LitCovid-sentences  

PMC:7408073 / 61653-70862 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T294 0-4 Sentence denotes 5.3.
T295 5-53 Sentence denotes Safety and Efficacy Concerns of Chelating Agents
T296 54-271 Sentence denotes Based on ACE2 mechanism of action, there are alternative ways to inhibit ACE2 (and ACE), for example concentration of cation/anion might also targets of intervention to inhibit the zinc metalloprotease ACE2 (and ACE).
T297 272-369 Sentence denotes In this regard, EDTA, a cation chelator, has been shown to be able to inhibit ACE2 activity [79].
T298 370-664 Sentence denotes Of interest, EDTA binds with 106- and 102-fold higher affinity to Zn2+ than to Ca2+ and Fe2+, respectively [123], and in plasma, free Ca2+ concentration (1.05–1.30 mmol/L) is “only” about 103-fold higher than free Zn2+ (0.1–2.0 µmol/L), while majority of iron in plasma is bound to transferrin.
T299 665-777 Sentence denotes As a consequence, the iron concentration in plasma of healthy subjects is very low on the order of 10−18M [112].
T300 778-1085 Sentence denotes Among the essential metal ions present in the organisms, the specific affinity of EDTA for systemic Zn2+ in physiologic conditions is highlighted by the evidence that prolonged treatment with CaNa2EDTA results in specific zinc depletion that is believed to mediate the teratogenic effects of the drug [123].
T301 1086-1415 Sentence denotes As already mentioned, zinc is an important mediator/messenger involved in several cellular activities and excess of free zinc has been shown to be toxic (see also Box 4); however, zinc deficiency has also detrimental effects on growth, neuronal development, and immunity, and in severe cases its consequences can be deadly [102].
T302 1416-1608 Sentence denotes For these reasons, treatments with CaNa2EDTA require a careful monitoring of the patient for the therapeutic effects as well as possible complications, so as to titrate the appropriate dosage.
T303 1609-1714 Sentence denotes CaNa2EDTA was approved by FDA in chelation therapy for lowering blood lead levels a long time ago (1953).
T304 1715-1848 Sentence denotes Then, different (commercially available) iron chelating agents, expected to work in chelating zinc ion as well, were approved by FDA.
T305 1849-1982 Sentence denotes Chelation therapy comprises intravenous or oral administration of chelating agents that remove metal ions such as zinc from the body.
T306 1983-2080 Sentence denotes Cells synthesising high amounts of ACE or ACE2 needs of high amounts of bioavailable (free) zinc.
T307 2081-2223 Sentence denotes Therefore, it is conceivable that plasma levels of free zinc may influence not only ACE and ACE2 activities but also their cellular synthesis.
T308 2224-2355 Sentence denotes Indeed, both ACE and ACE2 synthesis might be particularly sensitive to reduction of free zinc levels in case of their upregulation.
T309 2356-2548 Sentence denotes In addition, metal chelating agents, by limiting the availability of free zinc to cells, might have effects on both ACE2/ACE synthesis and conformation (when assembled on the plasma membrane).
T310 2549-2846 Sentence denotes Indeed, the closed conformer of ACE2 homodimer that is the preferential conformation for virus binding [28], needs the presence of both zinc and substrate/inhibitor in the catalytic site [90], suggesting that zinc chelation (differently from MLN-4760) might also inhibit ACE2-mediated viral entry.
T311 2847-3093 Sentence denotes Intriguingly, chloroquine has been shown to specifically enhance zinc uptake and its accumulation/sequestration in the lysosomes [124], raising the possibility that it might work on COVID-19 patients by reducing zinc recycling and zinc functions.
T312 3094-3303 Sentence denotes As already mentioned, free Zn2+ promotes clot stability by binding to fibrinogen (see Box 4 and [91]) and chloroquine has been shown to have an anti-thrombotic activity by inhibiting platelet activation [125].
T313 3304-3684 Sentence denotes To this regard, upon platelet activation the release of Zn2+ store from their secretory granules has been shown to participate to the pro-coagulant activity in platelet-dependent fibrin formation [126], suggesting that an elevated free Zn2+ concentration might occur and contribute to thrombotic predisposition in COVID-19 patients, a phenomenon possibly countered by chloroquine.
T314 3685-3926 Sentence denotes For all of the above reasons, cation chelating agents, administered alone or in combination with other therapies, might be effective to counter COVID-19 infection, in particular when, induced by hypoxia, both arms of the RAS are upregulated.
T315 3927-3974 Sentence denotes A scenario that would deserve an investigation.
T316 3975-4337 Sentence denotes However, some formulations of metal chelating agents carry a black box warning because they may cause serious and fatal renal toxicity and failure, hepatic toxicity and failure, gastrointestinal haemorrhage, arrhythmias, tetany, hypocalcaemia, hypotension, convulsions, respiratory arrest, and agranulocytosis that can lead to serious infections and death [123].
T317 4338-4505 Sentence denotes For the sake of completeness, besides renal toxicity linked to the route of drug excretion, EDTA has been shown to be effective in chronic renal artery diseases [123].
T318 4506-4596 Sentence denotes Finally, for its teratogenic effects, the drug is also contraindicated in pregnancy [123].
T319 4597-4819 Sentence denotes As a result, treatments with metal chelating agents require close patient monitoring, including laboratory tests of renal and hepatic function, and absolute neutrophil count should be monitored before and during treatment.
T320 4820-4891 Sentence denotes Alternative ways of RAS pathway inhibition are also described in Box 5.
T321 4892-4942 Sentence denotes Box 5 Alternative ways of RAS pathway inhibition.
T322 4943-5050 Sentence denotes Of interest, a small cationic inhibitor of ACE2 (but not of ACE) has been detected in plasma samples [116].
T323 5051-5305 Sentence denotes The endogenous inhibitor might play a compensatory fine-control (within a threshold limit) for normal fluctuation of ACE2 protein in plasma and it has been hypothesized to be a basic AA or a small basic peptide able to compete with ACE2 substrates [116].
T324 5306-5413 Sentence denotes I have already mentioned that AA can chelate zinc forming labile zinc complexes of amino acids (see Box 4).
T325 5414-5599 Sentence denotes It is therefore possible that a basic AA or a small basic peptide capable to specifically accommodate into the catalytic site of ACE2, but into that of ACE, could inhibit ACE2 activity.
T326 5600-5764 Sentence denotes Indeed, despite the similarities, ACE and ACE2 possess different substrate specificity that depends on the smaller ACE2 binding pocket compared to that of ACE [90].
T327 5765-5941 Sentence denotes This specific aspect might determine the specificity for a specific basic amino acid or molecule that is able to accommodate into the catalytic pocket of ACE2 and bind to zinc.
T328 5942-6102 Sentence denotes Among the possible endogenous ACE2 inhibitors, agmatine, decarboxylated arginine, has a chemical structure that resembles that of an ACE2 inhibitor, NAAE [127].
T329 6103-6279 Sentence denotes NAAE is a small molecule that had demonstrated an anti-SARS-CoV activity, by acting on both ACE2 catalytic activity and ACE2 binding domain for spike protein of SARS-CoV [127].
T330 6280-6328 Sentence denotes Unfortunately, NAAE has never been used in vivo.
T331 6329-6619 Sentence denotes Indeed, NAAE is a weak ACE2 inhibitor, it is in fact more than a thousand-fold less potent than MLN-4760; however, if agmatine will be proven to have ACE2 inhibitory activity, it might be helpful to prevent the trigger of the positive feedback loops in the first mild phases of the disease.
T332 6620-6742 Sentence denotes Indeed, it has an important role in down-regulating NO synthesis reducing NO overproduction by different mechanisms [128].
T333 6743-6904 Sentence denotes Of note, NOS pathway has been shown to be upregulated by both Ang (1–7)/MasR and Ang (1–9)/AT2 receptor pathways that are downstream ACE2 activity [38,39,41,43].
T334 6905-7096 Sentence denotes Moreover, agmatine has a regulated plasma concentration in the range of 20-80 ng/mL and the use of dietary agmatine has been shown to be safe and effective in reducing neuropathic pain [129].
T335 7097-7172 Sentence denotes Moreover, agmatine sulfate is regularly taken as a bodybuilding supplement.
T336 7173-7383 Sentence denotes Among natural metal-chelating agents, phytates and folic acid are two chelating agents from vegetables that might reduce zinc intestinal absorption and possibly its systemic concentration (see Box 4 and [111]).
T337 7384-7536 Sentence denotes Similarly, nicotianamine that is extracted from plants (soybean) is a low-molecular weight metal chelator with high affinity for divalent metal cations.
T338 7537-7640 Sentence denotes Nicotianamine has been shown to inhibit the activity of both zinc metalloproteases, ACE2 and ACE [130].
T339 7641-7722 Sentence denotes In addition, zeolites might also be effective in reducing free zinc availability.
T340 7723-7851 Sentence denotes Zeolites are a group of aluminosilicate minerals with crystalline microporous structure that are originated from volcanic rocks.
T341 7852-8023 Sentence denotes Their molecular structure generates cavities that allow high absorbency capacity for a wide range of charged elements such as water, heavy metals, cations and many toxins.
T342 8024-8124 Sentence denotes Clinoptilolite is one of the zeolites that has been widely studied in veterinary and human medicine.
T343 8125-8311 Sentence denotes The increased usage of clinoptilolite-based products in vivo has stimulated several investigations on its safety and its positive medical effects related to human health (see [131,132]).
T344 8312-8449 Sentence denotes Finally, soluble and catalytically inactive forms of ACE2 have been shown to be potent inhibitors of SARS-CoV infection products [19,21].
T345 8450-8550 Sentence denotes An approach that could be pursued (in combination with other therapies) to inhibit SARS-CoV-2 entry.
T346 8551-8767 Sentence denotes Indeed, soluble forms of ACE2 are expected to protect from viral infection and a similar strategy using a recombinant form of human ACE2 has been proposed not only in COVID-19, but also in ARDS and PAH [108,133,134].
T347 8768-8898 Sentence denotes However, it is possible that catalytic active form of ACE2 might favour adverse effects in these specific pathological conditions.
T348 8899-9209 Sentence denotes To this regard, a clinical trial using recombinant hACE2 protein has been recently started (ClinicalTrials.gov number, NCT04287686) in COVID-19 patients and pilot clinical trials of rhACE2 in ARDS and PAH started in 2017 and 2018, respectively [108,134]; unfortunately, no conclusive results are available yet.