LitCovid-sentences  

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Id Subject Object Predicate Lexical cue
T177 0-2 Sentence denotes 5.
T178 3-88 Sentence denotes Mechanism of Action and Potential Risk of Using RAS Pathway Inhibitors Targeting ACE2
T179 90-94 Sentence denotes 5.1.
T180 95-124 Sentence denotes ACE2 (and ACE) Hyperactivity:
T181 125-155 Sentence denotes Is It a Matter of (Free) Zinc?
T182 156-251 Sentence denotes ACE2 and ACE are two zinc metalloprotease that function differently despite their similarities.
T183 252-442 Sentence denotes ACE2 is a monocarboxypeptidase (cleaves a C-terminal single amino acid from its substrate), whereas ACE is a dipeptidylpeptidase (releases a C-terminal dipeptide from its substrate) [86,87].
T184 443-749 Sentence denotes ACE2 has a substrate preference for hydrolysis between proline and a hydrophobic or basic C-terminal residue [79,86,87] and acts not only on the RAS and bradykinin peptides but also on the C-terminus of the apelin, casomorphin dynorphin peptides [79], possibly inhibiting Apelin-13 hypotensive action [44].
T185 750-866 Sentence denotes It is expressed in the heart, kidneys, liver, colon, small intestine, lung, brain and testes [39,44,45,46,76,77,87].
T186 867-1076 Sentence denotes Among the tissues expressing ACE2 there are cardiomyocytes, endothelium, alveolar type II cells, ciliated airway cells, vascular smooth muscle cells and testicular Leydig cells [14,39,44,45,46,76,77,87,88,89].
T187 1077-1373 Sentence denotes ACE2 is present on the apical surface of epithelial cells of renal tubules, lung alveoli and vascular endothelia, in these last cells the production of Ang (1–7) induces autocrine activation of MasR axis leading to NOS-mediated vasodilation and consequently hypotension [14,44,45,46,86,87,88,89].
T188 1374-1559 Sentence denotes ACE2, as well as ACE, is a zinc metalloprotease that can be inhibited by zinc chelating EDTA and activated by high concentrations of chloride or fluoride anions and zinc cation [79,90].
T189 1560-1624 Sentence denotes Indeed, both enzymes have chloride- and zinc-binding sites [90].
T190 1625-1749 Sentence denotes It is conceivable that these sites are responsible for the anion and zinc activation effect in both homologous enzymes [90].
T191 1750-2008 Sentence denotes However, the presence of chloride ions increases Ang I cleavage by ACE and ACE2 (increasing both Ang II and Ang (1–9)) and decreases Ang II cleavage by ACE2, suggesting that chloride induces specific ACE2 conformational changes in its active site (see [44]).
T192 2009-2179 Sentence denotes To this regard, in plasma samples of COVID–19 patients, chloride range is usually normal or slightly higher (99.6–107.0 mmol/L) than normal values (96.–106.0 mmol/L) [5].
T193 2180-2266 Sentence denotes Unfortunately, I was not able to find plasma zinc concentrations in COVID-19 patients.
T194 2267-2386 Sentence denotes Zinc is involved in several cellular activities and its systemic concentration is tightly regulated by several factors.
T195 2387-2987 Sentence denotes Of interest, the major transporter/reservoir of zinc in plasma is albumin [91], a protein that was detected at significantly low concentrations in SARS-CoV-2 as well as severe adult respiratory distress syndrome (ARDS, a COVID-19-like disease) (usually < 3.5 g/dL, normal range 3.5–5.4) and inflammatory bowel disease (IBD, a disease with increased ACE2 activity) [6,8,66,92] Since most of zinc in plasma is sequestered by albumin, the total amount of plasma zinc mostly depends on albumin concentration and even small changes in albumin’s capacity for zinc binding may have significant consequences.
T196 2988-3210 Sentence denotes To this regard, reduced concentrations of plasma albumin is believed to increase plasma levels of free zinc, while reducing the total plasma zinc concentrations [91], a condition that was observed in ARDS patients [93,94].
T197 3211-3353 Sentence denotes Indeed, albumin can potentially deplete free bioavailable forms of zinc; vice versa, hypoalbuminaemia may increase free zinc levels in plasma.
T198 3354-3489 Sentence denotes Therefore, some ARDS patients with low levels of both total zinc and albumin might have rather higher than lower free zinc levels [93].
T199 3490-3704 Sentence denotes The free zinc concentration, which describes the fraction of zinc that is loosely bound and easily exchangeable, represents the highly bioavailable (and toxic) part of plasma zinc but it is not clinically detected.
T200 3705-3785 Sentence denotes To that end, zinc/albumin ratio might be a surrogate marker of free zinc levels.
T201 3786-3925 Sentence denotes Indeed, only recently it was described a fluorescence-based method for determining the free zinc concentration in human serum samples [95].
T202 3926-4049 Sentence denotes With this method it was shown that free zinc concentration in sera from females was significantly lower than in males [95].
T203 4050-4199 Sentence denotes Moreover, free zinc concentration did correlate neither with total serum concentrations of zinc (or other metal ions such as iron) nor with age [95].
T204 4200-4423 Sentence denotes Notably, increased plasma zinc bioavailability consequent to reduced albumin levels induces zinc import into cells and likely increases the cellular functions associated to cellular zinc concentrations such as ACE and ACE2.
T205 4424-4610 Sentence denotes Indeed, enzymatic activity of both enzymes seems significantly upregulated in ARDS patients as detected by analysis of Ang peptide concentrations in plasma (see Box later in ARDS topic).
T206 4611-4849 Sentence denotes In addition, serum albumin levels in COVID-19 were usually very low (in severe forms is usually < 3.1 g/dL) [6,8], raising the possibility of a negative correlation between albumin concentration in plasma and increase of the RAS activity.
T207 4850-5172 Sentence denotes In line with these hypotheses, both asthmatic/allergic disease patients and chronic kidney disease patients without a history of cardiovascular disease, which are protected from developing COVID-19, showed a significant decrease in both circulating zinc levels and ACE2 activity as compared to normal values [96,97,98,99].
T208 5173-5479 Sentence denotes Interestingly, chronic renal disease patients with low zinc levels had normal concentrations of albumin but higher urinary zinc excretion than healthy controls [97], suggesting that low ACE2 activity in chronic renal diseases (and protection from SARS) might derive from a higher free Zn2+ renal excretion.
T209 5480-5617 Sentence denotes A similar mechanism mediated by a reduction of extracellular levels of free Zn2+ might be hypothesised for asthma patients, as well [98].
T210 5618-5815 Sentence denotes Unfortunately, I could not find information on plasma albumin concentrations for asthma patients; nevertheless, we might suppose that in these patients the albumin concentration is in normal range.
T211 5816-6049 Sentence denotes Intriguingly, inhalation exposure to ZnCl2/ZnO/hexachloroethane (the main ingredients in smoke bombs) induces both elevated plasma levels of zinc and ARDS with clinical pictures that strongly resemble those of COVID-19 [100,101,102].
T212 6050-6285 Sentence denotes Since both ACE2 and ACE enzymes are activated by high concentrations of chloride and zinc ions [79,90], it is possible to hypothesise an activation of both arms of the RAS in ARDS induced by smoke bombs as well as in COVID-19 patients.
T213 6286-6537 Sentence denotes In addition, metal fume fever, a flu-like syndrome caused by inhalation of welding fumes (mainly containing zinc) can be a predictor for the development of respiratory symptoms and welders have an increased pneumonia and cardiovascular risk [103,104].
T214 6538-6810 Sentence denotes In this regard, metal fume fever has been shown to produce fever, fatigue, muscle ache, cough, dyspnea, and an increase of several cytokines including IL-1β, IL-6, IL-8 and TNF-α [103], symptoms and cytokines that have already been described for COVID-19 patients [2,8,9].
T215 6811-6996 Sentence denotes Notably, TNF-α was upregulated early while IL-6 and IL-8 increased later, suggesting a subsequent involvement of these latter cytokines in response to inhalation of welding fumes [103].
T216 6997-7165 Sentence denotes Moreover, elevated levels of zinc have been shown not only to stimulate pro-inflammatory cytokine secretion by monocytes, but also inhibit T cell functions (see [102]).
T217 7166-7528 Sentence denotes Zinc supplementation that has also been proposed for COVID-19 treatment [105,106,107], is able to suppress allogeneic immune response (see [102]) and incubation of blood cells with welding fume particles resulted in a considerable increase not only of pro-inflammatory cytokines (including IL-1β, IL-6, IL-8, TNF-α) but also the tolerogenic cytokine IL-10 [104].
T218 7529-7857 Sentence denotes Similarly, in pulmonary arterial hypertension (PAH) as well as SARS-CoV, both arms of the inflammatory system (namely IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and TNF-α) have been shown to be upregulated [108,109,110], suggesting a common systemic pathway of activation in welding syndrome, ARDS, PAH and SARS-CoV infections.
T219 7858-8027 Sentence denotes Finally, the correlations between zinc exposure (metal fume) and cytokine storm [103,104] suggests a possible link between free zinc increase and these type of diseases.
T220 8028-8208 Sentence denotes More information on systemic zinc homeostasis and multiorgan effects of elevated levels of extracellular free zinc (such as in subjects inhaling ZnCl2 smoke) is available in Box 4.
T221 8209-8311 Sentence denotes Box 4 Systemic zinc homeostasis and multiorgan effects of elevated levels of extracellular free zinc.
T222 8312-8553 Sentence denotes Zinc absorption occurs throughout the gastrointestinal tract into enterocytes by zinc transporters of the Zrt- and Irt-like protein (ZIP) family that take up Zn2+, but also Cu2+ and Fe2+ ions, both of which can inhibit zinc absorption [111].
T223 8554-8851 Sentence denotes The bioavailability of zinc is affected by several factors among them the amount of zinc in food, its chemical form (from very low availability, e.g., zinc oxide, to comparatively high, e.g., zinc chloride salt) and its binding to other (intestinal absorbed or non-absorbed) food components [111].
T224 8852-9056 Sentence denotes For example, phytates (components present in foods like rice, cereals and corn) and folic acid can form insoluble complexes with zinc that decrease zinc absorption and increase fecal zinc excretion [111].
T225 9057-9293 Sentence denotes On the other hand, Zn2+ can form complexes with most natural amino acids (AA) that for example can come from digested proteins; each Zn2+ can be coordinated with the amine groups and carboxylate anions of two AAs (a molar ratio of 1:2).
T226 9294-9568 Sentence denotes Interestingly, in an in vitro model, the formulation of either ZnCl2 salt or Zn-AA complexes were absorbed by enterocytes and zinc was released on the opposite side of the enterocyte membrane, thus mimicking the intestinal absorption and release into the blood stream [111].
T227 9569-9700 Sentence denotes It is therefore conceivable that zinc chelates of AA, as well as zinc salts, may participate in bioavailability and uptake of zinc.
T228 9701-9987 Sentence denotes The uptake of zinc-AA complexes by AA transporters of human enterocytes suggests that B0AT1 neutral AA transporter associated with ACE2 [28] might also be involved in zinc-AA uptake (a similar mechanism might be supposable for insulin biosynthesis/secretion in pancreatic β cells [91]).
T229 9988-10139 Sentence denotes Indeed, a recycling of zinc-AAs, possibly supplied by membrane bound ACE2 monocarboxypeptidase cleavage, for ACE2 synthesis could be also hypothesised.
T230 10140-10357 Sentence denotes Plasma zinc concentration is mainly regulated through a balance between intestinal absorption and renal excretion involving specific mechanisms sensitive to both dietary zinc availability and its cellular utilization.
T231 10358-10484 Sentence denotes The majority of Zn2+ in blood binds to serum albumin, which represents the major zinc transporter/reservoir protein in plasma.
T232 10485-10744 Sentence denotes On the other hand, labile-bound pool of Zn2+ labile complexes (e.g., of AA) and free Zn2+ are the biologically available forms of zinc for cellular internalization and/or enzymatic activities (0.1–1% of the total zinc in blood plasma under normal conditions).
T233 10745-10928 Sentence denotes Free Zn2+ is subsequently accumulated by endothelial cells and zinc uptake and release by endothelial cells is the crucial step for redistribution of Zn2+ from plasma to tissues [91].
T234 10929-11108 Sentence denotes Zinc is considered a relatively nontoxic metal; however, several data report that excessive free extracellular zinc is toxic and induce apoptosis in different cell types [91,102].
T235 11109-11442 Sentence denotes Plasma excess of free Zn2+ is uptaken by ZIP transporters on the cell surface of each cells in contact with plasma (including immune cells, endothelial cells, neurons and cardiomyocytes), leading to increase of intracellular zinc that can modulate zinc associated cellular functions in both physiological and pathological conditions.
T236 11443-11873 Sentence denotes Indeed, zinc is an important mediator/messenger involved in several cellular activities and the shift of zinc from plasma to cells may be significant for both normal physiological processes including energy metabolism, blood coagulation, and zinc signalling, and a range of disease states, including neurodegenerative and cardiovascular diseases, metabolic syndrome, inflammation, endothelial stress, diabetes and thrombosis [91].
T237 11874-12100 Sentence denotes For example, excess zinc intake has been shown to contribute to both amyloid beta-peptide plaque formation in Alzheimer’s disease and cardiac dysfunction, indicating that free zinc ion may be much more toxic than thought [91].
T238 12101-12377 Sentence denotes It has been reported that Alzheimer and other neurodegenerative disease patients show elevated levels not only of Zn2+ but also of other divalent metals such as Fe2+ and Cu2+ [112], suggesting a possible link between the increase metal ions and saturation of ZIP transporters.
T239 12378-12591 Sentence denotes On the other hand, increased plasma ferritin levels (such as in COVID-19 [2,3,6]) might reduce free Fe2+ and its “competition” with Zn2+ for ZIP transporters, finally increasing cellular zinc uptake and functions.
T240 12592-12731 Sentence denotes To this regard, EDTA metal chelator has been shown to protect from neural cell death and it was tested in neurodegenerative diseases [102].
T241 12732-12914 Sentence denotes Of interest, plasma albumin acts as a transport protein for both metal ions such as zinc and hydrophobic molecules such as free fatty acid (FFA) to allow their systemic distribution.
T242 12915-13096 Sentence denotes Indeed, albumin is well beyond a mere carrier of metal ions and hydrophobic molecules, and by binding of these different molecules mediates their crosstalk and bioavailability [91].
T243 13097-13209 Sentence denotes To this regard, one particularly intriguing allosteric link exists between FFA and zinc binding to albumin [91].
T244 13210-13415 Sentence denotes When FFAs with ten or more carbon atoms bind to albumin causes the release of Zn2+, suggesting a possible link between dyslipidemia and toxic effects mediated by consequent increase of free zinc in plasma.
T245 13416-13604 Sentence denotes For example, endothelial stress and activation and pro-inflammatory action of FFAs may be mediated by their effects on free zinc release from albumin and its consequent efflux from plasma.
T246 13605-13775 Sentence denotes Different studies have suggested a role of albumin to inhibit interaction of free Zn2+ with amyloid beta-peptides and combat plaque formation in Alzheimer’s disease [91].
T247 13776-13889 Sentence denotes Zn2+ has also been shown to promote clot stability by binding to fibrinogen and inhibiting heparin activity [91].
T248 13890-14011 Sentence denotes An evidence that has suggested a possible positive correlation between increased levels of FFAs and thrombotic risk [91].
T249 14012-14241 Sentence denotes In addition, physiological conditions associated with elevated plasma FFAs, such as physical exercise, can also produce an increased plasma level of free zinc and its downstream physiological events (e.g., activation of the RAS).
T250 14242-14410 Sentence denotes On the other hand, reduced concentrations of plasma albumin (such as IBD, ARDS and COVID-19) will induce elevated plasma levels of both free FFAs and bioavailable zinc.
T251 14411-14573 Sentence denotes Intriguingly, ARDS is induced after inhalation exposure to ZnCl2/ZnO/hexachloroethane, the main ingredients in smoke bombs used for crowd dispersal [100,101,102].
T252 14574-14691 Sentence denotes To this regard, soldiers that breathed smoke-bomb fumes have been shown to quickly or slowly develope ARDS [100,101].
T253 14692-14874 Sentence denotes Interestingly, a patient who had the highest level of serum zinc rapidly developed ARDS that leads to death from multiorgan failure (including respiratory and hepatic failure) [100].
T254 14875-15162 Sentence denotes Instead, a slow progressive clinical course was associated with a significant increase of plasma zinc concentration that negatively correlated with pulmonary and liver function [100], finally leading to death for severe respiratory failure three to five weeks after inhalation [100,101].
T255 15163-15263 Sentence denotes At autopsy diffuse microvascular obliteration and marked endothelial cell injury was apparent [101].
T256 15264-15456 Sentence denotes Widespread occlusion of the pulmonary arteries may contribute to the development of acute pulmonary hypertension and extensive interstitial and intra-alveolar fibrosis was also observed [101].
T257 15457-15669 Sentence denotes Other soldiers wearing gas masks, immediately developed severe coughing and dyspnea, and slowly improved their lung function (only twelve months after exposure their lung function tests were nearly normal) [101].
T258 15670-15754 Sentence denotes All clinical conditions that strongly resemble those described in COVID-19 patients.
T259 15756-15760 Sentence denotes 5.2.
T260 15761-15827 Sentence denotes Safety and Efficacy Concerns of MLN4760 and Dx600 ACE2 Inhibitors.
T261 15828-15967 Sentence denotes It is known that the catalytic cleft of ACE2 consists of two peptidase subdomains: one membrane-distal and the other one membrane-proximal.
T262 15968-16088 Sentence denotes Their weak interactions are consistent with the ability to transition from open to the closed ACE2 conformation [28,90].
T263 16089-16364 Sentence denotes Indeed, the two subdomains undergo a large hinge-bending motion in which membrane-proximal subdomain remains almost unchanged, while membrane-distal subdomain moves to close the distance between the two subdomains, mimicking the opening/closing movement of a clam shell [90].
T264 16365-16655 Sentence denotes ACE2 open conformation likely reflects free state of the enzyme available to catch substrates (or inhibitors), then, when the ACE2 receptor binds to a substrate, the membrane-distal subdomain closes around the substrate (or the inhibitor), finally performing the enzymatic activity [24,90].
T265 16656-16836 Sentence denotes Interestingly, in cryo–electron microscopy structures of full-length human ACE2, only the closed/substrate-bound conformation of ACE2 was observed in the spike-ACE2 complexes [28].
T266 16837-17081 Sentence denotes Since human ACE2 is assembled on cell surface as a homodimer [28], binding of the spike protein trimer onto ACE2 dimer suggests simultaneous binding of two spike protein trimers to substrate-bound conformer of ACE2 homodimer on plasma membrane.
T267 17082-17338 Sentence denotes The spike binding sites on ACE2 homodimer are localized above the membrane-distal peptidase subdomain of each ACE2 monomer, nevertheless neither ACE2 shedding nor ACE2 binding to spike proteins have been shown to inhibit ACE2 enzymatic activity [16,17,24].
T268 17339-17606 Sentence denotes On the other hand, the S-protein-binding region of membrane-distal ACE2 subdomain is not significantly perturbed by the receptor conformational changes and maintains the ability to associate with soluble spike proteins independently on open/closed conformations [24].
T269 17607-17809 Sentence denotes Interestingly, an ACE2 specific inhibitor (MLN-4760) has been shown to induce the closed (inhibitor-bound) ACE2 structure [90] and to retain its inhibitory effects on sACE2 bound to spike proteins [24].
T270 17810-18010 Sentence denotes MLN4760 is a potent and selective human ACE2 inhibitor (IC50 = 0.44 nM against soluble human ACE2) whose synthesis produces a racemic mixture of two diastereomers that showed 75:25 ratio for Isomer A:
T271 18011-18120 Sentence denotes Isomer B [113,114] and the purified isomer B is the isomer commercially available from Merck Millipore [114].
T272 18121-18306 Sentence denotes Testing MLN-4760 racemic mixture and its isomers, it was observed a concentration-dependent inhibition of recombinant human (rh)ACE or rhACE2 activities with all three inhibitors [114].
T273 18307-18657 Sentence denotes The isomer B was less selective (near minimal-maximal rhACE inhibition range 10−6M-10−4M) than the racemate or the isomer A (near minimal-maximal rhACE inhibition range 10−6M-10−2M) and less effective (near maximal rhACE2 inhibition at 10−7M) than the racemate or the isomer A (near maximal rhACE2 inhibition at 10−8 M) for rhACE2 versus rhACE [114].
T274 18658-19024 Sentence denotes Moreover, all three inhibitors exerted a significantly higher inhibitory activity against soluble than membrane-bound forms of (m)ACE2 (near maximal mACE2 inhibition at 10−6M), being the isomer B more selective and effective than the racemate or the isomer A for mACE2 vs. mACE expressed on the surface of mononuclear cells (or CD34 hematopoietic progenitors) [114].
T275 19025-19124 Sentence denotes A second ACE2 inhibitor, Dx600, produced similar results to those obtained with the isomer B [114].
T276 19125-19291 Sentence denotes Another study evaluated the inhibitory activity of both MLN-4760 and DX600 (either the linear conformational form or the disulfide bridged cyclic variant) inhibitors.
T277 19292-19503 Sentence denotes In this report, the experiments were performed at pH 6.5 [115], a pH at which rhACE2 proteolysis operates at maximal activity [79] and a condition that resembles hypercapnic acidosis which may occur during SARS.
T278 19504-19840 Sentence denotes MLN-4760 was still able to strongly and specifically inhibit rhACE2 activity (near maximal inhibition at 10−8 M), preventing rhACE2-driven Ang II degradation into Ang (1–7), whereas DX600 (either linear or cyclic variant) inhibits rhACE2 at relatively higher concentration (near maximal inhibition at 10−6 M–10−7 M, respectively) [115].
T279 19841-19985 Sentence denotes Altogether these data indicate that the racemate or the isomer A are more effective in inhibiting soluble forms of ACE2 than isomer B and Dx600.
T280 19986-20339 Sentence denotes Therefore, these inhibitors at opportune (low) concentrations are expected to preferentially reduce systemic sACE2 activity, while preserving the ACE2 activity of (local) membrane-associated forms of ACE2, knowing that catalytic activity of circulating ACE2 was undetectable in human plasma of healthy subjects due to an endogenous ACE2 inhibitor [116].
T281 20340-20695 Sentence denotes Since MLN-4760 inhibitor promotes the closed ACE2 conformation [90] which is the preferential conformer for virus binding [28], MLN-4760 is expected to not prevent viral entry; nevertheless, its inhibitory function on ACE2 pathway might work on the positive feedback loops (above described) that ultimately favour ACE2 membrane expression and viral entry.
T282 20696-20813 Sentence denotes A potential risk factor of inhibiting the Ang II metabolization into Ang 1–7 could be the increase of blood pressure.
T283 20814-21323 Sentence denotes Although ACE2 pathway inhibition might lead to hypertensive effects, treatment with MLN-4760 for 4-5 weeks had no effect on blood pressure when administered 10 mg/kg/day in drinking water in wild type mice [117] nor in male (mRen2)27 transgenic hypertensive rats (administered 30 mg/kg/day subcutaneously via mini-osmotic pumps) [118], suggesting that hypertensive activity mediated by ACE2 inhibition is promptly balanced by compensatory mechanisms either in normal or hypertensive blood pressure conditions.
T284 21324-21529 Sentence denotes In addition, injections of MLN4760 into the nucleus tractus solitarii has been shown to reduce the baroreceptor reflex in rats, suggesting a role for ACE2 in controlling a reflex bradycardia (see [39,44]).
T285 21530-21764 Sentence denotes Finally, chronic inhibition of ACE2 with MLN-4760 led to increase of ACE, albuminuria and glomerular injury in streptozotocin-induced diabetic mice, indicating a possible adverse effect of the inhibitor in a diabetic background [119].
T286 21765-21938 Sentence denotes Extensive experiments have been also performed with DX600, a specific peptide ACE2 inhibitor that exhibited a mixed competitive and non-competitive type of inhibition [120].
T287 21939-22036 Sentence denotes Actually, several reports describing Dx600 inhibitor administration in mice suggest its safe use.
T288 22037-22317 Sentence denotes Of interest, a report described its (safe) use alone (1 mg/kg per day) by nasal inhalation for 3 days in a mouse model of endotoxin-induced lung inflammation [121]; however, this inhibitor is less efficacious than MLN-4760 in inhibiting the soluble forms of human rACE2 [114,115].
T289 22318-22514 Sentence denotes Altogether these reports on administration of ACE2 inhibitors do not reveal significant adverse impacts or mortality in experimental animals, which suggests their safety in chronic administration.
T290 22515-22614 Sentence denotes This was also confirmed in human clinical trials with MLN-4760 (clinical name: ORE1001, see later).
T291 22615-23134 Sentence denotes Of interest, a report showed that on day 28 post-myocardial infarction, adult male Sprague-Dawley rats that had received MLN-4760 (also called C16) 25 mg/mL/day by daily intraperitoneal injection (as a solution of 42 mg/mL in distilled water) tended to have lower left ventricular pulse pressure, mean arterial pressures and left ventricular relaxation time constant-Tau compared to untreated group (see table 2 of the paper) [52], suggesting a possible protective role of ACE2 inhibition in post-myocardial infarction.
T292 23135-23415 Sentence denotes Therefore, MLN-4760 might be helpful not only for COVID-19 but also in targeted therapies for pathologies correlated with an excessive increase of ACE2 activity that may involve heart, lung, liver, colon or other tissues/organs expressing ACE2 such as blood and endothelial cells.
T293 23416-23642 Sentence denotes As an example, GL1001 (old name of MLN-4760) showed to produce an anti-inflammatory activity in a mouse model of colitis [122], highlighting the importance of the yin-yang balance of ACE/ACE2 pathways (“in medio stat virtus”).
T294 23644-23648 Sentence denotes 5.3.
T295 23649-23697 Sentence denotes Safety and Efficacy Concerns of Chelating Agents
T296 23698-23915 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 23916-24013 Sentence denotes In this regard, EDTA, a cation chelator, has been shown to be able to inhibit ACE2 activity [79].
T298 24014-24308 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 24309-24421 Sentence denotes As a consequence, the iron concentration in plasma of healthy subjects is very low on the order of 10−18M [112].
T300 24422-24729 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 24730-25059 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 25060-25252 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 25253-25358 Sentence denotes CaNa2EDTA was approved by FDA in chelation therapy for lowering blood lead levels a long time ago (1953).
T304 25359-25492 Sentence denotes Then, different (commercially available) iron chelating agents, expected to work in chelating zinc ion as well, were approved by FDA.
T305 25493-25626 Sentence denotes Chelation therapy comprises intravenous or oral administration of chelating agents that remove metal ions such as zinc from the body.
T306 25627-25724 Sentence denotes Cells synthesising high amounts of ACE or ACE2 needs of high amounts of bioavailable (free) zinc.
T307 25725-25867 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 25868-25999 Sentence denotes Indeed, both ACE and ACE2 synthesis might be particularly sensitive to reduction of free zinc levels in case of their upregulation.
T309 26000-26192 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 26193-26490 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 26491-26737 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 26738-26947 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 26948-27328 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 27329-27570 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 27571-27618 Sentence denotes A scenario that would deserve an investigation.
T316 27619-27981 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 27982-28149 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 28150-28240 Sentence denotes Finally, for its teratogenic effects, the drug is also contraindicated in pregnancy [123].
T319 28241-28463 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 28464-28535 Sentence denotes Alternative ways of RAS pathway inhibition are also described in Box 5.
T321 28536-28586 Sentence denotes Box 5 Alternative ways of RAS pathway inhibition.
T322 28587-28694 Sentence denotes Of interest, a small cationic inhibitor of ACE2 (but not of ACE) has been detected in plasma samples [116].
T323 28695-28949 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 28950-29057 Sentence denotes I have already mentioned that AA can chelate zinc forming labile zinc complexes of amino acids (see Box 4).
T325 29058-29243 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 29244-29408 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 29409-29585 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 29586-29746 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 29747-29923 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 29924-29972 Sentence denotes Unfortunately, NAAE has never been used in vivo.
T331 29973-30263 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 30264-30386 Sentence denotes Indeed, it has an important role in down-regulating NO synthesis reducing NO overproduction by different mechanisms [128].
T333 30387-30548 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 30549-30740 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 30741-30816 Sentence denotes Moreover, agmatine sulfate is regularly taken as a bodybuilding supplement.
T336 30817-31027 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 31028-31180 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 31181-31284 Sentence denotes Nicotianamine has been shown to inhibit the activity of both zinc metalloproteases, ACE2 and ACE [130].
T339 31285-31366 Sentence denotes In addition, zeolites might also be effective in reducing free zinc availability.
T340 31367-31495 Sentence denotes Zeolites are a group of aluminosilicate minerals with crystalline microporous structure that are originated from volcanic rocks.
T341 31496-31667 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 31668-31768 Sentence denotes Clinoptilolite is one of the zeolites that has been widely studied in veterinary and human medicine.
T343 31769-31955 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 31956-32093 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 32094-32194 Sentence denotes An approach that could be pursued (in combination with other therapies) to inhibit SARS-CoV-2 entry.
T346 32195-32411 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 32412-32542 Sentence denotes However, it is possible that catalytic active form of ACE2 might favour adverse effects in these specific pathological conditions.
T348 32543-32853 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.