Berberine-loaded nanostructured lipid carriers mitigate warm hepatic ischemia/reperfusion-induced lesion through modulation of HMGB1/TLR4/NF-?B signaling and autophagy - 04/09/21

Doi : 10.1016/j.biopha.2021.112122

Abdallah M. Gendy ^a,^⁎ , Mohamed R. Elnagar ^b, Mona M. Allam ^c, Mohamed R. Mousa ^d, Ahmed E. Khodir ^e, Alaadin E. El-Haddad ^f, Osama S. Elnahas ^g, Sahar M. Fayez ^g, Shereen S. El-Mancy ^g
^a Pharmacology and Toxicology Department, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt
^b Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt
^c Physiology Department, Faculty of Medicine, Benha University, Qalubiya 13518, Egypt
^d Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt
^e Pharmacology Department, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt
^f Pharmacognosy Department, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt
^g Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt

^⁎Corresponding author.

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Abstract

Objective

Berberine (BBR) is a known alkaloid that has verified its protective effects against ischemia/reperfusion (I/RN) lesion in multiple organs but its poor oral bioavailability limited its use. Despite the previous works, its possible impact on the warm hepatic I/RN-induced lesion is not clear. Accordingly, a nanostructured lipid carrier of BBR (NLC BBR) was developed for enhancing its efficiency and to inspect its protective mechanistic against warm hepatic I/RN.

Methods

NLC BBR formula was evaluated pharmaceutically. Wistar rats were orally pre-treated with either BBR or NLC BBR (100 mg/kg) for 2 weeks followed by hepatic I/RN (30 min/24 h). Biochemical, ELISA, qPCR, western blot, histopathological, and immunohistochemical studies were performed.

Key findings

Optimized NLC BBR was prepared with a particle size of 130 ± 8.3 nm. NLC BBR divulged its aptitude to safeguard the hepatic tissues partly due to anti-inflammatory capacity through downsizing the HMGB1/TLR4/NF-κB trajectory with concomitant rebating of TNF-α, iNOS, COX-2, and MPO content. Furthermore, NLC BBR antiapoptotic trait was confirmed by boosting the prosurvival protein (Bcl-2) and cutting down the pro-apoptotic marker (Bax). Moreover, its antioxidant nature was confirmed by TAC uplifting besides MDA subsiding. On the other hand, NLC BBR action embroiled autophagy flux spiking merit exemplified in Beclin-1 and LC3-II enhancement. Finally, NLC BBR administration ascertained its hepatocyte guarding action by recovering the histopathological ailment and diminishing serum transaminases.

Conclusion

NLC BBR purveyed reasonable shielding mechanisms and subsided incidents contemporaneous to warm hepatic I/RN lesion in part, by moderating HMGB1/TLR4/NF-κB inﬂammatory signaling, autophagy, and apoptosis.

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Graphical Abstract

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Highlights

•	The nanostructured lipid carriers formula of berberine enhance its efficiency.
•	Berberine-loaded nanostructured lipid carriers lessen warm hepatic ischemia/reperfusion-induced oxidative stress and apoptosis.
•	Berberine-loaded nanostructured lipid carriers motivate autophagy to exert its defensive effect.

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Abbreviations : ALT, ANOVA, AST, Bax, Bcl-2, BBR, COX-2, DSC, EE%, GMS, gp, H&E, HMGB1, IHC, iNOS, I/RN, LC3, MDA, MPLC, MPO, NF-κB, NLC, NLC BBR, OS, PDI, PS, qRT-PCR, SM, Sd.De, TAC, TLR4, TNF-α, ZP, ZS