Enhanced hepatoprotective effects of fisetin-loaded liposomal nanoparticles against DEHP-induced liver injury in rats: modulation of oxidative stress, inflammation, apoptosis, and ferroptosis pathways.
Aug 2026· Naunyn-Schmiedeberg's Archives of Pharmacology· 0 citations· 43 references
Medicine
TL;DR
FSN-LNPs provided enhanced hepatoprotection against DEHP-induced toxicity compared with free FSN, which was associated with attenuation of oxidative stress and inflammation and modulation of apoptosis- and ferroptosis-related pathways, likely due to improved bioavailability and cellular delivery.
Paracetamol is the most common cause of drug- induced liver injury,
which is associated with oxidative stress, cytokine release, and apoptosis. Boswellic acid (BA),
with anti- inflammatory and antioxidant effects, can ameliorate liver injury but has poor solubility
and bioavailability. The objective of this study was to design boswellic acid nanoparticles
(BA-NPs) and test their protective effect against paracetamol-induced liver injury in mice.
BA-NPs were prepared by a surfactant-assisted emulsion method and characterized by
UV-Vis spectroscopy, FT-IR analysis, dynamic light scattering (DLS), zeta potential measurements,
and transmission electron microscopy (TEM). Acute oral toxicity (LD₂⁽) was assessed in
healthy mice. Liver- intoxicated mice were treated with paracetamol (1 g/kg, po) and pretreated
for 14 days with BA- NPs (75 mg/kg, po) or silymarin (50 mg/kg). Measurements included serum
liver enzymes (ALT, AST, and ALP), lipid profile markers (TC, TG, and HDL), oxidative
stress indicators (GSH, CAT, GPx, SOD, and MDA), inflammatory cytokines and their markers
(IL- 6 and TNF–α), the apoptotic marker p 53, caspase- 8 and STAT 3 mRNA expression measured
by qPCR, and molecular docking simulations to predict boswellic acid's binding affinity to
target proteins.
The formulated BA- NPs were spherical and monodisperse (54. 54.54 ± 2. 76 nm) with
colloidal stability (zeta potential:- 18. 84 mV; PDI: 0. 26). The LD50 was estimated to be 1500
mg/kg, indicating relatively low acute toxicity. BA-NP pretreatment alleviated paracetamolinduced
increases in ALT, AST, and ALP; normalized dyslipidemia; restored antioxidant activity;
and decreased MDA levels. We observed that the levels of pro- inflammatory cytokines (IL-
6, TNF- α) and p 53 were strongly downregulated. The expression of both caspase-8 and STAT3
was also downregulated by BA-NPs. Molecular docking data showed that boswellic acid bound
significantly to caspase-8 (ΔG = -7.97 kcal/mol) and STAT3 (ΔG = -7.95 kcal/mol), supporting
its mechanism of hepatoprotection.
Our results indicate that BA- NPs prepared by Span 60/Tween 80 emulsification
provide potent hepatoprotection against paracetamol- induced liver injury through synergistic,
multi- mechanistic action, significantly protecting against hepatic injury by concurrently suppressing
oxidative stress, inflammatory signaling pathways, and apoptosis, three interconnected
molecular events critical to the pathogenesis of paracetamol hepatotoxicity.
BA-NPs prepared via emulsification of Span 60/Tween 80 offer potent hepatoprotection
against paracetamol-induced liver injury by primarily modulating oxidative stress, inflammation,
and apoptosis. This approach not only highlights a potentially novel therapeutic for
drug- induced hepatotoxicity but also overcomes the pharmacokinetic barriers of the native boswellic
acid agent and provides an improved alternative to currently available drugs.
Ola Abdallah Ahmed, M. Hussein, Azza Mahmoud Abdullah· The Natural Products Journal· 0 citations
Background/Objectives: Oxidative stress, chronic inflammation, disrupted apoptosis, and altered autophagy are biological processes implicated in colorectal tumor development. Morin is a plant-derived flavonoid with antioxidant and anti-inflammatory properties, but its limited solubility and bioavailability may limit its biological activity. This study evaluated the effects of free morin and morin-loaded liposomes (MOR-Lips) on 1,2-dimethylhydrazine (DMH)-associated colonic biochemical, molecular, and histopathological alterations in rats. Methods: Rats were randomly assigned to six groups—vehicle control, MOR, MOR-Lips, DMH, DMH + MOR, and DMH + MOR-Lips—and treated for 10 weeks. Serum and colonic tissues were evaluated for cancer-associated biomarkers (CEA, CA19-9, CA125, HMG-CoA reductase), oxidative stress and antioxidant indices, nitrosative and oxidative DNA-damage markers (MDA, NO, 8-OHdG), inflammatory mediators (TLR4/NF-κB/COX-2, cytokines, MPO), proliferative indices (Ki-67, PCNA), apoptotic and autophagy-related regulators (Bax, caspase-3, p53, cytochrome c, BCL-2, p-AKT, LC3-II, Beclin-1, p62), and histopathological and immunohistochemical changes. Results: DMH exposure was associated with increased CEA, CA19-9, CA125, HMG-CoA reductase, MDA, NO, 8-OHdG, TLR4/NF-κB/COX-2, cytokines, MPO, Ki-67, and PCNA. DMH also reduced NRF2/HO-1 signaling and antioxidant defenses, shifted apoptosis-related markers toward a pro-survival profile, altered autophagy-related markers, and produced marked colonic histopathological abnormalities. Both free MOR and MOR-Lips attenuated several of these DMH-associated alterations, with MOR-Lips generally producing greater effects than free MOR. MOR-LIP treatment was associated with restoration of antioxidant marker profiles, reduced levels of inflammatory and proliferative markers, a shift toward a pro-apoptotic marker profile, partial normalization of autophagy-related markers, and improved colonic histopathological appearance. Conclusions: In DMH-exposed rats, MOR-Lips were associated with more favorable redox, inflammatory, proliferative, apoptosis-related, autophagy-related, and histopathological profiles than free MOR. These findings support further investigation of MOR-Lips as a formulation strategy for improving the biological activity of morin. Because quantitative preneoplastic and neoplastic endpoints were not measured, the results do not establish inhibition of colorectal carcinogenesis or chemopreventive efficacy.
Overall, nano-liposomal delivery enhanced the renoprotective efficacy of limonene, highlighting its potential as a therapeutic strategy against pesticide-induced kidney injury.
E. Elmorsy, Amina A. Farag, Amal M. Abdel-Kareim et al.· Toxics· 0 citations
N-Cur mitigates oxidative damage and inflammation, thereby preserving hepatic function during CDDP-based chemotherapy, and demonstrates significant potential as a hepatoprotective agent when administered concomitantly with CDDP chemotherapy.
Q. Alqahtani, M. Atteya, T. Almatrafi et al.· Biomedicines· 0 citations
Abstract Objectives This study aimed to investigate the interactions between biochemical, oxidative, and morphological markers of liver injury in an experimental model of alcoholic hepatitis and to evaluate the hepatoprotective efficacy of a herbal phytocomplex (AZHEPOFIT) within an integrated mechanistic framework. Methods Alcoholic hepatitis was induced in 40 male rats by oral ethanol administration combined with a high-fat diet for 21 days. From day 22, animals received AZHEPOFIT (1 mL/100 g body weight) daily for 14 days. Biochemical parameters, oxidative stress markers, antioxidant status, lipid profile, and liver histomorphology were assessed. Correlation analysis was performed using Spearman’s coefficient. Results Alcoholic hepatitis was associated with pronounced cytolysis, cholestasis, oxidative stress, dyslipidemia, and marked histopathological alterations, including steatosis, hepatocyte ballooning, inflammation, necrosis, and early fibrosis. AZHEPOFIT administration significantly reduced cytolytic enzyme activity and lipid peroxidation, enhanced antioxidant defense, improved lipid metabolism, and attenuated structural liver damage. Strong correlations exist between oxidative stress markers and cytolytic enzymes, and inverse relationships with antioxidant parameters, indicating a coordinated pathogenic network linking oxidative stress, lipid metabolism, and hepatocellular injury. Conclusions The hepatoprotective effects of AZHEPOFIT are associated with the modulation of interconnected oxidative stress–metabolic pathways. These findings provide mechanistic insight into phytotherapeutic intervention in alcohol-induced liver injury and support targeting redox-dependent pathways as a promising therapeutic strategy.
R. Jafarova, S. Guliyeva, S.A. Abasova et al.· Journal of Complementary and...· 0 citations
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