Blackberry-Loaded AgNPs Attenuate Hepatic Ischemia/Reperfusion Injury via PI3K/Akt/mTOR Pathway

Abstract

Liver ischemia-reperfusion injury (IRI) is a pathophysiological insult that often occurs during liver surgery. Blackberry leaves are known for their anti-inflammatory and antioxidant activities. Aims: To achieve site-specific delivery of blackberry leaves extract (BBE) loaded AgNPs to the hepatocyte in IRI and to verify possible molecular mechanisms. Methods: IRI was induced in male Wister rats. Liver injury, hepatic histology, oxidative stress markers, hepatic expression of apoptosis-related proteins were evaluated. Non-targeted metabolomics for chemical characterization of blackberry leaves extract was performed. Key findings: Pre-treatment with BBE protected against the deterioration caused by I/R, depicted by a significant improvement of liver functions and structure, as well as reduction of oxidative stress with a concomitant increase in antioxidants. Additionally, BBE promoted phosphorylation of antiapoptotic proteins; PI3K, Akt and mTOR, while apoptotic proteins; Bax, Casp-9 and cleaved Casp-3 expressions were decreased. LC-HRMS-based metabolomics identified a range of metabolites, mainly flavonoids and anthocyanins. Upon comprehensive virtual screening and molecular dynamics simulation, the major annotated anthocyanins, cyanidin and pelargonidin glucosides, were suggested to act as PLA2 inhibitors. Significance: BBE can ameliorate hepatic IRI augmented by BBE-AgNPs nano-formulation via suppressing, oxidative stress and apoptosis as well as stimulation of PI3K/Akt/mTOR signaling pathway.

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

“…Recently, many groups have demonstrated a vital role for the PI3K/AKT pathway in autoimmune diseases and implicated its suppression in the progression of liver IRI. [40][41][42] The PI3K pathway includes AKT and mTOR signaling, which are activated by tyrosine kinase receptor dimerization in response to growth factor binding. 43 This pathway represents an important regulatory component for both pro-inflammatory cytokines and apoptosis.…”

Targeting PI3K/p‐Akt/eNOS, Nrf2/HO‐1, and NF‐κB/p53 signaling pathways by angiotensin 1–7 protects against liver injury induced by ischemia–reperfusion in rats

“…Conversely, proinflammatory and apoptotic insults are reduced by the endogenous negative feedback regulator, phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt) axis, which enables cells to respond to a variety of stresses, particularly anti‐apoptosis and pro‐survival responses 3 . Accordingly, activation of PI3K/Akt axis has been identified as a probable therapeutic target to alleviate HIR injury 11,12 …”

“…3 Accordingly, activation of PI3K/Akt axis has been identified as a probable therapeutic target to alleviate HIR injury. 11,12 Nowadays, seeking protective agents for HIR injury is considered a pressing clinical concern. 13 Currently, angiotensin (1-7) (ang-(1-7)) is recognized as an active component of nonclassic renin-angiotensin system (RAS), 14 which is produced by angiotensin converting enzyme 2 (ACE2).…”

METTL3 Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Activating the MAPK Signaling Pathway

“…Despite the continuous development of surgical techniques and equipment improving the safety of liver surgery, hepatic ischemia/reperfusion injury (I/R) injury remains a significant cause of postoperative complications and mortality 2 . I/R injury is a complex pathological process involving inflammation, cellular apoptosis, and oxidative stress 3 , and is regulated by multiple signaling pathways such as the MAPK 4 , NF-κB 5 and PI3K/AKT 6 , 7 signaling pathways. Despite many studies on the mechanisms involved, few strategies have been translated into clinical practice 8 .…”