Mitogen Activated Protein Kinases in Steatotic and Non-Steatotic Livers Submitted to Ischemia-Reperfusion

Abstract

: We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of liver tolerate poorly to I-R injury. Also, a further increase in the prevalence of steatosis in liver surgery is to be expected. The possible therapies based on MAPK regulation aimed at reducing hepatic I-R injury will be discussed. Moreover, we reviewed the relevance of MAPK in ischemic preconditioning (PC) and evaluated whether MAPK regulators could mimic its benefits. Clinical studies indicated that this surgical strategy could be appropriate for liver surgery in both steatotic and non-steatotic livers undergoing I-R. The data presented herein suggest that further investigations are required to elucidate more extensively the mechanisms by which these kinases work in hepatic I-R. Also, further researchers based in the development of drugs that regulate MAPKs selectively are required before such approaches can be translated into clinical liver surgery.

Single-Nuclei RNA Sequencing Assessment of the Hepatic Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin

“…Previous studies have linked RAS/MAPK signaling to inflammation in human NAFLD, likely through the production of growth factors, cytokines, chemokines, and adhesion molecules. 42 Moreover, TCDD repressed hepatocyte proliferation, 43 and RAS induction by TCDD in HepG2 cells does not activate the downstream effector, MAPK. 44 The lack of hepatocyte enrichment is also consistent with the inhibition of hepatocyte proliferation and infiltration of immune cells.…”

Transient Expression of Reck Under Hepatic Ischemia/Reperfusion Conditions Is Associated with Mapk Signaling Pathways

“…In particular, activation of the p38 pathway and p38-associated inflammatory processes play a crucial role in post-ischemic damage [27]. Although several studies have demonstrated a detrimental role of JNK activation in I/R injury [28], the results about a protection by JNK inhibition are still controversial [27,29]. There are also studies indicating the potential involvement of ERK 1/2 in hepatic I/R injury [30]; to date, the potential role of ERK1/2 as a therapeutic target for liver I/R injury has not been clarified yet, because the molecules used are also able to modulate other pathways different from ERK1/2 [28].…”

Application of single nuclei RNA sequencing to assess the hepatic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…RAS/MAPK signaling was activated in hepatic NPCs in response to TCDD to promote cell proliferation and cell survival (Yang and Liu, 2017). Previous studies have linked RAS/MAPK signaling to inflammation in human NAFLD, likely through the production of growth factors, cytokines, chemokines, and adhesion molecules (Jimenez-Castro et al, 2019). Moreover, TCDD represses hepatocyte proliferation (Jackson et al, 2014), and RAS induction by TCDD in HepG2 cells does not activate the downstream effector, MAPK (Yamaguchi and Hankinson, 2018).…”