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. 2024 Oct 23:15:1485525.
doi: 10.3389/fphar.2024.1485525. eCollection 2024.

Antimutagenic and anticoagulant therapeutic effects of Ag/Ag2O nanoparticles from Olea europaea leaf extract: mitigating metribuzin-induced hepato-and nephrotoxicity

Manel Azzi  1   2 , Ibtissam Laib  2 , Abderrhmane Bouafia  3   4 , Ifriqya Medila  1   2 , Ali Tliba  5 , Salah Eddine Laouini  3   4 , Huda Alsaeedi  5 , David Cornu  6 , Mikhael Bechelany  6   7 , Ahmed Barhoum  8
Affiliations

Antimutagenic and anticoagulant therapeutic effects of Ag/Ag2O nanoparticles from Olea europaea leaf extract: mitigating metribuzin-induced hepato-and nephrotoxicity

Manel Azzi et al. Front Pharmacol. .

Abstract

Background: Silver nanoparticles (Ag/Ag₂O NPs) have garnered attention for their potent antioxidant, antimicrobial, and anti-inflammatory properties, showing promise for therapeutic applications, particularly in mitigating chemical-induced toxicity.

Objective: This study aimed to synthesize Ag/Ag₂O NPs using Olea europaea (olive) leaf extract as a green, eco-friendly reducing agent and evaluate their protective effects against metribuzin-induced toxicity in Wistar rats, focusing on oxidative stress, hematological parameters, and lipid profiles, with specific dose optimization.

Methodology: Ag/Ag₂O NPs were synthesized using Olea europaea leaf extract, and their properties were confirmed via XRD, FTIR, SEM, EDS, and UV-visible spectroscopy. Wistar rats exposed to metribuzin (110 mg/kg/day) were treated with two doses of Ag/Ag₂O NPs (0.062 mg/kg and 0.125 mg/kg). Hematological and biochemical markers were assessed to evaluate the NPs' protective effects.

Results: Physicochemical characterization confirmed the successful formation of Ag/Ag₂O NPs loaded with phytochemicals, exhibiting crystallite sizes of 23 nm and 19 nm, a particle size of 25 nm, and significant peaks in XRD, FTIR, and UV-Vis spectra indicating the formation of Ag/Ag₂O. Metribuzin exposure led to significant hematological disruptions (elevated WBC, reduced RBC and hemoglobin) and worsened lipid profiles (increased cholesterol, LDL, and triglycerides). The lower NP dose (0.062 mg/kg) improved WBC, RBC, hemoglobin, and platelet counts, normalized lipid levels, and positively influenced biochemical markers such as serum creatinine and uric acid. In contrast, the higher NP dose (0.125 mg/kg) showed mixed results, with some improvements but an increase in triglycerides and continued elevation of ASAT and ALAT enzyme levels.

Conclusion: Ag/Ag₂O NPs synthesized via green methods using olive leaf extract effectively mitigated metribuzin-induced toxicity, especially at lower doses, by improving oxidative stress markers and hematological and biochemical profiles. Dose optimization is crucial to maximize therapeutic benefits and minimize adverse effects, underscoring their potential in treating chemical-induced toxicity.

Keywords: hematological parameters; lipid profiles; metribuzin-induced toxicity; oxidative stress; phytochemicals; plant extract; silver nanoparticles; silver oxide nanoparticles.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
XRD Analysis of Ag/Ag₂O NPs synthesized from Olea europaea Leaf Extract.
FIGURE 2
FIGURE 2
FT-IR Analysis of: (A) Ag/Ag2O NPs synthesized from Olea europaea Leaf Extract and Olea europaea leaf extract (B) Magnified spectrum (400–800 cm−1) of Ag/Ag2O NPs.
FIGURE 3
FIGURE 3
SEM analysis of the Ag/Ag₂O NPs Synthesized from Olea europaea Leaf Extract: (A) SEM images, (B) particle size diameter, (C) EDX elemental analysis.
FIGURE 4
FIGURE 4
Optical properties of Ag/Ag₂O NPs synthesized from Olea europaea Leaf Extract: (A) UV-vis spectra (B) direct bandgap energy (C) indirect bandgap energy (D) the Urbach energy (Eu).
FIGURE 5
FIGURE 5
Antimutagenic activity of the Ag/Ag₂O NPs biosynthesized by aqueous extract of O. europaea leaves against 1-NP in S. typhimurium TA98. (A) Revertants TA98, (B) Inhibition %.
FIGURE 6
FIGURE 6
Anticoagulant activity of Ag/Ag2O NPs synthesized using O. europaea: (A) Blood sample in EDTA tube, (B) Blood sample treated with 150 ppm Ag/Ag₂O NPs, (C) Blood control samples without any additives, (D, E) Microscopic examination of blood samples treated with 150 ppm Ag/Ag2O NPs.
FIGURE 7
FIGURE 7
Comparison of serum of Haematological Parameters in the four rat groups. Group I (Control): Normal water consumption. Group II (Met): addition of Metribuzin (110 mg/kg body weight/day) in drinking water for 21 days. Group III (Met + Ag/Ag2O 0.062 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs(dose 0.0625 mg/kg, body weight/day by intraperitoneal injection) for 21 days. Group IV (Met + Ag/Ag2O NPs0.125 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs (dose 0.125 mg/kg, body weight/day by intraperitoneal injection) for 21 days. (A): WBC cell 103/ul, (B): RBC cell 103/UI, (C): Hb (g/dL), (D): PLT 103/Ul. *p < 0.05, **p < 0.01, vs. Group I), c p < 0.001 vs. Group II.
FIGURE 8
FIGURE 8
Comparison of serum biomarker levels in the four rat groups. Group I (Control): Normal water consumption. Group II (Met): addition of Metribuzin (110 mg/kg body weight/day) in drinking water for 21 days. Group III (Met + Ag/Ag2O NPs 0.062 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs (dose 0.0625 mg/kg, body weight/day by intraperitoneal injection) for 21 days. Group IV (Met + Ag/Ag2O NPs0.125 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs (dose 0.125 mg/kg, body weight/day by intraperitoneal injection) for 21 days. (A): (Serum glucose g/L), (B): Serum cholesterol (mg/L), (C): Serum triglycerides (g/L), (D): HDL g/dL), (E): LDL mg/dL. *p < 0.05, vs. Group I), a p < 0.05, b p < 0.01 vs. Group II.
FIGURE 9
FIGURE 9
Comparison of liver and Kidney function biomarker levels in the four rat groups. Group I (Control): Normal water consumption. Group II (Met): addition of Metribuzin (110 mg/kg body weight/day) in drinking water for 21 days. Group III (8/Ag2O NPs0.062 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs (dose 0.0625 mg/kg, body weight/day by intraperitoneal injection) for 21 days. Group IV (Met + Ag/Ag2O NPs0.125 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs (dose 0.125 mg/kg, body weight/day by intraperitoneal injection) for 21 days. (A): (Serum Urea g/L), (B): Serum Creatinine mg/L, (C): Serum Uric Acid mg/L (D): ASAT U/mL, (E): ALAT U/mL. *p < 0.05, **p < 0.01: significantly different from Group I, a p < 0.05, b p < 0.01: significantly different from Group II.
FIGURE 10
FIGURE 10
Comparison of oxidative stress biomarker levels in each of the liver and kidney in the four rat groups. Group I (Control): Normal water consumption. Group II (Met): addition of Metribuzin (110 mg/kg body weight/day) in drinking water for 21 days. Group III (Met + Ag/Ag2O NPs0.062 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs (dose 0.0625 mg/kg, body weight/day by intraperitoneal injection) for 21 days. Group IV (Met + Ag/Ag2O NPs 0.125 mg/kg): Met exposure (as in Group II) followed by Ag/Ag2O NPs (dose 0.125 mg/kg, body weight/day by intraperitoneal injection) for 21 days. (A): MDA nM/mg Pro in Liver, (B): (MDA nM/mg Pro in Kidney), (C): GSH nM/mg Pro in Liver, (D): GSH nM/mg Pro in Kidney. *p < 0.05, **p < 0.01: significantly different from Group I, a p < 0.05, b p < 0.01: significantly different from Group II.
FIGURE 11
FIGURE 11
Micrographs of representative rat liver sections from different experimental groups showing the effect of metribuzin exposure and the protective effect of Ag/Ag2O NPs. (A) Liver section of a rat from Group I (control); (B) Liver section of a rat from Group II (metribuzin exposure); (C) Liver section from a rat of Group III (Ag/Ag2O NPs at 62.5 μg/kg after metribuzin exposure); (D) Liver section of a rat from Group IV (Ag/Ag2O NPs at 125 μg/kg after metribuzin exposure). N, normal hepatocyte; IF, Inflammatory cells; CO, Congestion of sinusoids; NE, Necrosis, × 40.
FIGURE 12
FIGURE 12
Micrographs of representative rat kidney sections from different experimental groups showing the effect of metribuzin exposure and the protective effect of Ag/Ag2O NPs. (A) Kidney section of a rat from Group I (control); (B) Kidney section of a rat from Group II (metribuzin exposure); (C) Kidney section from a rat of Group III (Ag/Ag2O NPs at 62.5 μg/kg after metribuzin exposure); (D) Kidney section of a rat from Group IV (Ag/Ag2O NPs at 125 μg/kg after metribuzin exposure). G, Glomeruli; T, Tubules; DI, Degenerative changes; A, Atrophy; C, Capsule distortion; IF, Inflammatory cells; × 40.
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