Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved..
Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:71 |
|---|---|
| Enthalten in: |
Redox biology - 71(2024) vom: 01. Apr., Seite 103088 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Marañón, Patricia [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
362O9ITL9D |
|---|
| Anmerkungen: |
Date Completed 01.04.2024 Date Revised 01.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.redox.2024.103088 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368912701 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368912701 | ||
| 003 | DE-627 | ||
| 005 | 20240401232647.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.redox.2024.103088 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1359.xml |
| 035 | |a (DE-627)NLM368912701 | ||
| 035 | |a (NLM)38401290 | ||
| 035 | |a (PII)S2213-2317(24)00064-8 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Marañón, Patricia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.04.2024 | ||
| 500 | |a Date Revised 01.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ALK3 | |
| 650 | 4 | |a Acetaminophen | |
| 650 | 4 | |a Acute liver failure | |
| 650 | 4 | |a Bone morphogenetic proteins | |
| 650 | 4 | |a DMH2 | |
| 650 | 4 | |a Drug induced liver injury | |
| 650 | 7 | |a Acetaminophen |2 NLM | |
| 650 | 7 | |a 362O9ITL9D |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a DMH2 |2 NLM | |
| 650 | 7 | |a Morpholines |2 NLM | |
| 700 | 1 | |a Rey, Esther |e verfasserin |4 aut | |
| 700 | 1 | |a Isaza, Stephania C |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Hanghang |e verfasserin |4 aut | |
| 700 | 1 | |a Rada, Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a Choya-Foces, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Martínez-Ruiz, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Martín, María Ángeles |e verfasserin |4 aut | |
| 700 | 1 | |a Ramos, Sonia |e verfasserin |4 aut | |
| 700 | 1 | |a García-Monzón, Carmelo |e verfasserin |4 aut | |
| 700 | 1 | |a Cubero, Francisco Javier |e verfasserin |4 aut | |
| 700 | 1 | |a Valverde, Ángela M |e verfasserin |4 aut | |
| 700 | 1 | |a González-Rodríguez, Águeda |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Redox biology |d 2013 |g 71(2024) vom: 01. Apr., Seite 103088 |w (DE-627)NLM22743725X |x 2213-2317 |7 nnns |
| 773 | 1 | 8 | |g volume:71 |g year:2024 |g day:01 |g month:04 |g pages:103088 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.redox.2024.103088 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 71 |j 2024 |b 01 |c 04 |h 103088 | ||