disorders of Manganese Metabolism.
Anagianni, S, Tuschl, K
Current neurology and neuroscience reports. 2019;(6):33
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PURPOSE OF REVIEW This article provides an overview of the pathogenesis, clinical presentation and treatment of inherited manganese transporter defects. RECENT FINDINGS Identification of a new group of manganese transportopathies has greatly advanced our understanding of how manganese homeostasis is regulated in vivo. While the manganese efflux transporter SLC30A10 and the uptake transporter SLC39A14 work synergistically to reduce the manganese load, SLC39A8 has an opposing function facilitating manganese uptake into the organism. Bi-allelic mutations in any of these transporter proteins disrupt the manganese equilibrium and lead to neurological disease: Hypermanganesaemia with dystonia 1 (SLC30A10 deficiency) and hypermanganesaemia with dystonia 2 (SLC39A14 deficiency) are characterised by manganese neurotoxicity while SLC39A8 mutations cause a congenital disorder of glycosylation type IIn due to Mn deficiency. Inherited manganese transporter defects are an important differential diagnosis of paediatric movement disorders. Manganese blood levels and MRI brain are diagnostic and allow early diagnosis to avoid treatment delay.
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A review of the implications and challenges of manganese removal from mine drainage.
Neculita, CM, Rosa, E
Chemosphere. 2019;:491-510
Abstract
Manganese (Mn) is the third most abundant transition metal in the Earth's crust. Decades of increasing worldwide mining activities have inevitably led to the release of large amounts of this metal into the environment. Mine drainage, either acidic or neutral, often contains high levels of Mn, which have potentially detrimental effects on ecosystems and receiving water bodies. This review provides a comprehensive assessment of the main implications and challenges of Mn treatment in mine drainage. With this aim, the beneficial and adverse effects of Mn on ecosystems and human health are presented first. A comparison of background and mine effluents Mn contents is also provided, further stressing the need for Mn removal from mine drainage. Several technical options to address Mn contamination in acid and neutral mine drainage, and the challenges associated with Mn removal, are subsequently discussed. Thus, this paper presents up-to-date knowledge on the available physicochemical and biological processes deemed operative in Mn removal during mine drainage treatment and their limitations considering the distinctive behavior of Mn. The discussion is further extended to passive treatment systems, which are the most commonly implemented systems for mine drainage treatment on abandoned or closed mine sites, and highlights both their design criteria and operation requirements, as well as the factors that influence Mn removal efficiency. Finally, new perspectives on future research and development needs are identified to address the challenges in Mn removal during mine drainage treatment.
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A case of dystonia with polycythemia and hypermanganesemia caused by SLC30A10 mutation: a treatable inborn error of manganese metabolism.
Tavasoli, A, Arjmandi Rafsanjani, K, Hemmati, S, Mojbafan, M, Zarei, E, Hosseini, S
BMC pediatrics. 2019;(1):229
Abstract
BACKGROUND Manganese is a critical trace element that not only has antioxidant properties, but also is essential for various metabolic pathways and neurotransmitters production. However, it can be toxic at high levels, particularly in the central nervous system. Manganese intoxication can be acquired, but an inherited form due to autosomal-recessive mutations in the SLC30A10 gene encoding a Mn transporter protein has also been reported recently. These mutations are associated with significant failure of manganese excretion and its storage in the liver, brain (especially basal ganglia), and other peripheral tissues, resulting in toxicity. CASE PRESENTATION A 10-year-old boy from consanguineous parents presented with a history of progressive truncal instability, gait difficulty, and frequent falls for 2 months. He had dystonia, rigidity, ataxia, dysarthria, bradykinesia and a plethoric skin. Investigations showed polycythemia, low serum iron and ferritin levels, and increased total iron binding capacity. A brain MRI revealed symmetric hyperintensities in the basal ganglia and dentate nucleuses on TI images that were suggestive of brain metal deposition together with clinical manifestations. Serum calcium and copper levels were normal, while the manganese level was significantly higher than normal values. There was no history of environmental overexposure to manganese. Genetic testing showed a homozygous missense mutation in SLC30A10 (c.C1006T, p.His336Tyr) and Sanger sequencing confirmed a homozygous state in the proband and a heterozygous state in the parents. Regular treatment with monthly infusions of disodium calcium edetate and oral iron compounds resulted in decreased serum manganese and hemoglobin levels to normal values, significant resolution of MRI lesions, and partial improvement of neurological symptoms during 6 months of follow-up. CONCLUSION The syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by SLC30A10 mutation is a treatable inherited metal deposition syndrome. The patient may only have pure neurological without hepatic manifestations. Although this is a rare and potentially fatal inborn error of metabolism, early diagnosis and continuous chelation therapy might improve the symptoms and prevent disease progression.
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Advances in the Mechanisms of Plant Tolerance to Manganese Toxicity.
Li, J, Jia, Y, Dong, R, Huang, R, Liu, P, Li, X, Wang, Z, Liu, G, Chen, Z
International journal of molecular sciences. 2019;(20)
Abstract
Manganese (Mn) is an essential element for plant growth due to its participation in a series of physiological and metabolic processes. Mn is also considered a heavy metal that causes phytotoxicity when present in excess, disrupting photosynthesis and enzyme activity in plants. Thus, Mn toxicity is a major constraint limiting plant growth and production, especially in acid soils. To cope with Mn toxicity, plants have evolved a wide range of adaptive strategies to improve their growth under this stress. Mn tolerance mechanisms include activation of the antioxidant system, regulation of Mn uptake and homeostasis, and compartmentalization of Mn into subcellular compartments (e.g., vacuoles, endoplasmic reticulum, Golgi apparatus, and cell walls). In this regard, numerous genes are involved in specific pathways controlling Mn detoxification. Here, we summarize the recent advances in the mechanisms of Mn toxicity tolerance in plants and highlight the roles of genes responsible for Mn uptake, translocation, and distribution, contributing to Mn detoxification. We hope this review will provide a comprehensive understanding of the adaptive strategies of plants to Mn toxicity through gene regulation, which will aid in breeding crop varieties with Mn tolerance via genetic improvement approaches, enhancing the yield and quality of crops.
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Importing Manganese into the Chloroplast: Many Membranes to Cross.
Krieger-Liszkay, A, Thomine, S
Molecular plant. 2018;(9):1109-1111
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Oxidation catalysis by iron and manganese porphyrins within enzyme-like cages.
Chino, M, Leone, L, Zambrano, G, Pirro, F, D'Alonzo, D, Firpo, V, Aref, D, Lista, L, Maglio, O, Nastri, F, et al
Biopolymers. 2018;(10):e23107
Abstract
Inspired by natural heme-proteins, scientists have attempted for decades to design efficient and selective metalloporphyrin-based oxidation catalysts. Starting from the pioneering work on small molecule mimics in the late 1970s, we have assisted to a tremendous progress in designing cages of different nature and complexity, able to accommodate metalloporphyrins. With the intent of tuning and controlling their reactivity, more and more sophisticated and diverse environments are continuously exploited. In this review, we will survey the current state of art in oxidation catalysis using iron- and manganese-porphyrins housed within designed or engineered protein cages. We will also examine the innovative metal-organic framework (MOF) systems, exploited to achieving an enzyme-like environment around the metalloporphyrin cofactor.