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Methionine cycle rewiring by targeting miR-873-5p modulates ammonia metabolism to protect the liver from acetaminophen

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Methionine cycle rewiring by targeting miR-873-5p modulates ammonia metabolism to protect the liver from acetaminophen

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dc.contributor.author Rodríguez Agudo, Rubén
dc.contributor.author Petrov, Petar D.
dc.contributor.author Castell, José V.
dc.contributor.author over Atienza, Ramiro
dc.date.accessioned 2023-05-29T13:33:09Z
dc.date.available 2023-05-29T13:33:09Z
dc.date.issued 2022
dc.identifier.citation Rodríguez Agudo, Rubén Petrov, Petar D. Castell, José V. over Atienza, Ramiro 2022 Methionine cycle rewiring by targeting miR-873-5p modulates ammonia metabolism to protect the liver from acetaminophen Antioxidants 11 5 897
dc.identifier.uri https://hdl.handle.net/10550/87070
dc.description.abstract 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.
dc.language.iso eng
dc.relation.ispartof Antioxidants, 2022, vol. 11, num. 5, p. 897
dc.subject Bioquímica clínica
dc.title Methionine cycle rewiring by targeting miR-873-5p modulates ammonia metabolism to protect the liver from acetaminophen
dc.type journal article
dc.date.updated 2023-05-29T13:33:09Z
dc.identifier.doi 10.3390/antiox11050897
dc.identifier.idgrec 159246
dc.rights.accessRights open access

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