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oai:repisalud.isciii.es:20.500.12105/186322024-02-27T15:07:10Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927col_20.500.12105_16976col_20.500.12105_16975col_20.500.12105_16978

00925njm 22002777a 4500 dc Rodríguez-Agudo, Rubén author Goikoetxea-Usandizaga, Naroa author Serrano-Maciá, Marina author Fernández-Tussy, Pablo author Fernández-Ramos, David author Lachiondo-Ortega, Sofía author González-Recio, Irene author Gil-Pitarch, Clàudia author Mercado-Gómez, María author Morán, Laura author Bizkarguenaga, Maider author Lopitz-Otsoa, Fernando author Petrov, Petar author Bravo, Miren author Van Liempd, Sebastiaan Martijn author Falcon-Perez, Juan Manuel author Zabala-Letona, Amaia author Carracedo, Arkaitz author Castell, Jose Vicente author Jover, Ramiro author Martínez-Cruz, Luis Alfonso author Delgado, Teresa Cardoso author Cubero, Francisco Javier author Lucena, María Isabel author Andrade, Raúl Jesús author Mabe, Jon author Simón, Jorge author Martínez-Chantar, María Luz author 2022-04-30 Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response. 10.3390/antiox11050897 2076-3921 Antioxidants (Basel, Switzerland) http://hdl.handle.net/10668/20781 35624761 http://hdl.handle.net/20.500.12105/18632 acetaminophen (APAP) ammonia drug-induced liver injury (DILI) methionine cycle miR-873-5p mitochondria polyamines therapy Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.