الفهرس 
Introduction and Aim of WorkOnly 14 pages are availabe for public view
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Abstract
Liver I/R injury is a pathological process that often occurs during liver and trauma surgery. There are numerous causes of liver I/R injury, but the mechanism is unknown. BBE is one of the most valuable antioxidant natural drugs that has anti-inflammatory, antioxidant, and antitumor activity. Unfortunately, it is only effective at higher doses, which limits its clinical utility.
The present work was conducted to explore the potential hepato-protective role of BBE loaded-AgNPs on hepatic I/R injury. Moreover, the underlying signaling pathway of this inhibition was investigated.
An I/R model was created in male Wistar rats by clamping the hepatoportal vein, hepatic artery, and hepatic duct for 30 min followed by reperfusion for 2 h.
The experiment was performed on 7 groups: sham-operated, I/R without pre-treatment, and 6 groups that were pretreated with BBE (200 mg/kg), empty AgNPs (100 mg/kg), different doses of BBE-AgNPs (200 mg/kg) and (50 mg/kg) and silymarin (100 mg/kg), as a positive control. Treatments are given orally for 14 days prior to I/R injury induction. The extent of liver injury was assessed by serum ALT/AST and hepatic histology. Oxidative stress was assessed by tissue GSH, CAT, SOD, and MDA. Expression of apoptosis-related proteins in liver tissues was assayed by western blotting and immunohistochemistry. Non-targeted metabolomics for the chemical characterization of blackberry leaf extract was performed using LC-HR-MS. And finally, employing virtual screening and molecular dynamics simulation to elucidate the potential of BBE’s major active constituents to act as PLA2 inhibitors
Hepatic I/R injury significantly deteriorated liver functions. In addition, GSH content, CAT, and SOD activity were significantly decreased with a concomitant increase in the content of liver MDA after I/R injury. Histological changes were extensive in the hepatic central vein and sinusoids. Decreased phosphorylation of p-PI3K, p-Akt, and p-mTOR was observed after I/R injury, while Bax, caspase-9, and caspase-3 expression were increased. On the contrary, pretreatment with BBE or both doses of BBE-AgNPs protects against the modifications caused by I/R injury. 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.
In conclusion, blackberry leaf extract has an ameliorative effect on hepatic I/R injury in rats via suppressing oxidative stress, apoptosis, and stimulation of the pro-survival PI3K/Akt/mTOR signaling pathway in liver tissue. Upregulation of this pathway likely contributed to their anti-apoptotic effects. This effect is significantly augmented by using the nano-formulation of BBE-loaded AgNPs. This suggests that the nano-sized formulation improved the bioavailability and drug delivery of the active components in BBE to the hepatocytes.
It makes BBE-AgNPs a potential therapeutic candidate for mitigating liver damage caused by I/R. However, further studies are still needed to optimize the dosage, confirm the molecular mechanisms, and evaluate toxicity and safety aspects before clinical translation.