Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose
Background Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug’s mode of inhibition has not been fully investigated. Methods We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide ($ H_{2} $$ O_{2} $) as a surrogate of oxidative stress in non-lethal APAP overdose. Results Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant ($ K_{i} $) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion. Conclusions T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
|---|---|
| Enthalten in: |
Molecular medicine - 30(2024), 1 vom: 27. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bloom, Joshua [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| BKL: | |
|---|---|
| Themen: |
Acetaminophen |
| Anmerkungen: |
© The Author(s) 2024 |
|---|
| doi: |
10.1186/s10020-024-00803-0 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
SPR055317561 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | SPR055317561 | ||
| 003 | DE-627 | ||
| 005 | 20240328072119.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240328s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s10020-024-00803-0 |2 doi | |
| 035 | |a (DE-627)SPR055317561 | ||
| 035 | |a (SPR)s10020-024-00803-0-e | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | 4 | |a 610 |q VZ |
| 082 | 0 | 4 | |a 610 |q VZ |
| 084 | |a 44.00 |2 bkl | ||
| 100 | 1 | |a Bloom, Joshua |e verfasserin |0 (orcid)0000-0001-7654-7828 |4 aut | |
| 245 | 1 | 0 | |a Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © The Author(s) 2024 | ||
| 520 | |a Background Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug’s mode of inhibition has not been fully investigated. Methods We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide ($ H_{2} $$ O_{2} $) as a surrogate of oxidative stress in non-lethal APAP overdose. Results Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant ($ K_{i} $) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion. Conclusions T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity. | ||
| 650 | 4 | |a MIF |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Iguratimod |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Acetaminophen |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Enzyme |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Drug screening |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Inflammation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Drug discovery |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Toxicology |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Pantouris, Georgios |4 aut | |
| 700 | 1 | |a He, Mingzhu |4 aut | |
| 700 | 1 | |a Aljabari, Bayan |4 aut | |
| 700 | 1 | |a Mishra, Lopa |4 aut | |
| 700 | 1 | |a Manjula, Ramu |4 aut | |
| 700 | 1 | |a Parkins, Andrew |4 aut | |
| 700 | 1 | |a Lolis, Elias J. |4 aut | |
| 700 | 1 | |a Al-Abed, Yousef |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular medicine |d BioMed Central, 1994 |g 30(2024), 1 vom: 27. März |w (DE-627)SPR008052611 |w (DE-600)1475577-4 |x 1528-3658 |7 nnns |
| 773 | 1 | 8 | |g volume:30 |g year:2024 |g number:1 |g day:27 |g month:03 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1186/s10020-024-00803-0 |z kostenfrei |3 Volltext |
| 912 | |a GBV_SPRINGER | ||
| 912 | |a SSG-OLC-PHA | ||
| 936 | b | k | |a 44.00 |q VZ |
| 951 | |a AR | ||
| 952 | |d 30 |j 2024 |e 1 |b 27 |c 03 | ||