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LitCovid_Glycan-Motif-Structure

Id Subject Object Predicate Lexical cue
T1 1510-1513 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T2 1510-1513 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T3 1622-1625 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T4 1622-1625 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T5 1672-1675 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T6 1672-1675 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T7 1831-1834 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T8 1831-1834 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T9 5103-5106 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T10 5103-5106 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T11 5458-5461 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T12 5458-5461 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T13 5566-5569 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T14 5566-5569 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T15 5840-5843 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T16 5840-5843 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T17 6595-6598 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T18 6595-6598 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T19 6913-6916 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T20 6913-6916 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T21 7447-7450 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T22 7447-7450 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T23 12938-12941 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T24 12938-12941 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T25 13574-13577 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T26 13574-13577 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T27 13598-13601 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T28 13598-13601 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T29 13926-13929 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T30 13926-13929 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T31 14169-14172 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T32 14169-14172 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T33 14439-14442 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T34 14439-14442 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T35 14617-14620 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T36 14617-14620 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T37 15209-15212 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T38 15209-15212 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T39 15316-15319 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T40 15316-15319 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T41 15415-15418 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T42 15415-15418 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T43 15747-15750 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T44 15747-15750 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T45 15990-15993 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T46 15990-15993 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T47 16173-16176 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T48 16173-16176 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T49 16179-16182 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T50 16179-16182 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T51 16963-16966 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T52 16963-16966 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T53 17128-17131 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T54 17128-17131 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T55 17184-17187 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T56 17184-17187 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T57 17306-17309 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T58 17306-17309 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T59 24392-24395 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T60 24392-24395 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T61 24526-24529 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T62 24526-24529 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T63 24576-24579 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T64 24576-24579 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T65 26686-26689 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T66 26686-26689 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T67 27111-27114 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T68 27111-27114 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T69 28721-28724 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T70 28721-28724 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T71 28993-28996 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T72 28993-28996 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T73 29088-29091 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T74 29088-29091 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T75 29328-29331 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T76 29328-29331 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T77 29454-29457 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T78 29454-29457 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T79 29611-29614 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T80 29611-29614 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T81 29676-29679 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T82 29676-29679 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T83 29859-29862 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T84 29859-29862 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T85 29927-29930 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T86 29927-29930 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN
T87 30422-30425 https://glytoucan.org/Structures/Glycans/G00057MO denotes LDN
T88 30422-30425 https://glytoucan.org/Structures/Glycans/G31736BK denotes LDN

LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T1 680-694 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T2 779-798 Phenotype denotes respiratory failure http://purl.obolibrary.org/obo/HP_0002878
T3 1143-1158 Phenotype denotes cytokines storm http://purl.obolibrary.org/obo/HP_0033041
T4 2568-2582 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T5 12975-12989 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T6 12990-13004 Phenotype denotes Cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T7 13271-13285 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T8 13372-13378 Phenotype denotes sepsis http://purl.obolibrary.org/obo/HP_0100806
T9 16553-16567 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T10 24807-24815 Phenotype denotes Pruritus http://purl.obolibrary.org/obo/HP_0000989
T11 27830-27849 Phenotype denotes respiratory failure http://purl.obolibrary.org/obo/HP_0002878

LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
2 0-10 Chemical denotes Naltrexone MESH:D009271
3 49-57 Disease denotes COVID-19 MESH:C000657245
30 573-603 Gene denotes Angiotensin-Converting Enzyme2 Gene:59272
31 605-609 Gene denotes ACE2 Gene:59272
32 890-896 Gene denotes ERK1/2 Gene:5595
33 942-948 Gene denotes ERK1/2 Gene:5595
34 1091-1096 Gene denotes Spike Gene:43740568
35 1108-1112 Gene denotes ACE2 Gene:59272
36 1169-1175 Gene denotes ERK1/2 Gene:5595
37 1546-1552 Gene denotes ERK1/2 Gene:5595
38 1657-1661 Gene denotes ACE2 Gene:59272
39 142-189 Species denotes Severe Acute Respiratory Syndrome Coronavirus 2 Tax:2697049
40 191-201 Species denotes SARS-CoV-2 Tax:2697049
41 389-402 Species denotes coronaviruses Tax:11118
42 404-414 Species denotes SARS-CoV-2 Tax:2697049
43 850-858 Species denotes patients Tax:9606
44 1080-1090 Species denotes SARS-CoV-2 Tax:2697049
45 1344-1354 Chemical denotes naltrexone MESH:D009271
46 1498-1508 Chemical denotes Naltrexone MESH:D009271
47 1841-1851 Chemical denotes naltrexone MESH:D009271
48 219-238 Disease denotes Coronavirus Disease MESH:D018352
49 240-248 Disease denotes COVID-19 MESH:C000657245
50 612-632 Disease denotes SARS-CoV-2 infection MESH:C000657245
51 779-798 Disease denotes respiratory failure MESH:D012131
52 815-837 Disease denotes multiple organ failure MESH:D009102
53 841-849 Disease denotes COVID-19 MESH:C000657245
54 1753-1774 Disease denotes coronavirus infection MESH:D018352
55 1785-1793 Disease denotes toxicity MESH:D064420
65 2242-2250 Species denotes patients Tax:9606
66 1959-1983 Disease denotes Coronavirus Disease 2019 MESH:C000657245
67 1985-1993 Disease denotes COVID-19 MESH:C000657245
68 2109-2128 Disease denotes multi-organ failure MESH:D009102
69 2180-2188 Disease denotes diabetes MESH:D003920
70 2190-2206 Disease denotes cardiac diseases MESH:D006331
71 2233-2241 Disease denotes COVID-19 MESH:C000657245
72 2326-2335 Disease denotes mortality MESH:D003643
73 2343-2351 Disease denotes COVID-19 MESH:C000657245
86 2732-2736 Gene denotes MAPK
87 2737-2740 Gene denotes ERK Gene:5594
88 2861-2865 Gene denotes ERK1 Gene:5595
89 2870-2874 Gene denotes ERK2 Gene:5594
90 2984-2990 Gene denotes ERK1/2 Gene:5595
91 3036-3042 Gene denotes ERK1/2 Gene:5595
92 3180-3186 Gene denotes ERK1/2 Gene:5595
93 2544-2552 Species denotes patients Tax:9606
94 2889-2894 Species denotes HIV-1 Tax:11676
95 3241-3251 Species denotes SARS-COV-2 Tax:2697049
96 2535-2543 Disease denotes COVID-19 MESH:C000657245
97 2627-2636 Disease denotes mortality MESH:D003643
117 3406-3410 Gene denotes ACE2 Gene:59272
118 3513-3517 Gene denotes ACE2 Gene:59272
119 3739-3743 Gene denotes ACE2 Gene:59272
120 3827-3831 Gene denotes ACE2 Gene:59272
121 3894-3898 Gene denotes ACE2 Gene:59272
122 3961-3965 Gene denotes ACE2 Gene:59272
123 4071-4075 Gene denotes ACE2 Gene:59272
124 4224-4228 Gene denotes ACE2 Gene:59272
125 3270-3280 Species denotes SARS-CoV-2 Tax:2697049
126 3540-3550 Species denotes SARS-CoV-2 Tax:2697049
127 3733-3738 Species denotes human Tax:9606
128 3854-3864 Species denotes SARS-CoV-2 Tax:2697049
129 4047-4057 Species denotes SARS-CoV-2 Tax:2697049
130 4210-4220 Species denotes SARS-CoV-2 Tax:2697049
131 4315-4325 Species denotes SARS-CoV-2 Tax:2697049
132 3923-3938 Disease denotes CoV-2 infection MESH:C000657245
133 4284-4305 Disease denotes coronavirus infection MESH:D018352
134 3788-3792 CellLine denotes HeLa CVCL:0030
135 3872-3876 CellLine denotes HeLa CVCL:0030
140 4675-4679 Gene denotes ACE2 Gene:59272
141 4454-4464 Species denotes SARS-CoV-2 Tax:2697049
142 4664-4669 Species denotes human Tax:9606
143 4962-4970 Disease denotes COVID-19 MESH:C000657245
155 5489-5495 Gene denotes ERK1/2 Gene:5595
156 5601-5605 Gene denotes ACE2 Gene:59272
157 5786-5794 Species denotes patients Tax:9606
158 5079-5089 Chemical denotes naltrexone MESH:D009271
159 5244-5254 Chemical denotes naltrexone MESH:D009271
160 5356-5366 Chemical denotes naltrexone MESH:D009271
161 5630-5638 Disease denotes COVID-19 MESH:C000657245
162 5691-5700 Disease denotes infection MESH:D007239
163 5704-5712 Disease denotes COVID-19 MESH:C000657245
164 5777-5785 Disease denotes COVID-19 MESH:C000657245
165 5936-5944 Disease denotes COVID-19 MESH:C000657245
167 6004-6028 Chemical denotes Naltrexone hydrochloride MESH:D009271
173 6106-6112 Species denotes Murine Tax:10090
174 6161-6171 Chemical denotes RPMI media
175 6220-6230 Chemical denotes penicillin MESH:D010406
176 6231-6243 Chemical denotes streptomycin MESH:D013307
177 6125-6133 CellLine denotes Raw264.7 CVCL:0493
185 6321-6324 Chemical denotes MTT MESH:C070243
186 6330-6393 Chemical denotes 3-(4, 5-dimethyl thiazol-2yl)-2, 5-diphenyl tetrazolium bromide MESH:C022616
187 6634-6637 Chemical denotes MTT MESH:C070243
188 6656-6659 Chemical denotes PBS MESH:D007854
189 6693-6701 Chemical denotes formazan MESH:D005562
190 6750-6754 Chemical denotes DMSO MESH:D004121
191 6300-6308 CellLine denotes Raw264.7 CVCL:0493
197 7105-7108 Gene denotes Rad Gene:6236
198 7193-7196 Gene denotes Rad Gene:56437
199 7204-7209 Species denotes mouse Tax:10090
200 6913-6916 Chemical denotes LDN
201 6863-6871 CellLine denotes Raw264.7 CVCL:0493
208 7536-7547 Chemical denotes RIPA buffer
209 7745-7748 Chemical denotes SDS MESH:D012967
210 7780-7784 Chemical denotes PVDF MESH:C024865
211 7940-7944 Chemical denotes TBST
212 7965-7969 Chemical denotes TBST
213 7403-7411 CellLine denotes Raw264.7 CVCL:0493
215 8172-8175 Gene denotes ATM Gene:472
225 8992-8997 Gene denotes CD11b Gene:16409
226 9166-9169 Gene denotes APC Gene:324
227 9177-9182 Gene denotes CD11b Gene:16409
228 8199-8203 Species denotes Mice Tax:10090
229 8986-8991 Species denotes mouse Tax:10090
230 8322-8325 Chemical denotes PBS MESH:D007854
231 8356-8361 Chemical denotes HEPES MESH:D006531
232 8362-8373 Chemical denotes DMEM buffer
233 8235-8245 Disease denotes epididymal MESH:D004823
244 9424-9428 Gene denotes ACE2 Gene:59272
245 9705-9709 Gene denotes ACE2 Gene:59272
246 10820-10824 Gene denotes ACE2 Gene:59272
247 9409-9419 Species denotes SARS CoV-2 Tax:2697049
248 9522-9532 Chemical denotes naltrexone MESH:D009271
249 9656-9666 Chemical denotes naltrexone MESH:D009271
250 9701-9704 Chemical denotes RBD
251 9892-9900 Chemical denotes hydrogen MESH:D006859
252 10481-10489 Chemical denotes hydrogen MESH:D006859
253 10800-10810 Chemical denotes naltrexone MESH:D009271
258 10947-10951 Gene denotes ACE2 Gene:59272
259 11069-11073 Gene denotes ACE2 Gene:59272
260 10986-10998 Chemical denotes Bisoctrizole
261 11053-11063 Chemical denotes naltrexone MESH:D009271
271 11248-11252 Gene denotes ACE2 Gene:59272
272 12104-12107 Gene denotes atm Gene:472
273 11675-11680 Chemical denotes water MESH:D014867
274 11694-11699 Chemical denotes water MESH:D014867
275 11766-11770 Chemical denotes NaCl MESH:D012965
276 11932-11940 Chemical denotes hydrogen MESH:D006859
277 12534-12542 Chemical denotes hydrogen MESH:D006859
278 11278-11286 Disease denotes atoms MD MESH:D009436
279 11540-11546 Disease denotes CHARMM
281 12938-12941 Chemical denotes LDN
292 13064-13072 Species denotes patients Tax:9606
293 13231-13239 Species denotes patients Tax:9606
294 13442-13448 Species denotes murine Tax:10090
295 13338-13356 Chemical denotes lipopolysaccharide MESH:D008070
296 13667-13670 Chemical denotes MTT MESH:C070243
297 13672-13728 Chemical denotes 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide
298 13055-13063 Disease denotes COVID-19 MESH:C000657245
299 13111-13120 Disease denotes mortality MESH:D003643
300 13222-13230 Disease denotes COVID-19 MESH:C000657245
301 13372-13378 Disease denotes sepsis MESH:D018805
316 13894-13899 Gene denotes IL-1β Gene:16175
317 13901-13905 Gene denotes IL-6 Gene:16193
318 13972-13977 Gene denotes IL-1β Gene:16175
319 13979-13983 Gene denotes IL-6 Gene:16193
320 14384-14389 Gene denotes IL-1β Gene:16175
321 14401-14405 Gene denotes IL-6 Gene:16193
322 14476-14481 Gene denotes IL-1β Gene:16175
323 14492-14496 Gene denotes IL-6 Gene:16193
324 15153-15158 Gene denotes IL-1β Gene:16175
325 15170-15174 Gene denotes IL-6 Gene:16193
326 14439-14442 Chemical denotes LDN
327 14617-14620 Chemical denotes LDN
328 15316-15319 Chemical denotes LDN
329 15386-15398 Disease denotes inflammation MESH:D007249
342 15546-15550 Gene denotes il-6 Gene:16193
343 15555-15559 Gene denotes Il1b Gene:16176
344 15636-15640 Gene denotes IL-6 Gene:16193
345 15645-15650 Gene denotes IL-1β Gene:16175
346 15787-15792 Gene denotes IL-1β Gene:16175
347 15804-15808 Gene denotes IL-6 Gene:16193
348 16030-16037 Gene denotes insulin Gene:3630
349 16083-16089 Gene denotes ERK1/2 Gene:5595
350 15564-15570 Species denotes murine Tax:10090
351 15693-15699 Species denotes murine Tax:10090
352 15841-15845 Species denotes mice Tax:10090
353 16106-16109 CellLine denotes RAW CVCL:F681
356 16216-16222 Gene denotes ERK1/2 Gene:5595
357 16179-16182 Chemical denotes LDN
367 16239-16243 Gene denotes ERK1 Gene:5595
368 16248-16252 Gene denotes ERK2 Gene:5594
369 16762-16768 Gene denotes ERK1/2 Gene:5595
370 16822-16828 Gene denotes ERK1/2 Gene:5595
371 17049-17056 Gene denotes ERK 1/2 Gene:5595
372 17217-17223 Gene denotes ERK1/2 Gene:5595
373 16963-16966 Chemical denotes LDN
374 16627-16636 Disease denotes mortality MESH:D003643
375 16640-16647 Disease denotes COVID19 MESH:C000657245
377 17355-17365 Species denotes SARS-CoV-2 Tax:2697049
385 17493-17497 Gene denotes ACE2 Gene:59272
386 17511-17515 Gene denotes ACE2 Gene:59272
387 17622-17626 Gene denotes ACE2 Gene:59272
388 17453-17463 Species denotes SARS-CoV-2 Tax:2697049
389 17713-17723 Species denotes SARS-CoV-2 Tax:2697049
390 17405-17410 Gene denotes spike Gene:43740568
391 17682-17703 Disease denotes coronavirus infection MESH:D018352
407 17831-17835 Gene denotes ACE2 Gene:59272
408 18099-18103 Gene denotes ACE2 Gene:59272
409 18317-18321 Gene denotes ACE2 Gene:59272
410 17788-17798 Chemical denotes naltrexone MESH:D009271
411 17827-17830 Chemical denotes RBD
412 18043-18053 Chemical denotes naltrexone MESH:D009271
413 18114-18120 Chemical denotes Tyr505
414 18125-18131 Chemical denotes Glu406
415 18158-18166 Chemical denotes hydrogen MESH:D006859
416 18182-18192 Chemical denotes naltrexone MESH:D009271
417 18242-18248 Chemical denotes Arg403
418 18289-18294 Chemical denotes His34
419 18296-18301 Chemical denotes Glu37
420 18307-18313 Chemical denotes Phe390
421 18393-18403 Chemical denotes naltrexone MESH:D009271
425 18486-18490 Gene denotes ACE2 Gene:59272
426 18669-18673 Gene denotes ACE2 Gene:59272
427 18443-18453 Chemical denotes naltrexone MESH:D009271
443 18696-18700 Gene denotes ACE2 Gene:59272
444 18771-18775 Gene denotes ACE2 Gene:59272
445 18910-18914 Gene denotes ACE2 Gene:59272
446 19188-19192 Gene denotes ACE2 Gene:59272
447 19414-19418 Gene denotes ACE2 Gene:59272
448 19565-19569 Gene denotes ACE2 Gene:59272
449 19354-19364 Species denotes SARS Cov-2 Tax:2697049
450 19709-19720 Species denotes coronavirus Tax:11118
451 18705-18715 Chemical denotes Naltrexone MESH:D009271
452 18798-18806 Chemical denotes SSAA09E2 MESH:C583223
453 18811-18823 Chemical denotes Bisoctrizole
454 18942-18952 Chemical denotes Naltrexone MESH:D009271
455 19102-19112 Chemical denotes Naltrexone MESH:D009271
456 19259-19269 Chemical denotes Naltrexone MESH:D009271
457 19369-19379 Chemical denotes Naltrexone MESH:D009271
462 19792-19796 Gene denotes ACE2 Gene:59272
463 19910-19914 Gene denotes ACE2 Gene:59272
464 20130-20134 Gene denotes ACE2 Gene:59272
465 19906-19909 Chemical denotes RBD
472 20209-20213 Gene denotes ACE2 Gene:59272
473 20492-20496 Gene denotes ACE2 Gene:59272
474 21159-21163 Gene denotes ACE2 Gene:59272
475 21284-21288 Gene denotes ACE2 Gene:59272
476 21164-21174 Chemical denotes Naltrexone MESH:D009271
477 20264-20272 Disease denotes atoms MD MESH:D009436
497 21941-21945 Gene denotes ACE2 Gene:59272
498 22964-22967 Gene denotes ACE Gene:1636
499 23064-23068 Gene denotes ACE2 Gene:59272
500 23207-23211 Gene denotes ACE2 Gene:59272
501 21634-21642 Chemical denotes hydrogen MESH:D006859
502 21946-21956 Chemical denotes Naltrexone MESH:D009271
503 22419-22429 Chemical denotes naltrexone MESH:D009271
504 22921-22929 Chemical denotes hydrogen MESH:D006859
505 23110-23120 Chemical denotes naltrexone MESH:D009271
506 23122-23128 Chemical denotes Lys417
507 23133-23139 Chemical denotes Asp405
508 23160-23168 Chemical denotes hydrogen MESH:D006859
509 23180-23190 Chemical denotes naltrexone MESH:D009271
510 23198-23203 Chemical denotes Glu37
511 23228-23236 Chemical denotes hydrogen MESH:D006859
512 23352-23358 Chemical denotes Ile418
513 23360-23366 Chemical denotes Gln409
514 23372-23378 Chemical denotes Tyr505
515 23502-23512 Chemical denotes naltrexone MESH:D009271
522 23639-23643 Gene denotes ACE2 Gene:59272
523 23711-23715 Gene denotes ACE2 Gene:59272
524 23541-23549 Chemical denotes hydrogen MESH:D006859
525 23644-23654 Chemical denotes naltrexone MESH:D009271
526 23716-23726 Chemical denotes naltrexone MESH:D009271
527 23767-23775 Chemical denotes hydrogen MESH:D006859
537 24444-24450 Gene denotes ERK1/2 Gene:5595
538 24561-24565 Gene denotes ACE2 Gene:59272
539 24360-24368 Species denotes patients Tax:9606
540 24792-24802 Chemical denotes Naltrexone MESH:D009271
541 24089-24097 Disease denotes COVID-19 MESH:C000657245
542 24150-24159 Disease denotes infection MESH:D007239
543 24163-24171 Disease denotes COVID-19 MESH:C000657245
544 24352-24359 Disease denotes COVID19 MESH:C000657245
545 24807-24837 Disease denotes Pruritus in Systemic Sclerosis MESH:D011537
574 24847-24852 Gene denotes Spike Gene:43740568
575 24987-24992 Gene denotes Spike Gene:43740568
576 25124-25129 Gene denotes Spike Gene:43740568
577 25187-25194 Gene denotes TMPRSS2 Gene:7113
578 25269-25273 Gene denotes ACE2 Gene:59272
579 25585-25590 Gene denotes Spike Gene:43740568
580 25623-25627 Gene denotes ACE2 Gene:59272
581 25752-25756 Gene denotes ACE2 Gene:59272
582 25903-25907 Gene denotes ACE2 Gene:59272
583 25939-25943 Gene denotes ACE2 Gene:59272
584 26062-26067 Gene denotes spike Gene:43740568
585 26117-26121 Gene denotes ACE2 Gene:59272
586 26230-26234 Gene denotes ACE2 Gene:59272
587 25365-25370 Gene denotes Spike Gene:43740568
588 24887-24898 Species denotes coronavirus Tax:11118
589 25535-25546 Species denotes coronavirus Tax:11118
590 26079-26089 Species denotes SARS-CoV-2 Tax:2697049
591 26215-26225 Species denotes SARS-CoV-2 Tax:2697049
592 26333-26343 Species denotes SARS-CoV-2 Tax:2697049
593 26193-26201 Chemical denotes hydrogen MESH:D006859
594 26269-26277 Chemical denotes tyrosine MESH:D014443
595 26288-26294 Chemical denotes Tyr436
596 26296-26302 Chemical denotes Tyr449
597 26304-26310 Chemical denotes Tyr489
598 26316-26322 Chemical denotes Tyr505
599 26356-26364 Chemical denotes hydrogen MESH:D006859
600 25817-25837 Disease denotes SARS-CoV-2 infection MESH:C000657245
601 25973-25984 Disease denotes lung injury MESH:D055370
622 26486-26491 Gene denotes spike Gene:43740568
623 26548-26552 Gene denotes ACE2 Gene:59272
624 26566-26570 Gene denotes ACE2 Gene:59272
625 26705-26709 Gene denotes ACE2 Gene:59272
626 26786-26790 Gene denotes ACE2 Gene:59272
627 27004-27008 Gene denotes ACE2 Gene:59272
628 27203-27207 Gene denotes ACE2 Gene:59272
629 26508-26518 Species denotes SARS-CoV-2 Tax:2697049
630 26767-26777 Species denotes SARS-CoV-2 Tax:2697049
631 27142-27152 Species denotes SARS-CoV-2 Tax:2697049
632 26711-26721 Chemical denotes Naltrexone MESH:D009271
633 26801-26807 Chemical denotes Tyr505
634 26812-26818 Chemical denotes Glu406
635 26845-26853 Chemical denotes hydrogen MESH:D006859
636 26869-26879 Chemical denotes naltrexone MESH:D009271
637 26929-26935 Chemical denotes Arg403
638 26976-26981 Chemical denotes His34
639 26983-26988 Chemical denotes Glu37
640 26994-27000 Chemical denotes Phe390
641 27077-27087 Chemical denotes naltrexone MESH:D009271
661 27923-27927 Gene denotes IL-6 Gene:3569
662 28138-28142 Gene denotes IL-6 Gene:3569
663 28006-28014 Species denotes patients Tax:9606
664 28201-28209 Species denotes patients Tax:9606
665 27804-27811 Chemical denotes steroid MESH:D013256
666 28082-28093 Chemical denotes Tocilizumab MESH:C502936
667 28211-28222 Chemical denotes Tocilizumab MESH:C502936
668 28349-28360 Chemical denotes tocilizumab MESH:C502936
669 28469-28480 Chemical denotes tocilizumab MESH:C502936
670 27275-27283 Disease denotes COVID-19 MESH:C000657245
671 27387-27395 Disease denotes COVID-19 MESH:C000657245
672 27425-27451 Disease denotes hyperinflammation symptoms MESH:D051271
673 27588-27607 Disease denotes infectious diseases MESH:D003141
674 27665-27673 Disease denotes COVID-19 MESH:C000657245
675 27830-27849 Disease denotes respiratory failure MESH:D012131
676 27997-28005 Disease denotes COVID-19 MESH:C000657245
677 28186-28200 Disease denotes critically ill MESH:D016638
678 28364-28377 Disease denotes viral disease MESH:D001102
679 28501-28509 Disease denotes COVID-19 MESH:C000657245
698 28787-28791 Gene denotes TLR4 Gene:7099
699 29157-29161 Gene denotes TLR4 Gene:7099
700 29625-29629 Gene denotes TLR4 Gene:7099
701 29715-29748 Gene denotes pro-inflammatory cytokines (IL)-1 Gene:3553
702 29750-29754 Gene denotes IL-2 Gene:3558
703 29763-29768 Gene denotes IL-18 Gene:3606
704 29647-29652 Species denotes human Tax:9606
705 28511-28535 Chemical denotes Naltrexone hydrochloride MESH:D009271
706 28641-28651 Chemical denotes naltrexone MESH:D009271
707 28681-28688 Chemical denotes alcohol MESH:D000438
708 28709-28719 Chemical denotes Naltrexone MESH:D009271
709 28897-28907 Chemical denotes naltrexone MESH:D009271
710 29316-29326 Chemical denotes naltrexone MESH:D009271
711 29414-29424 Chemical denotes Naltrexone MESH:D009271
712 29571-29581 Chemical denotes Naltrexone MESH:D009271
713 29676-29679 Chemical denotes LDN
714 30062-30080 Chemical denotes hydroxychloroquine MESH:D006886
715 30130-30138 Disease denotes COVID-19 MESH:C000657245
725 30412-30420 Species denotes patients Tax:9606
726 30570-30578 Species denotes patients Tax:9606
727 30268-30278 Chemical denotes naltrexone MESH:D009271
728 30422-30425 Chemical denotes LDN
729 30463-30481 Chemical denotes hydroxychloroquine MESH:D006886
730 30341-30349 Disease denotes COVID-19 MESH:C000657245
731 30350-30360 Disease denotes infections MESH:D007239
732 30403-30411 Disease denotes COVID-19 MESH:C000657245
733 30584-30592 Disease denotes COVID-19 MESH:C000657245

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T1 0-57 Sentence denotes Naltrexone a potential therapeutic candidate for COVID-19
T2 58-60 Sentence denotes A.
T3 61-75 Sentence denotes Choubey et al.
T4 76-122 Sentence denotes Journal of Biomolecular Structure and Dynamics
T5 124-132 Sentence denotes Abstract
T6 133-141 Sentence denotes Abstract
T7 142-289 Sentence denotes Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease (COVID-19) that has resulted in a global pandemic.
T8 290-377 Sentence denotes At the time of writing, approximately 16.06 million cases have been reported worldwide.
T9 378-611 Sentence denotes Like other coronaviruses, SARS-CoV-2 relies on the surface Spike glycoprotein to access the host cells, mainly through the interaction of its Receptor Binding Domain (RBD) with the host receptor Angiotensin-Converting Enzyme2 (ACE2).
T10 612-695 Sentence denotes SARS-CoV-2 infection induces a profound downstream pro-inflammatory cytokine storm.
T11 696-859 Sentence denotes This release of the pro-inflammatory cytokines is underpinning lung tissue damage, respiratory failure, and eventually multiple organ failure in COVID-19 patients.
T12 860-1011 Sentence denotes The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity.
T13 1012-1267 Sentence denotes Therefore, molecular entities able to interfere with binding of the SARS-CoV-2 Spike protein to ACE2, or damping hyperinflammatory cytokines storm, blocking ERK1/2 phosphorylation have a great potential to inhibit viral entry along with viral infectivity.
T14 1268-1478 Sentence denotes Herein, we report that the FDA-approved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage.
T15 1479-1563 Sentence denotes Moreover, Low Dose Naltrexone (LDN) also showed its activity as an ERK1/2 inhibitor.
T16 1564-1671 Sentence denotes Notably, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD.
T17 1672-1775 Sentence denotes LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection.
T18 1776-1909 Sentence denotes Clinical toxicity measurements may not be required for LDN since naltrexone was previously tested and is an approved drug by the FDA.
T19 1910-1938 Sentence denotes Communicated by Ramaswamy H.
T20 1939-1944 Sentence denotes Sarma
T21 1946-1958 Sentence denotes Introduction
T22 1959-2168 Sentence denotes Coronavirus Disease 2019 (COVID-19) is a major health concern, clinical symptoms of the disease vary from a mild illness, acute respiratory issues to multi-organ failure (Wang et al., 2020; Zaim et al., 2020).
T23 2169-2292 Sentence denotes Older age, diabetes, cardiac diseases predict poor prognosis in COVID-19 patients (Fang et al., 2020; Madjid et al., 2020).
T24 2293-2424 Sentence denotes Although much is known about the mortality of the COVID-19, however, details of the cellular responses to this virus are not known.
T25 2425-2708 Sentence denotes Several preclinical and clinical trials data have indicated an elevated cytokine/chemokine response in severe COVID-19 patients and identifies cytokine storm as the most potentially dangerous event for mortality (Coperchini et al., 2020; Rahmati & Moosavi, 2020; Zhang et al., 2020).
T26 2709-2860 Sentence denotes Several kinases in the MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinases) pathway are essential for viral replication.
T27 2861-2953 Sentence denotes ERK1 and ERK2 phosphorylate HIV-1 proteins and enhance viral infectivity (Cai et al., 2007).
T28 2954-3124 Sentence denotes The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity (Cai et al., 2007).
T29 3125-3269 Sentence denotes Some preclinical findings have suggested targeting the ERK1/2 pathway to halt the viral replication and severity of SARS-COV-2 (Mizutani, 2010).
T30 3270-3453 Sentence denotes SARS-CoV-2 uses the homotrimeric spike glycoprotein as the main protein that interacts with the host by binding to host cell receptors (ACE2) to mediate virus invasion for cell entry.
T31 3454-3595 Sentence denotes Some recent studies have highlighted the important role of ACE2 in mediating entry of SARS-CoV-2 (Hoffmann et al., 2020; Walls et al., 2020).
T32 3596-3763 Sentence denotes A recent report also recognized several critical residues in RBD, including its Receptor-Binding Motif (RBM) that directly contacts with human ACE2 (Lan et al., 2020).
T33 3764-3974 Sentence denotes An in-vitro study using HeLa cells also reinforced the role of ACE2 in mediating entry of SARS-CoV-2, where HeLa cells expressing ACE2 are susceptible to SARS-CoV-2 infection whereas those without ACE2 are not.
T34 3975-4390 Sentence denotes Furthermore, in-vitro binding measurements, experiments showed that the SARS-CoV-2 RBD binds to ACE2 with an affinity in the nanomolar range, indicating that the RBD is a key functional component that is responsible for the binding of SARS-CoV-2 by ACE2 and can be considered as a target for the treatment of coronavirus infection to block SARS-CoV-2 from entering host cells (Lan et al., 2020; Walls et al., 2020).
T35 4391-4481 Sentence denotes There is a very fast ongoing search for therapeutics acting on SARS-CoV-2 (Hussain, 2020).
T36 4482-4786 Sentence denotes Depending on the activity, the therapies can be divided into majorly main categories: (1) Inhibiting the viral RNA synthesis and replication, (2) Deterring the virus from binding to human cell ACE2 receptors, (3) Reinstating the innate immunity, and (4) Blocking the host’s specific receptors or enzymes.
T37 4787-4971 Sentence denotes Despite many experimental and computational studies currently exploring all of these categories, to date, there is no confirmed effective treatment specifically available for COVID-19.
T38 4972-5239 Sentence denotes In this study, we report that the FDA-approved non-peptide opioid antagonist drug (Vickers & Jolly, 2006), naltrexone in low dose (LDN) suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose tissue macrophages (ATMs).
T39 5240-5457 Sentence denotes The naltrexone is already an FDA approved drug and thus the pharmacology (pharmacokinetics and pharmacodynamics) of naltrexone is well known and reported elsewhere (Gonzalez & Brogden, 1988; Toljan and Vrooman, 2018).
T40 5458-5506 Sentence denotes LDN also showed activity as an ERK1/2 inhibitor.
T41 5507-5615 Sentence denotes Moreover, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD.
T42 5616-5953 Sentence denotes As a reliable COVID-19 vaccine is unlikely to available before the maximal infection of COVID-19 has occurred, it is essential to establish therapeutics for the COVID-19 patients, based on our data, we proposed FDA-approved LDN can be used in combination or as an adjuvants therapy to treat mild to moderate symptomatic COVID-19 patients
T43 5955-5982 Sentence denotes Research design and methods
T44 5984-6003 Sentence denotes Drugs and chemicals
T45 6004-6071 Sentence denotes Naltrexone hydrochloride was obtained from MP Biomedicals (151725).
T46 6073-6105 Sentence denotes Cell lines and culture treatment
T47 6106-6243 Sentence denotes Murine macrophage (Raw264.7) cell line was cultured in RPMI media supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin
T48 6245-6259 Sentence denotes Cell viability
T49 6260-6436 Sentence denotes Cell viability assay was carried out in Raw264.7 cells using MTT dye (3-(4, 5-dimethyl thiazol-2yl)-2, 5-diphenyl tetrazolium bromide) as reported earlier (Dogra et al., 2019).
T50 6437-6504 Sentence denotes Cells were seeded in a 96-well plate and allowed to grow overnight.
T51 6505-6608 Sentence denotes Further cells were treated with varying doses (0, 2, 5, 10, 15, 20, 30, and 40 µM) of the LDN for 24 h.
T52 6609-6688 Sentence denotes Post-treatment, 10 µl of MTT (5 mg/ml stock in PBS) was added to all the wells.
T53 6689-6819 Sentence denotes The formazan crystals thus formed were solubilized in 200 µl DMSO and the absorbance was recorded using (Infinite M200 Pro TECAN).
T54 6821-6862 Sentence denotes RNA isolation and gene expression profile
T55 6863-6952 Sentence denotes Raw264.7 cultured cells were treated with 5 μM of LDN in the presence and absence of LPS.
T56 6953-7110 Sentence denotes RNA was isolated from the cells using RNA-Xpress reagent (HiMedia-MB601) and 1 µg of RNA was reverse-transcribed (using iScript cDNA Synthesis kit- Bio-Rad).
T57 7111-7254 Sentence denotes Real time PCR was carried out following standard procedures using SYBR green (Bio-Rad) using mouse primers indicated in Supplementary table S4.
T58 7255-7379 Sentence denotes Expression levels were calculated using the 2-ΔΔCT method with 18S rRNA as an internal control (Livak and Schmittgen, 2001).
T59 7381-7402 Sentence denotes Western blot analysis
T60 7403-7498 Sentence denotes Raw264.7 cultured cells were incubated with LDN (0 and 5 µM) in the presence or absence of LPS.
T61 7499-7595 Sentence denotes After treatment, cells were lysed in RIPA buffer containing 1% protease- phosphatase inhibitors.
T62 7596-7722 Sentence denotes Protein concentration was determined by BCA assay reagent as described in the manufacturer’s (Thermo Scientific-23227) manual.
T63 7723-7795 Sentence denotes Protein was loaded on SDS-PAGE and electro-blotted on to PVDF membranes.
T64 7796-8085 Sentence denotes The membrane was incubated in 5% milk blocking solution for 2 h at room temperature (RT) and probed against primary antibody (1:2000 diluted in TBST; After washing with TBST, the membrane was incubated with HRP conjugated IgG secondary antibody for 2 h and visualized by chemiluminescence.
T65 8086-8170 Sentence denotes A list of antibodies is provided in supplemental experimental procedures (Table S3).
T66 8172-8198 Sentence denotes ATM isolation and analysis
T67 8199-8285 Sentence denotes Mice were euthanized chemically and epididymal fat was processed for isolation of ATM.
T68 8286-8398 Sentence denotes 1 gram of adipose fat was rinsed in PBS and minced to small pieces in HEPES-DMEM buffer containing 10 mg/ml BSA.
T69 8399-8512 Sentence denotes The suspension was centrifuged at 1000 g for 10 min and the resultant supernatant was pipette off to fresh tubes.
T70 8513-8759 Sentence denotes 1 mg/ml of collagenase type-IV and 50 U/ml DNAse-II were added to this suspension and incubated at 37 °C for 45 mins with moderate shaking, filtered through 250-micron filter and the resultant solution was centrifuged again at 1000 g for 10 mins.
T71 8760-8814 Sentence denotes Floating cells contained adipocyte and pellet are SVC.
T72 8815-8928 Sentence denotes RBC lysis buffer was added gently to disrupt the sedimented pellets and centrifuged at 1000 g for 10 min at 4 °C.
T73 8929-9067 Sentence denotes Fat macrophage cells were isolated by using BD IMag anti-mouse CD11b + magnetic beads through positive selection under the magnetic field.
T74 9068-9203 Sentence denotes The percentage purity of macrophage isolation was determined by FACSCANTO II flow cytometer using APC tagged CD11b monoclonal antibody.
T75 9204-9337 Sentence denotes The isolated macrophage was processed for RNA isolation, cDNA synthesis and various M1-M2 markers were evaluated using real-time PCR.
T76 9339-9382 Sentence denotes Structure preparation and molecular docking
T77 9383-9445 Sentence denotes The experimentally solved SARS CoV-2 RBD-ACE2 complex (PDB ID:
T78 9446-9510 Sentence denotes 6M0J solved at 2.45 Å) was obtained from PDB (Lan et al., 2020).
T79 9511-9546 Sentence denotes The ligand naltrexone (PubChem CID:
T80 9547-9596 Sentence denotes 5360515) was extracted from the PubChem database.
T81 9597-9792 Sentence denotes An attempt was made to dock to explore the binding mode of naltrexone onto the binding interface of the RBD-ACE2 complex using AutoDock version 4.2 (Morris et al., 2009) and AUTODOCK tools 1.5.6.
T82 9793-9879 Sentence denotes Before docking, the protein was prepared by the removal of small molecules and waters.
T83 9880-9977 Sentence denotes Then, polar-hydrogen atoms were added to the structure followed by Gasteiger charges calculation.
T84 9978-10261 Sentence denotes Ligand centered map was generated with a spacing of 0.375 Å and grid dimensions of 46 × 46 × 46 Å3 (x-y-z) covering the biding interfaces residues (which includes the receptor-binding motif viz., RBM) of the complex (coordinates of central grid point of maps:-34.512, 20.978, 4.521).
T85 10262-10372 Sentence denotes Default settings were used for all other parameters while performing docking with the number of GA run to 100.
T86 10373-10605 Sentence denotes From the resultant docked conformations, the top-ranked conformation with the least free energy of binding, hydrogen-bonding and interatomic-bonding pattern was selected for further optimization by employing long term MD simulation.
T87 10606-10833 Sentence denotes PyMOL (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC.) and BIOVIA Discovery Studio Visualizer version4.5 were employed used to visualize the inter-molecular contacts between naltrexone with RBD-ACE2 complex.
T88 10834-10972 Sentence denotes In order to perform target prediction calculation and comparative analysis, we docked two reported inhibitors of ACE2 named SSAA09E2 (CID:
T89 10973-11004 Sentence denotes 2738575) and Bisoctrizole (CID:
T90 11005-11139 Sentence denotes 3571576) using the same parameters employed for naltrexone with ACE2-RBD complex through AutoDock (Adedeji et al., 2013; Patil, 2020).
T91 11141-11170 Sentence denotes Molecular dynamics simulation
T92 11171-11387 Sentence denotes To study the dynamic behavior, stability, and conformational flexibility RBD-ACE2- naltrexone complex, all-atoms MD simulations were performed as reported previously (Dehury et al., 2014; 2017; Girdhar et al., 2019).
T93 11388-11502 Sentence denotes CHARMM36 force fields were used for topology building of protein in GROMACSv2019.4 package (Abraham et al., 2015).
T94 11503-11636 Sentence denotes The ligand topology was derived from CHARMM General Force Field (https://cgenff.umaryland.edu/) (Vanommeslaeghe and MacKerell, 2012).
T95 11637-11706 Sentence denotes The structure was solvated in a cubic water box in TIP3P water model.
T96 11707-11794 Sentence denotes The system charge was electro-neutralized by adding 0.15 M NaCl to the solvated system.
T97 11795-11923 Sentence denotes To eliminate bad contacts in the complex system energy minimization was done with the steepest descent algorithm in 5,000 steps.
T98 11924-12109 Sentence denotes The non-hydrogen atoms of the ligands were restrained, and system equilibration was done in two steps including NVT and NPT ensembles in 10 ns at 300 K in atmospheric condition (1 atm).
T99 12110-12225 Sentence denotes Finally, production MD was performed 100 ns at 300 K with a 2-femtosecond (fs) time step using Leapfrog integrator.
T100 12226-12368 Sentence denotes The resultant trajectory was explored to understand the structural dynamics of the complex system through various utility toolkits of GROMACS.
T101 12369-12608 Sentence denotes Stability parameters including backbone root mean square deviation (RMSD), the radius of gyration (Rg), Cα-root mean squared fluctuations (RMSF), and intermolecular hydrogen bond (H-bond) distributions were computed for the complex system.
T102 12609-12712 Sentence denotes 2D graphs were plotted using XMGrace, while, interaction images were plotted using BIVIA DSV and PyMOL.
T103 12714-12734 Sentence denotes Statistical analysis
T104 12735-12824 Sentence denotes All the data presented is as mean ± SEM of three individual experiments unless specified.
T105 12825-12927 Sentence denotes Comparisons between means were performed using Student t-test for unpaired data within two conditions.
T106 12929-12936 Sentence denotes Results
T107 12938-12989 Sentence denotes LDN treatment diminishes LPS induced cytokine storm
T108 12990-13194 Sentence denotes Cytokine storm is a very commonly observed factor in most severe COVID-19 patients and also one of the leading causes of mortality (Coperchini et al., 2020; Rahmati and Moosavi, 2020; Zhang et al., 2020).
T109 13195-13306 Sentence denotes Peripheral blood of severe COVID-19 patients has also shown a high level of cytokine storm (Wu and Yang, 2020).
T110 13307-13585 Sentence denotes Keeping in mind the ability of lipopolysaccharide (LPS) to cause sepsis and triggers an uncontrolled systemic inflammatory response in murine macrophage cells (Ramos-Benitez et al., 2018), we treated macrophage cells with LPS (1 µg/ml) in the presence and absence of LDN (5 µM).
T111 13586-13789 Sentence denotes The dose of LDN chosen is non-toxic (Figure S2) as found in cell viability using MTT (4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay following the standard protocol (Dogra et al., 2019).
T112 13790-14028 Sentence denotes Results demonstrated that LPS treatment significantly induced expression on pro-inflammatory cytokines (IL-1β, IL-6 and mcp-1) whereas, LDN significantly inhibited LPS expression of IL-1β, IL-6 and mcp-1 in macrophage cells (Figure 1(A)).
T113 14029-14260 Sentence denotes Next, we tested the possible involvement of LPS in inducing the release of pro-inflammatory cytokines, and we also determine the effects of LDN on release of pro-inflammatory mediators in LPS induced macrophage cells (Figure 1(B)).
T114 14261-14517 Sentence denotes Conditioned media from LPS challenged macrophage cells showed a significantly enhanced release pro-inflammatory mediators (IL-1β, MCP-1 and IL-6) and interestingly we found that LDN treatment attenuated LPS induced IL-1β, MCP1 and IL-6 level (Figure 1(B)).
T115 14518-14717 Sentence denotes These data suggest that LPS induced macrophage cells, to release - pro-inflammatory mediators, and LDN treatment can significantly abrogate LPS induced release of pro-inflammatory mediators in media.
T116 14718-14994 Sentence denotes Adipose tissue macrophages (ATMs) is closely linked to this inflammatory condition which leads to numbers of diseases and the ability of High Fat Diet (HFD) feeding on increased LPS uptake and trafficking to macrophages and other targets are well known (Hersoug et al., 2016).
T117 14995-15274 Sentence denotes Hence in this study, we investigated the effect of HFD on proinflammatory markers expression in purified ATMs. Expression of pro-inflammatory markers such as IL-1β, MCP-1 and IL-6 was induced (Figure 1(C)) whereas LDN attenuates HFD induced pro-inflammatory cytokines expression.
T118 15275-15399 Sentence denotes Altogether, this data clearly shows that LDN treatment may protect (by reducing elevated M1 cytokines) against inflammation.
T119 15400-15846 Sentence denotes Figure 1. (A) LDN prevents LPS induced pro-inflammatory cytokines expression and release Quantitative mRNA expression of indicated genes (mcp-1, il-6 and Il1b) in murine macrophage cells. (B) ELISA of pro-inflammatory proteins (MCP-1, IL-6 and IL-1β) in conditioned media from LPS challenged murine macrophage cells in the present and absence of LDN (C) Quantitative mRNA expression of IL-1β, mcp-1 and IL-6 in purified ATMs from all group mice.
T120 15847-16082 Sentence denotes Values are expressed as mean ± SEM (n = 3) from three independent sets of repeats (mean ± SEM ***p < 0.001, **p, ^^p < 0.01 *p,^p < 0.05.) (D) LDN acts as EKR1 inhibitor and improved insulin sensitivity in LPS treated macrophage cells.
T121 16083-16177 Sentence denotes ERK1/2 (Immunoblot) in RAW cells treated with LPS (1ug/ml) in the presence and absence of LDN.
T122 16179-16238 Sentence denotes LDN treatment attenuates LPS induced ERK1/2 phosphorylation
T123 16239-16431 Sentence denotes ERK1 and ERK2 mitogen-activated protein kinases (MAPK) play a critical role in the regulation of cell proliferation and differentiation in response to mitogens and other extracellular stimuli.
T124 16432-16548 Sentence denotes Mitogens and cytokines that activate MAPK in cells have been shown to activate virus replication (Cai et al., 2007).
T125 16549-16721 Sentence denotes The cytokine storm is a well-known factor that is increasing the severity and mortality in COVID19 (Coperchini et al., 2020; Rahmati and Moosavi, 2020; Zhang et al., 2020).
T126 16722-16932 Sentence denotes Moreover, the phosphorylation status of ERK1/2 is positively correlated with virus load and reduced ERK1/2 phosphorylation suppressed viral replication significantly, thus reduced viral load (Cai et al., 2007).
T127 16933-17000 Sentence denotes We pre-treated the cells with LDN and were exposed to LPS for 18 h.
T128 17001-17156 Sentence denotes As shown in Figure 1(D), the phosphorylation of ERK 1/2 was increased after LPS exposure which was significantly suppressed by LDN treatment (Figure 1(D)).
T129 17157-17277 Sentence denotes This finding suggests that LDN can acts as an inhibitor for ERK1/2 activation and may reduce the infectivity of virions.
T130 17279-17369 Sentence denotes In-silico studies revealed LDN interacts with the receptor-binding motif of SARS-CoV-2-RBD
T131 17370-17573 Sentence denotes The latest research shows that the spike-receptor binding domain (RBD) sequence of SARS-CoV-2 interacts with host receptor ACE2 and this RBD-ACE2 complex plays a key role in virus invasion and virulence.
T132 17574-17749 Sentence denotes Based on the current research progress, the RBD-ACE2 complex is considered as a target for the treatment of coronavirus infection to block SARS-CoV-2 from entering host cells.
T133 17750-17892 Sentence denotes To understand the mode of interaction naltrexone in the binding interface of RBD-ACE2 complex, molecular docking was performed using AutoDock.
T134 17893-17970 Sentence denotes The docking scores of the top ten complexes have been summarized in Table S1.
T135 17971-18113 Sentence denotes As evidenced by the top-ranked conformation (as shown in Figure 2), the naltrexone prefers to bind in the cavity formed RBD and ACE2 receptor.
T136 18114-18278 Sentence denotes Tyr505 and Glu406 of RBD formed two crucial hydrogen bonds with the naltrexone with an atomic distance of 2.08 and 1.80, while, Arg403 formed electrostatic contact.
T137 18279-18404 Sentence denotes While the His34, Glu37, and Phe390 of ACE2 displayed several hydrophobic contacts (mostly pi-alkyl contacts) with naltrexone.
T138 18405-18414 Sentence denotes Figure 2.
T139 18416-18609 Sentence denotes The docked conformation of naltrexone at the binding interface of RBD-ACE2 complex obtained from AutoDock (A) and interface amino acid residues involved in non-bonded contacts are labelled (B).
T140 18610-18674 Sentence denotes The residues labeled in blue represent RBD and in pink are ACE2.
T141 18675-18791 Sentence denotes Further, we compared ACE2-RBD/Naltrexone binding affinity with some recently reported potential ACE2-RBD inhibitors.
T142 18792-19015 Sentence denotes Both (SSAA09E2 and Bisoctrizole) displayed an affinity score of −6.7 kcal/mol and −8.5 kcal/mol respectively with the ACE2-RBD complex as compared to Naltrexone which shows an affinity score of −6.01 kcal mol−1 (Figure S3).
T143 19016-19365 Sentence denotes Comparative analysis of docked conformation of two reported inhibitors as compared to Naltrexone revealed that the former two prefers to occupy the inner central cavity in ACE2-RBD complex (close to the N-terminus contact interface) and while Naltrexone occupied the core central surface with a greater number of contacts with the RBD of SARS Cov-2.
T144 19366-19570 Sentence denotes As Naltrexone occupies the central interface of ACE2-RBD complex, thus, it can be expected to break a greater number of crucial contacts which in turn can inhibit the binding of RBD to host receptor ACE2.
T145 19571-19754 Sentence denotes Further in-vitro and in-vivo studies are required to understand the efficacy of these compounds to understand the molecular basis of anti-coronavirus activity or inhibitory potential.
T146 19755-19764 Sentence denotes Figure 3.
T147 19766-20153 Sentence denotes Dynamics stability of RBD-ACE2-Naltrexone complex during 100 ns molecular dynamics simulation. (A) The root-mean square deviation (RMSD) of RBD-ACE2-Naltrexone complex during 100 ns MD in aqueous solution. (B) The compactness of the measured by the radius of gyration profile of complex with respect to time (C) The Cα-root mean squared fluctuation profile of the ACE2 and RBD during MD.
T148 20155-20174 Sentence denotes Trajectory analysis
T149 20175-20306 Sentence denotes The dynamics stability of the RBD-ACE2-naltrexone complex was analyzed by performing all-atoms MD simulations of 100 ns in GROMACS.
T150 20307-20471 Sentence denotes The backbone RMSD analysis provides important information on the stability of protein and protein-ligand complexes and the time when simulation reached equilibrium.
T151 20472-20597 Sentence denotes The RMSD of the RBD-ACE2-naltrexone complex displayed an average RMSD ∼2.46 Å throughout the entire simulation (Figure 3(A)).
T152 20598-20749 Sentence denotes Besides, the RMSD of ligand was also found to be stable (red line in Figure 3(A)) with very minimal deviation as compared to the starting conformation.
T153 20750-20911 Sentence denotes Overall, the complex system displayed the least backbone deviation, indicates that docked conformation is accurate and remained stable over the 100 ns timescale.
T154 20912-21114 Sentence denotes Radiuses of gyration assess the compactness of the system, where a compact gyradius of ∼3.24 nm for the complex indicates the consistent shape and size of the system during the simulation (Figure 3(B)).
T155 21115-21263 Sentence denotes The residue flexibility of protease and RBD-ACE2/Naltrexone complex was examined by performing Cα RMSF analysis of both the sub-units (Figure 3(C)).
T156 21264-21404 Sentence denotes The average RMSF of ACE2 was found to be 0.14 nm, while for the RBD it was reported to be 0.17 nm (for the receptor-binding motif ∼0.16 nm).
T157 21405-21614 Sentence denotes The receptor-binding motif of RBD displayed a high degree of flexibility and the residues participated in the ligand interaction also portrayed higher RMSF indicating their participation in ligand recognition.
T158 21615-21810 Sentence denotes The intermolecular hydrogen bonds (H-bonds) between interacting atom pairs in a protein-ligand complex plays a vital role in the stability and molecular recognition process (Dehury et al., 2014).
T159 21811-21979 Sentence denotes The intermolecular H-bonds were calculated with respect to time during the 100 ns MD simulation to see the dynamics stability RBD-ACE2-Naltrexone complex (Figure 4(A)).
T160 21980-22167 Sentence denotes Though we observed an increased differential H-bonding during the initial 20 ns equilibration phase, however a stable trend with an average of ∼4.13 H-bonds are noticed from 60 to 100 ns.
T161 22168-22359 Sentence denotes Close inspection of snapshots from MD revealed that some of the H-bonds were broken out during MD simulation, but at a later stage they well rewarded by new H-bonds, and hydrophobic contacts.
T162 22360-22452 Sentence denotes This may be due to the structural re-orientation of ligand naltrexone in the binding pocket.
T163 22453-22699 Sentence denotes The structural superposition of the docked complex with the cluster representative obtained from clustering analysis displayed Cα RMSD of 0.65 Å indicated that the complex retained its structural integrity throughout the simulation (Figure 4(B)).
T164 22700-22983 Sentence denotes However, close observation of the ligand for the initial starting structure used MD revealed that the ligand tends to reorient within the binding site during MD (as shown in Figure 4(C)) but form a close tight network of hydrogen bonds and non-bonded contact with ACE and RBM of RBD.
T165 22984-23121 Sentence denotes Analysis of the cluster representative revealed the crucial residues of RBD and ACE2 involved in the crucial interaction with naltrexone.
T166 23122-23254 Sentence denotes Lys417 and Asp405 from RBD formed two hydrogen bonds with naltrexone, while Glu37 of ACE2-formed the lone hydrogen bond (Figure S2).
T167 23255-23513 Sentence denotes Many electrostatic and hydrophobic contacts were also observed in the complex (Figure S2) where, Ile418, Gln409, and Tyr505 from RBD consistently formed close contact with ligand indicates their strong participation in the interaction mediated by naltrexone.
T168 23514-23523 Sentence denotes Figure 4.
T169 23525-24062 Sentence denotes Inter-molecular hydrogen bond dynamics and structural superposition of the initial complex with the simulated RBD-ACE2-naltrexone complex during 100 ns MD. (A) Dynamics stability of RBD-ACE2-naltrexone complex with respect to inter-molecular hydrogen bonds along the 100 ns time scale. (B) Structural superimposed view of the starting complex used for MD (green) and the snapshot obtained from clustering analysis (cyan) of MD trajectory during the last 50 ns. (C) Inter-molecular contacts of the docked complex and MD simulated complex.
T170 24064-24074 Sentence denotes Discussion
T171 24075-24289 Sentence denotes As a reliable COVID-19 vaccine is unlikely to available before the maximal infection of COVID-19 has occurred, it is essential to establish therapeutics for the individuals at moderate and high risk of the disease.
T172 24290-24391 Sentence denotes So far, anti-viral medication is a major available option for COVID19 patients (Madjid et al., 2020).
T173 24392-24575 Sentence denotes LDN which showed properties like anti-inflammatory, ERK1/2 inhibitory, and as well virtual docking and simulation data also suggested LDN may disrupt the interaction of ACE2 with RBD.
T174 24576-24846 Sentence denotes LDN has been gaining credibility in its ability to halt the progression of several diseases without significant side effects when administered in low dosage ( Toljan and Vrooman, 2018; Younger et al., 2014; Low-Dose Naltrexone for Pruritus in Systemic Sclerosis, XXXX ).
T175 24847-24986 Sentence denotes Spike is the main structural protein of coronavirus and assembles into a special corolla structure on the surface of the virus as a trimer.
T176 24987-25123 Sentence denotes Spike is the main protein that interacts with the host by binding to host cell receptors to mediate virus invasion (Walls et al., 2020).
T177 25124-25200 Sentence denotes Spike is cleaved into S1 and S2 by the host cell protease like TMPRSS2, etc.
T178 25201-25364 Sentence denotes The main function of S1 is to bind with host cell surface receptor; ACE2 and the S2 subunit mediates virus-cell and cell-cell membrane fusion (Walls et al., 2020).
T179 25365-25502 Sentence denotes Spike structural integrity and cleavage activation play a key role in virus invasion and virulence (Lu et al., 2020; Walls et al., 2020).
T180 25503-25718 Sentence denotes Therapeutic strategies to block coronavirus from entering host cells by targeting Spike proteins or specific receptors (ACE2) on the host surface are valuable for the development of anti-viral drugs (Hussain, 2020).
T181 25719-25985 Sentence denotes It is anticipated that potential ACE2 inhibitors may not be suitable to use as drugs for treating SARS-CoV-2 infection because the poor prognosis would be induced by the inhibition of ACE2 enzyme activities, considering ACE2 is a protective role against lung injury.
T182 25986-26159 Sentence denotes Recently, the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2 has been reported (Lan et al., 2020).
T183 26160-26435 Sentence denotes Lan et al mentioned there are 13 hydrogen bonds at the SARS-CoV-2 RBD–ACE2 interface, this involves multiple tyrosine residues (Tyr436, Tyr449, Tyr489, and Tyr505) from the SARS-CoV-2 RBD to form hydrogen-bonding interactions with the polar hydroxyl group (Lan et al., 2020).
T184 26436-26649 Sentence denotes The latest research further strengthened that the spike-RBD sequence of SARS-CoV-2 interacts with host receptor ACE2 and this RBD-ACE2 complex plays a key role in virus invasion and virulence (Walls et al., 2020).
T185 26650-26710 Sentence denotes Based on virtual screening results, LDN interacts with ACE2.
T186 26711-26800 Sentence denotes Naltrexone prefers to bind in the central cavity formed SARS-CoV-2 RBD and ACE2 receptor.
T187 26801-26965 Sentence denotes Tyr505 and Glu406 of RBD formed two crucial hydrogen bonds with the naltrexone with an atomic distance of 2.08 and 1.80, while, Arg403 formed electrostatic contact.
T188 26966-27088 Sentence denotes While the His34, Glu37, and Phe390 of ACE2 displayed some hydrophobic contacts (mostly pi-alkyl contacts) with naltrexone.
T189 27089-27243 Sentence denotes Overall this suggests LDN can strongly interact with SARS-CoV-2 RBD, including its RBM may further influence RDB- ACE2 binding, and host cell infectivity.
T190 27244-27500 Sentence denotes Therapeutic options for severe COVID-19 remain limited to date, immunomodulatory agents that directly target the crucial cytokines involved in COVID-19 may also help in alleviating hyperinflammation symptoms, mild and severe cases in particular(Zha, 2020).
T191 27501-27608 Sentence denotes Corticosteroids are among the most commonly used drugs for immunomodulatory therapy of infectious diseases.
T192 27609-27762 Sentence denotes However, the use of corticosteroids in the treatment of COVID-19 can cause host immune suppression and may delay viral clearance (Stockman et al., 2006).
T193 27763-27906 Sentence denotes Combination of antibiotic, antiviral and steroid therapy exhibited respiratory failure and required non-invasive ventilation (Wu et al., 2020).
T194 27907-28053 Sentence denotes Elevated plasma IL-6 levels have been reported and to be predictive of a fatal outcome in COVID-19 patients (Coperchini et al., 2020; Zhao, 2020).
T195 28054-28210 Sentence denotes Other than corticosteroids, Tocilizumab, a specific monoclonal antibody that blocks IL-6, has been recommended for use in severe or critically ill patients.
T196 28211-28314 Sentence denotes Tocilizumab specifically binds to IL-6 receptor and blocks its signaling cascade (Tanaka et al., 2016).
T197 28315-28394 Sentence denotes However, clinical experience with tocilizumab in viral disease is very limited.
T198 28395-28510 Sentence denotes Moreover, high costs and safety risks may be a barrier to the wide use of tocilizumab in the treatment of COVID-19.
T199 28511-28608 Sentence denotes Naltrexone hydrochloride is an FDA-approved non-peptide opioid antagonist (Cornish et al., 1997).
T200 28609-28699 Sentence denotes In 1995, the FDA approved 50 mg naltrexone (ReVia) for the treatment of alcohol addiction.
T201 28700-28887 Sentence denotes Low Dose Naltrexone (LDN; dose between 1 and 5 mg) is an immune-modulator, and a known TLR4 and opioid receptor antagonist (Cant et al., 2017; Hutchinson et al., 2008; Wang et al., 2016).
T202 28888-29294 Sentence denotes Although naltrexone was synthesized as an orally active competitive opioid receptor antagonist, however, LDN exhibits paradoxical properties, including analgesia and anti-inflammatory actions, where, LDN simultaneously has an antagonist effect on non-opioid receptors (TLR4) which have not been reported at higher doses (Cant et al., 2017; Hutchinson et al., 2008; Wang et al., 2016; Younger et al., 2014).
T203 29295-29453 Sentence denotes Unlike high doses of naltrexone, LDN has several mechanisms of action reported in the literature (The Uses of Low-Dose Naltrexone in Clinical Practice, 2020).
T204 29454-29610 Sentence denotes LDN stimulates the release of β-endorphins by acting on the opioid receptor (Gold et al., 1982; The Uses of Low-Dose Naltrexone in Clinical Practice, 2020).
T205 29611-29803 Sentence denotes LDN acts as a TLR4 antagonist, in a human pilot study (4.5 mg of LDN daily) significantly reduced serum pro-inflammatory cytokines (IL)-1, IL-2, IL-12, IL-18, etc (Parkitny and Younger, 2017).
T206 29804-30139 Sentence denotes Importantly, low cost, low side effects, no reports of LDN interactions with other medications, and oral availability make LDN as a lucrative option to be used as an immunomodulatory agent and may be considered for use in combination with antiviral drugs or hydroxychloroquine for the treatment of severe or critical cases of COVID-19.
T207 30140-30361 Sentence denotes Our data provide a proof-of-concept for the potential feasibility of repurposing of FDA approved non-peptide opioid antagonist; naltrexone as host-targeted broad-spectrum antiviral therapies to combat COVID-19 infections.
T208 30362-30421 Sentence denotes The next step will be to confirm data in COVID-19 patients.
T209 30422-30593 Sentence denotes LDN alone or as an adjuvant therapy with hydroxychloroquine or an antiviral agent may give physicians more time to provide supportive treatment for patients with COVID-19.
T210 30595-30617 Sentence denotes Supplementary Material
T211 30618-30652 Sentence denotes Supporting_Information_1......docx
T212 30653-30689 Sentence denotes Click here for additional data file.
T213 30691-30707 Sentence denotes Acknowledgements
T214 30708-30800 Sentence denotes We sincerely thank the BioX Centre of IIT Mandi for use of different analytical instruments.
T215 30801-30899 Sentence denotes AC thank Department of Science & Technology (DST) INSPIRE fellowship, for his research fellowship.
T216 30900-30956 Sentence denotes The authors received no funding from an external source.
T217 30958-30978 Sentence denotes Disclosure statement
T218 30979-31053 Sentence denotes No potential conflicts of interest relevant to this article were reported.
T219 31055-31075 Sentence denotes Author contributions
T220 31076-31143 Sentence denotes AC conducted the majority of the experiments and analyzed the data.
T221 31144-31182 Sentence denotes BD and SK conducted in silico studies.
T222 31183-31233 Sentence denotes PM, designed the study and supervised the project.
T223 31234-31298 Sentence denotes PM and AC, wrote the manuscript with support from BD, SK and BM.
T224 31299-31484 Sentence denotes PM is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

2_test

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