A Nano-Liposomal Formulation of Caffeic Acid Phenethyl Ester Modulates Nrf2 and NF-κβ Signaling and Alleviates Experimentally Induced Acute Pancreatitis in a Rat Model

Abstract

The currently available management strategies for acute pancreatitis are inadequately effective which calls for exploration of new approaches to treat this condition. Caffeic acid phenethyl ester (CAPE) is a major bioactive constituent of honeybee propolis with promising therapeutic and preventive applications. However, its pharmaceutical potential and clinical use are hindered by its poor water solubility and limited plasma stability. In this study, we aimed to prepare, characterize and evaluate a CAPE-loaded nanoliposomal formulation to improve the efficacy of CAPE for the management of acute pancreatitis. The CAPE-loaded nanoliposomes (CAPE-loaded-NL) were prepared by a thin layer evaporation technique and were optimized using three edge activators. CAPE-loaded-NL were characterized for their vesicle size (VS), zeta potential (ZP), encapsulation efficiency (EE), polydispersity index (PDI), crystalline state and morphology. The protective effect of the optimal CAPE-loaded-NL was evaluated in a rat model of acute pancreatitis induced by administering a single intraperitoneal injection of L-ornithine. Oral pretreatment with CAPE-loaded-NL significantly counteracted ornithine-induced elevation in serum activities of pancreatic digestive enzymes and pancreatic levels of malondialdehyde, nuclear factor kappa B (NF-κB) p65, tumor necrosis factor-alpha, nitrite/nitrate, cleaved caspase-3 and myeloperoxidase activity. Moreover, pretreatment with CAPE-loaded-NL significantly reinstated the ornithine-lowered glutathione reductase activity, glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 levels and ATP/ADP ratio, and potentiated the Bcl-2/Bax ratio in pancreatic tissue. CAPE-loaded-NL displayed superior antioxidant, anti-inflammatory and anti-apoptotic effects compared to free CAPE oral suspension and achieved a more potent correction of the derangements in serum amylase and pancreatic myeloperoxidase activities. The histological observations were in line with the biochemical findings. Our results suggest that CAPE-loaded-NL provide a promising interventional approach for acute pancreatitis mainly through the enhancement of the exerted antioxidant, anti-inflammatory and anti-apoptotic effects which may be mediated, at least in part, through modulation of Nrf2 and NF-κβ signaling.

Modulating Inflammation-Mediated Diseases via Natural Phenolic Compounds Loaded in Nanocarrier Systems

“…A synthesized caffeic acid-loaded nanoliposomal vesicle formed of sodium deoxycholate (SDC) was developed for attenuating pancreatitis. In addition to its improved bioavailability and stability, its oral pretreatment counteracted the biochemical dysregulation, caused by L-ornithine in the pancreatitis model, through the modulation of the Nrf2 and NF-kB signaling pathways [ 170 ]. Phospholipid entrapment of caffeic acid (CA-PC) also exerted the amelioration of lipid serum profile of HFD rats, following 4 weeks of oral administration.…”

Targeting and functional effects of biomaterials-based nanoagents for acute pancreatitis treatment

“…The bilirubin-loaded SF nanoparticles prevented the NF-κB pathway and activated the Nrf2/HO-1 pathway to inhibit oxidative stress and inflammatory responses. In another study, L-α-phosphatidylcholine and cholesterol were mainly used to prepare nanoliposomes by thin layer evaporation technique ( Shahin et al, 2022 ), loaded with caffeic acid phenethyl ester (CAPE) for oral administration in a rat model. The CAPE-loaded nanoliposomes decreased pancreatic secretions, oxidative stress, local inflammation, tissue apoptosis, and impaired energy status as therapeutic effects for AP treatment.…”

“…The in vivo biodistribution study of the nanoliposomes was not performed; thus, the targeting effects could not be supported directly. However, the enhanced treatment efficacy was attributed to the altering tissue biodistribution of smaller-size liposomes and cellular uptake mechanisms ( Shahin et al, 2022 ). Notably, liposomes particle size is their most influential characteristic affecting the circulation time and biodistribution after intravenous injection, which plays a vital role in passing through the leaky vasculature and accumulation at inflammatory sites in vivo ( Ren et al, 2019 ).…”

Microalgae as a Nutraceutical Tool to Antagonize the Impairment of Redox Status Induced by SNPs: Implications on Insulin Resistance

“…It can be produced in several microalgae including Phaeodactylum tricornutum , Tetraselmis suecica , Nannochloropsis gaditana , among others [ 179 , 180 ]. CA is capable of directly scavenging radicals such as the superoxide anion with both enzymatic and non-enzymatic reactions [ 181 ], to exert stimulatory effect on NRF2 presumably liberating NRF2 from the NRF2-keap1 complex [ 182 ], and it can also inhibit the NF-kB pathway, reducing inflammation as well oxidative stress, consequently improving insulin sensitivity [ 183 ].…”