LitCovid-sentences  

PMC:7796052 / 6256-13095 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T41 0-2 Sentence denotes 2.
T42 3-25 Sentence denotes Results and Discussion
T43 26-247 Sentence denotes In order to have a preliminary insight into the affinity of ralixofene towards the bradykinin receptors, the compound was first tested at 20 µM for its capacity to displace a reference ligand from B1 and B2, respectively.
T44 248-352 Sentence denotes Specifically, desArg10-kallidin was used in the case of the B1 receptor and NPC 567 for the B2 receptor.
T45 353-549 Sentence denotes The results of this study indicate that at this concentration, ralixofene does not displace desArg10-kallidin at the B1 receptor, whereas the reference ligand at the B2 receptor is displaced ~54%.
T46 550-726 Sentence denotes We subsequently proceeded to carry out a study of the pharmacodynamic profile of the compound towards the BK B2 receptor in vitro, using a functional efficacy measurement [31].
T47 727-857 Sentence denotes Accordingly, we tested its capacity to antagonize BK on Chinese Hamster Ovary (CHO) cells stably transfected with the B2 receptor.
T48 858-1215 Sentence denotes As can be seen in Figure 1a, raloxifene antagonizes BK with an IC50 ~16 µM with an apparent dissociation constant KB = 1.8 µM, computed using the modified Cheng Prusoff equation [32]:KB=IC501+AEC50 where, IC50 = 16 µM corresponds to raloxifene and EC50 = 2.4 pM corresponds to BK, and A = 0.03 nM is the concentration of BK that was used in the experiments.
T49 1216-1311 Sentence denotes We also tested its activity as an agonist on CHO cells stably transfected with the B2 receptor.
T50 1312-1478 Sentence denotes Present results also showed (Figure 1b) that the compound exhibited a partial agonistic profile, with a maximum effect of 20% of BK that was achieved at around 20 µM.
T51 1479-1561 Sentence denotes The antagonistic profile of the compound can be rationalized from docking studies.
T52 1562-1753 Sentence denotes Figure 2 shows the prospective bound conformation of raloxifene (orange) to the B2 receptor, superimposed with the conformation matching the query (yellow) from the virtual screening process.
T53 1754-1901 Sentence denotes Despite fulfilling the four pharmacophore points, the directionality of the hydrogen bond interactions (not included in the query) was not optimal.
T54 1902-2023 Sentence denotes However, in the docking process, the molecule was relaxed to satisfy new interactions that may improve its docking score.
T55 2024-2152 Sentence denotes As can be seen in Figure 2, from its initial position (yellow), the molecule tilts to get a few favorable interactions (orange).
T56 2153-2285 Sentence denotes Specifically, the phenoxyl moiety sacrifices a hydrogen bond interaction with Arg169 that is compensated with a new one with Asn104.
T57 2286-2433 Sentence denotes This in turn, permits the phenoxyl aromatic ring to get closer to Trp86 and the carbonyl group establishes a hydrogen bond interaction with Arg169.
T58 2434-2604 Sentence denotes On the other hand, some interactions are weakened, for example, the interaction of the bicycle moiety with Trp86 and the interaction of the pyridine nitrogen with Asp266.
T59 2605-2699 Sentence denotes Partial fulfilment of the pharmacophore may explain the low IC50 exhibited by raloxifene [26].
T60 2700-2886 Sentence denotes On the other hand, the fact that raloxifene does not bind to the B1 can only be explained by steric interactions, since most of the residues between the two receptors are conserved [27].
T61 2887-3099 Sentence denotes Inspection of the results of the docking study reveals that the pyridine nitrogen of raloxifene exhibits a hydrogen bond with Thr286 that cannot not be established in B1, since the position is occupied by Leu294.
T62 3100-3214 Sentence denotes Bradykinin signaling though the B2 receptor induces a proinflammatory action as well as a hypotensive effect [33].
T63 3215-3447 Sentence denotes The proinflammatory activity of BK involves the stimulation of cytokines, like IL-6 and IL-8, through the MAPK/AP-1 signaling axis [17,34], whereas the hypotensive effects are due to vasodilation and increased vascular permeability.
T64 3448-3637 Sentence denotes Due to the partial agonist profile of raloxifene, it is expected that the compound antagonizes the proinflammatory effects of BK, modulating the levels of diverse cytokines, including IL-6.
T65 3638-3985 Sentence denotes To support this hypothesis, in clinical trials aimed at understanding the effect of hormone replacement therapy for menopausal women on the risk of cardiovascular disease, in contrast to other compounds raloxifene did not exhibit a proinflammatory profile [35,36] that could, in part, be explained by its antagonistic effect on the BK B2 receptor.
T66 3986-4124 Sentence denotes The beneficial vascular effects of ralixofene could, in part, be explained by its partial agonist profile towards the BK B2 receptor [36].
T67 4125-4391 Sentence denotes Thus, in a study aimed at assessing the vasoprotective effects of the compound, rats treated with raloxifene showed an increased reduction of systolic blood pressure on administration of bradykinin, suggesting an enhanced bioavailability of NO in these animals [37].
T68 4392-4589 Sentence denotes Moreover, diverse experiments subsequently confirmed a role of raloxifene inducing endothelium-dependent relaxation as due to the upregulation of nitric-oxide synthase (eNOS) expression [38,39,40].
T69 4590-4782 Sentence denotes Although these results can be due to the partial agonist profile of raloxifene reported in this work [33], the effect can also be explained as due to the activation of the GPR30 receptor [41].
T70 4783-4865 Sentence denotes Accordingly, further experimental work is necessary to differentiate both effects.
T71 4866-5020 Sentence denotes Present results strongly support the need to perform a deeper investigation on the use of raloxifene as a therapeutic agent for the treatment of Covid-19.
T72 5021-5231 Sentence denotes As shown in the present communication, its pharmacological profile as a partial BK B2 agonist is expected to antagonize the inflammatory action of BK, shown to be upregulated in Covid-19 patients [12,13,14,15].
T73 5232-5404 Sentence denotes This, in turn, will produce a reduction of cytokine levels, including IL-6, which is the primary proinflammatory cytokine associated with the severity of the illness [5,6].
T74 5405-5550 Sentence denotes On the other hand, its partial agonism profile is expected to maintain a base level of BK, preserving its beneficial cardiovascular effects [42].
T75 5551-5721 Sentence denotes Despite the novel beneficial effects identified, caution should be paid due to the necessary higher dose required for the compound to be used for a novel therapeutic use.
T76 5722-5797 Sentence denotes The treatment of osteoporosis requires an oral dose between 30 to 150 mg/d.
T77 5798-5928 Sentence denotes Taking into account its poor bioavailability of 2%, a single dose of 100 mg gives a maximal concentration in plasma of ~2 nM [43].
T78 5929-6135 Sentence denotes Concentrations necessary for the therapeutical benefit of raloxifene towards the BK B2 receptor are expected to be, at most, around 100 times higher, which is within the therapeutic window of the drug [44].
T79 6136-6331 Sentence denotes The results of this work complement recent comments suggesting the use of raloxifene for the treatment of Covid-19 [45], based on its capacity to inhibit the IL-6/STAT3 signaling pathway [46,47].
T80 6332-6536 Sentence denotes In addition, the presumed antiviral profile of ralixofene against the SARS-Cov2 virus through its capability to block the two-pore channel TCP2 [48], as found for the ebola virus [49] has been underlined.
T81 6537-6716 Sentence denotes In conclusion, the pharmacodynamic profile exhibited by ralidoxene described in the present report represents a reasonable base to test the compound for the treatment of Covid-19.
T82 6717-6839 Sentence denotes Very recently a clinical trial in Italy has been approved to test ralixofene in COVID-19 patients with mild symptoms [50].