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PMC:7796052 / 941-6254 JSONTXT

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LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
45 466-479 Gene denotes interleukin-6 Gene:3569
46 481-485 Gene denotes IL-6 Gene:3569
47 29-37 Species denotes patients Tax:9606
48 52-62 Species denotes SARS-Cov-2 Tax:2697049
49 322-330 Species denotes patients Tax:9606
50 515-523 Species denotes patients Tax:9606
51 783-794 Species denotes Ebola virus Tax:205488
52 570-583 Chemical denotes dexamethasone MESH:D003907
53 693-703 Chemical denotes remdesivir MESH:C000606551
54 38-46 Disease denotes infected MESH:D007239
55 108-117 Disease denotes pneumonia MESH:D011014
56 145-154 Disease denotes hypoxemia MESH:D000860
57 156-191 Disease denotes acute respiratory distress syndrome MESH:D012128
58 193-197 Disease denotes ARDS MESH:D012128
59 200-215 Disease denotes pulmonary edema MESH:D011654
60 217-222 Disease denotes shock MESH:D012769
61 224-242 Disease denotes metabolic acidosis MESH:D000138
62 244-267 Disease denotes coagulation dysfunction MESH:D001778
63 272-305 Disease denotes multiple organ functional failure MESH:D009102
64 313-321 Disease denotes Covid-19 MESH:C000657245
65 657-667 Disease denotes infections MESH:D007239
94 1257-1261 Gene denotes IL-6 Gene:3569
95 1380-1390 Gene denotes bradykinin Gene:3827
96 1392-1394 Gene denotes BK Gene:3827
97 1664-1695 Gene denotes angiotensin converting enzyme 2 Gene:59272
98 1697-1701 Gene denotes ACE2 Gene:59272
99 1750-1754 Gene denotes ACE2 Gene:59272
100 1794-1807 Gene denotes angiotensin I Gene:183
101 1825-1854 Gene denotes angiotensin-converting enzyme Gene:1636
102 1856-1859 Gene denotes ACE Gene:1636
103 2021-2025 Gene denotes ACE2 Gene:59272
104 2130-2134 Gene denotes IL-6 Gene:3569
105 2211-2213 Gene denotes BK Gene:3827
106 2406-2408 Gene denotes BK Gene:3827
107 1579-1581 Gene denotes BK Gene:3827
108 2065-2067 Gene denotes BK Gene:3827
109 1610-1612 Gene denotes BK Gene:3827
110 1461-1469 Species denotes patients Tax:9606
111 1625-1633 Species denotes patients Tax:9606
112 1725-1735 Species denotes SARS-Cov-2 Tax:2697049
113 2147-2155 Species denotes patients Tax:9606
114 2498-2506 Species denotes patients Tax:9606
115 2456-2462 Chemical denotes oxygen MESH:D010100
116 846-854 Disease denotes Covid-19 MESH:C000657245
117 1179-1187 Disease denotes Covid-19 MESH:C000657245
118 1482-1490 Disease denotes Covid-19 MESH:C000657245
119 1616-1624 Disease denotes Covid-19 MESH:C000657245
120 2138-2146 Disease denotes Covid-19 MESH:C000657245
121 2489-2497 Disease denotes Covid-19 MESH:C000657245
131 2740-2750 Gene denotes bradykinin Gene:3827
132 2945-2947 Gene denotes BK Gene:3827
133 3197-3199 Gene denotes BK Gene:3827
134 2674-2676 Gene denotes BK Gene:3827
135 2545-2547 Gene denotes BK Gene:3827
136 2877-2885 Species denotes patients Tax:9606
137 2610-2631 Disease denotes hereditary angioedema MESH:D054179
138 2868-2876 Disease denotes covid-19 MESH:C000657245
139 3019-3027 Disease denotes Covid-19 MESH:C000657245
162 4449-4460 Gene denotes B1 receptor Gene:623
163 4847-4864 Gene denotes estrogen receptor Gene:2099
164 5193-5195 Gene denotes BK Gene:3827
165 3681-3683 Gene denotes BK Gene:3827
166 5081-5086 Species denotes women Tax:9606
167 3934-3944 Chemical denotes raloxifene MESH:D020849
168 3946-3956 Chemical denotes sildenafil MESH:D000068677
169 3958-3966 Chemical denotes cefepime MESH:D000077723
170 3968-3977 Chemical denotes cefpirome MESH:C038950
171 3979-3987 Chemical denotes imatinib MESH:D000068877
172 3989-3998 Chemical denotes ponatinib MESH:C545373
173 4000-4011 Chemical denotes abemaciclib MESH:C000590451
174 4016-4027 Chemical denotes entrectinib MESH:C000607349
175 4245-4255 Chemical denotes raloxifene MESH:D020849
176 4257-4267 Chemical denotes sildenafil MESH:D000068677
177 4272-4280 Chemical denotes cefepime MESH:D000077723
178 4590-4600 Chemical denotes Raloxifene MESH:D020849
179 4821-4831 Chemical denotes Ralixofene
180 5177-5187 Chemical denotes relixofene
181 5050-5062 Disease denotes osteoporosis MESH:D010024
182 5103-5109 Disease denotes cancer MESH:D009369
183 5304-5312 Disease denotes Covid-19 MESH:C000657245

LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T2 108-117 Phenotype denotes pneumonia http://purl.obolibrary.org/obo/HP_0002090
T3 145-154 Phenotype denotes hypoxemia http://purl.obolibrary.org/obo/HP_0012418
T4 162-182 Phenotype denotes respiratory distress http://purl.obolibrary.org/obo/HP_0002098
T5 200-215 Phenotype denotes pulmonary edema http://purl.obolibrary.org/obo/HP_0100598
T6 217-222 Phenotype denotes shock http://purl.obolibrary.org/obo/HP_0031273
T7 224-242 Phenotype denotes metabolic acidosis http://purl.obolibrary.org/obo/HP_0001942
T8 748-757 Phenotype denotes hepatitis http://purl.obolibrary.org/obo/HP_0012115
T9 1434-1448 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T10 2263-2277 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T11 2621-2631 Phenotype denotes angioedema http://purl.obolibrary.org/obo/HP_0100665
T12 5050-5062 Phenotype denotes osteoporosis http://purl.obolibrary.org/obo/HP_0000939
T13 5103-5109 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T8 0-2 Sentence denotes 1.
T9 3-15 Sentence denotes Introduction
T10 16-312 Sentence denotes About 20% of patients infected with SARS-Cov-2 develop respiratory complications, including pneumonia, that may evolve to severe hypoxemia, acute respiratory distress syndrome (ARDS), pulmonary edema, shock, metabolic acidosis, coagulation dysfunction and multiple organ functional failure [1,2].
T11 313-497 Sentence denotes Covid-19 patients with severe symptoms exhibit an immune response characterized by elevated serum levels of diverse proinflammatory molecules, including interleukin-6 (IL-6) [3,4,5,6].
T12 498-832 Sentence denotes Presently, these patients are treated with anti-inflammatory drugs like dexamethasone [7] or cytokine inhibitors, combined with antibiotics to treat secondary infections, sometimes combined with remdesivir, an antiviral originally developed to treat hepatitis C and tested against the Ebola virus disease to reduce the viral load [8].
T13 833-1066 Sentence denotes Treatment of Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in disease progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing.
T14 1067-1188 Sentence denotes Indeed, there is a number of ongoing clinical trials to test the efficacy of diverse FDA-approved drugs against Covid-19.
T15 1189-1335 Sentence denotes Among them, a few involve assessment of the therapeutic efficacy of IL-6 inhibition, unfortunately without reporting conclusive results [9,10,11].
T16 1336-1505 Sentence denotes Recently, it was proposed that dysregulated bradykinin (BK) signaling could be the trigger of the cytokine storm observed in patients with severe Covid-19 [12,13,14,15].
T17 1506-1741 Sentence denotes The rational for this hypothesis relies on the increased availability of BK and its metabolite des-Arg9-BK in Covid-19 patients, due to the downregulation of angiotensin converting enzyme 2 (ACE2), the entry protein of SARS-Cov-2 [16].
T18 1742-1923 Sentence denotes Indeed, ACE2 downregulation increases the amount of angiotensin I processed by the angiotensin-converting enzyme (ACE) with a concomitant decrease of its degradation activity on BK.
T19 1924-2060 Sentence denotes Moreover, levels of des-Arg9-BK are also increased due to the diminished degradative activity of ACE2 caused by its downregulation [12].
T20 2061-2161 Sentence denotes The BK hypothesis is consistent with the observed elevated levels of IL-6 in Covid-19 patients [17].
T21 2162-2299 Sentence denotes This new perspective suggests that inhibition of BK signaling may be a suitable therapy to avoid the cytokine storm and its consequences.
T22 2300-2512 Sentence denotes Indeed, as a proof of principle, preliminary results from a limited study suggests that inhibition of the BK signaling is associated with a decrease of the oxygen supplementation needed by Covid-19 patients [18].
T23 2513-2718 Sentence denotes Nowadays, icatibant is the only BK antagonist approved as therapeutic agent for the treatment of hereditary angioedema [19], in spite of the number of selective BK ligands described in the literature [20].
T24 2719-2891 Sentence denotes The discovery of the bradykinin hypothesis prompted the launch of an ongoing clinical trial to assess the benefits of icatibant for the treatment of covid-19 patients [21].
T25 2892-3082 Sentence denotes In other to swiftly test the efficacy of alternative BK antagonists with diverse pharmacological profiles for the treatment of Covid-19, drug repurposing represents a valuable strategy [22].
T26 3083-3253 Sentence denotes To this aim, we recently carried out a virtual screening study on the DrugBank database [23] aimed at identifying BK ligands among drugs already approved by the FDA [24].
T27 3254-3444 Sentence denotes The study was carried out using four points common to the pharmacophores derived for the B1 and B2 bradykinin receptors recently reported that were used as queries for the search [25,26,27].
T28 3445-3569 Sentence denotes Hits identified were subsequently subjected to a docking study using the Molecular Operating Environment (MOE) program [28].
T29 3570-3721 Sentence denotes The virtual screening process permitted the identification of a small set of drugs as prospective nonselective BK ligands, as described elsewhere [24].
T30 3722-3890 Sentence denotes Specifically, the DrugBank database, containing a total of 1703 molecules, was screened for compounds that fulfilled a common pharmacophore for the B1 and B2 receptors.
T31 3891-4028 Sentence denotes The study identified eight drugs including raloxifene, sildenafil, cefepime, cefpirome, imatinib, ponatinib, abemaciclib and entrectinib.
T32 4029-4211 Sentence denotes Subsequently, the eight compounds were purchased and tested for their capacity to displace a reference ligand in any of the two bradykinin receptors B1 and B2, respectively at 20 µM.
T33 4212-4390 Sentence denotes Three of the compounds including raloxifene, sildenafil and cefepime displaced the reference ligand from B2, which represents a 40% success rate as found in similar studies [29].
T34 4391-4483 Sentence denotes However, none of the compounds exhibited affinity for the B1 receptor at this concentration.
T35 4484-4589 Sentence denotes This might be due to the steric hindrance that was not properly included in the virtual screening search.
T36 4590-4726 Sentence denotes Raloxifene, the most potent antagonist identified was further investigated in a functional study in vitro, exhibiting an IC50 of ~16 µM.
T37 4727-4820 Sentence denotes Moreover, the compound showed a weak partial agonist profile with a maximal activity of ~20%.
T38 4821-4986 Sentence denotes Ralixofene is a selective estrogen receptor modulator, exerting estrogen agonist action in some target tissues while acting as an estrogen antagonist in others [30].
T39 4987-5126 Sentence denotes The compound was approved a few years ago for the treatment of osteoporosis in postmenopausal women, as well as for cancer chemoprotection.
T40 5127-5313 Sentence denotes The discovery of a new pharmacodynamic profile of relixofene as a BK partial agonist opens an opportunity for its repurposing as a therapeutic agent for the treatment of severe Covid-19.