Antioxidant and Hepatoprotective Effects of Fig Fruit Extract with Olive Oil and Date-Palm Fruit Extract on Hepatic Toxicity of Oral Subchronic Exposure to Some Nanoparticles in Wistar Rats

Fathy, Abdallah H.; Naji, Riyadh Musaed; Bashandy, Mohamed A.

doi:https://doi.org/10.1155/2023/7584688

Journal of Food Quality

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Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Ethical Approval Consent Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 7584688 | https://doi.org/10.1155/2023/7584688

Antioxidant and Hepatoprotective Effects of Fig Fruit Extract with Olive Oil and Date-Palm Fruit Extract on Hepatic Toxicity of Oral Subchronic Exposure to Some Nanoparticles in Wistar Rats

Abdallah H. Fathy,¹Riyadh Musaed Naji,^2,3and Mohamed A. Bashandy²

Academic Editor: Wen yi Kang

Received14 Sept 2022

Revised12 Jan 2023

Accepted24 Apr 2023

Published01 Jun 2023

Abstract

The aim is to study the possible protection of fig fruit extract with olive oil and date-palm fruit extract (FOD) as natural antioxidants in decreasing the subchronic toxicity hazards of SiO₂NPs, Al₂O₃NPs, or ZnONPs in male rats treated for 75 days. We used 80 male Wistar rats distributed into eight groups according to the treatment. The FOD antioxidant treatments were used at their recommended antioxidant doses. All nanoparticles (100 mg/kg) were given orally and daily for 75 days. Compared with the control, the oral administration of different NPs alone led to dramatic oxidative stress, liver function parameters, histopathological, p53, and inflammatory markers (TNF-α and IL-6). The FOD-NPs-treated groups recorded significantly reduced hepatotoxicity effects compared to those treated with NPs alone. In conclusion, the FOD supplementations to the rats ameliorate the NP’s hepatotoxicity.

1. Introduction

Nanotechnology provides solutions for diagnosing and treating complex diseases based on nanomaterial (particle size range from 1 to 100 nm) [1]. As nanotechnology develops, there is an increasing risk of human exposure to nanoparticles [2]. When ingested or inhaled, the different nanoparticles behave similarly to the tiny biological molecules due to their nanometer dimensions. Long-term and short-term toxicities due to exposure to other nanoparticles negatively impact humans and animals [3]. Nanoparticles may enter the human body via various routes and reach multiple organs and systems. The invasion of these systems by nanoparticles causes many pathological disorders, DNA mutations, and eventually cell apoptosis/death [4, 5].

Silicon technology is considered a favorable material widely used in electronic components with low manufacturing costs and a thermally stable nature, while its oxides are often employed in biomedical procedures [6]. The potential toxicity of SiO₂NPs is limited to certain aspects, including their cytotoxicity, cellular adhesion, their effect on cell proliferation, and distribution throughout the body [7, 8]. Aluminum oxide nanoparticles (Al₂O₃NPs) have a growing market in various industries and biomedical areas and are used in multiple aspects of life, such as drug delivery, treatment of diseases, and destruction of microbes [9]. Exposure to Al₂O₃NPs causes toxicity to various body organs [10, 11]. Zinc oxide NPs (ZnO NPs) are used in many applications, including UV detectors, varistors, cosmetic and other products, and antibacterial agents [12]. Some studies suggest that ZnONPs might be inducing damage and toxicity to the biomolecules due to ROS generation, their effect on the integrity of DNA, and apoptosis [13].

Functional foods (supplements) are now used to retard, block, or reverse the cytotoxicity processes [14]. When the endogenous antioxidant defenses are inadequate to prevent the damage entirely, there is a need to use an appropriate antioxidant intervention to reduce and inhibit free radical toxicity. Diet-derived antioxidants are essential in maintaining health [15].

The olive oil was divided into central (glycerol more than 98%) and minor (more than 230 chemical compounds, about 2%) fractions. The minor components include carotenoids, phenolic compounds, and antioxidants [16]. The fig was indigenous in southwestern Asia to northwest India. In numerous scientific studies, fig fruit has been reported to possess antioxidant, hepatoprotective, hypoglycemic, hypolipidemic, hypocholesterolemic, antipyretic, immunomodulatory, and anti-inflammatory [17, 18]. Dates were found to contain high-quality essential amino acids [19]. The date-palm fruit extract has potent antioxidants, antimutagenic, hepatoprotective, and immunomodulatory benefits to health [20]. The current research objected to explore the possible chemoprevention of fig fruit extract with olive oil and date-palm fruit extract (FOD) as natural antioxidants against different nanoparticle-induced subchronic hepatotoxicity in Wistar rats, including hepatic oxidative stress, inflammatory, histopathological alterations, and P53 content in the liver tissue.

2. Materials and Methods

2.1. Chemicals

We used analytical chemicals from standard suppliers.

2.1.1. Reagents

(1)Absolute ethanol used to prepare graduated ethanol (50%, 70%, 95%, and 100%)(2)Paraffin wax used for tissue blocking(3)10% formalin saline used for tissue fixation(4)Xylene(5)Hematoxylin stain(6)Eosin stain

2.2. Nanoparticles

The SiO₂NPs, Al₂O₃NPs, or ZnONPs were prepared (average size of less than 50 nm) and characterized in a private laboratory (Nanogate Laboratory, Cairo, Egypt). The structure of the nanoparticle was confirmed using a transmission electron microscope (JEM-2100, Jeol, Akishima, Japan) at the voltage of 200 kV and X-ray diffraction (XRD) analysis using a powder diffractometer system (X’pertPro-Panalytical, Malvern, United Kingdom) as shown in Figure 1.

(a)

(b)

(c)

2.3. Preparation of Nanoparticle (NPs) Treatments

The nanoparticles (SiO₂NPs, Al₂O₃NPs, and ZnONPs) were suspended in water. This suspension was vibrated by vortex for 5 min before injection to aid in preparing a homogeneous suspension. All nanoparticles were given orally by oral gavages for 75 consecutive days. All nanoparticles (SiO₂NPs, Al₂O₃NPs, and ZnONPs) were administered to rats at 100 mg/kg. bwt for 75 consecutive days as confirmed by a pilot study (data not shown), and the selected doses and dose regimen were found following previously published studies. The doses of SiO₂NPs followed Gmoshinski et al. [21], while Al₂O₃NPs doses followed Park et al. [22], and the doses of ZnONPs were following Yousef et al. [23].

2.4. Plant Materials and Authorities

We purchased the extra-virgin olive oil from Spain (Grup Pons Company), the fig fruit from Turkey (Kafoods Ltd.), and the date-palm fruit from Saudi Arabia (Al-MADINA AL-MUBARAK market). The plants were authenticated by Dr. Al-Baraa El-Saied (Al-Azhar University). The voucher specimens were placed at the medicinal plant’s station.

2.5. Preparation of Crude Extracts

Ficus carica fruit extract was prepared and lyophilized according to a previous method [17]. The fig fruit was cleaned of dirt, diced into little pieces, and dried in a 40°C oven. To preserve the active ingredients in the fig, the fig chunks were dried at this temperature before being electrically grounded coarsely. The powdered substance was combined five times with 80% ethanol for 72 hours while being sometimes shaken. On the plant debris, the previous extraction process was carried out twice. The filtrates were then mixed. The filtered material was evaporated on a rotary evaporator at a lower pressure, creating a thick paste-like substance that was dark brown in color.

The hydroalcoholic extract of the date fruit was made and lyophilized according to an earlier process [24]. The date-palm fruit was carefully removed from the pits and made clear of the surrounding dirt. Small chunks of the fruit’s flesh were removed, dried in a 40°C oven, and coarsely grounded using an electrical tool. We created the extract by blending the crushed date fruit with 50% ethanol (1 : 3 mass to volume ratio) for 48 hours at 4°C while stirring continuously. A 20-minute, 1788 g centrifugation at 4°C was performed on the entire solution. The supernatant was gathered, dried, lyophilized, and kept at −20°C until it was needed.

2.6. Preparation of the Antioxidant Treatments

The olive oil oral supplementation doses (7 g/kg. bwt), fig, and date-palm fruit extracts (1 g/kg. bwt) were used according to Fathy et al. [25].

2.7. The Experimental Animals

The rats in the present study were purchased from VACSERA, Giza, Egypt, and were acclimated and housed under standard conditions at the animal facility, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

2.8. Animal Welfare

The animal study was conducted under the National Research Centre guidelines for the use and care of laboratory animals [26] and was approved by an independent ethics committee of the Faculty of Pharmacy, Ain Shams University.

2.9. Experimental Design

We used 80 male Wistar rats average weight of 150–170 g divided into eight groups (n = 10) as the following:(i)Group I (control): this group was supplied with standard pellets and water for 75 days(ii)Group II (FOD): this antioxidant-treated group was orally supplied with extra-virgin olive oil (7 g/kg) and freshly prepared fig and date-palm fruit (1 g/kg) extracts daily for two weeks before and during the experimental period (75 days)(iii)Group III (SiO₂NPs): this group was orally administered with SiO₂NPs (100 mg/kg) daily for 75 days(iv)Group IV (FOD-SiO₂NPs): this group was supplied with FOD and SiO₂NPs as mentioned previously in groups II and III(v)Group V (Al₂O₃NPs): this group was orally administered with Al₂O₃NPs (100 mg/kg) daily for 75 days(viGroup VI (FOD-Al₂O₃NPs): this group was supplied with FOD and Al₂O₃NPs as mentioned previously in groups II and V(vii)Group VII (ZnONPs): this group was orally administered with ZnONPs (100 mg/kg) daily for 75 days(viii)Group VIII (FOD-ZnONPs): this group was supplied with FOD and ZnONPs as mentioned previously in groups II and VII

2.10. Preparation of Samples

At the end of each experiment, the rats were weighed, and the blood samples were collected from each animal under anesthesia (diethyl ether) from the retro-orbital venous plexus puncture using blood capillary tubes. The serum was prepared from the drained blood samples by centrifugation at 4000 rpm for 15 min. The prepared serum samples were frozen at −80°C until used. Then, the rats were dissected, and the liver tissues were removed, washed, and divided into two portions; one was used for the biochemical analysis, and the other was used for histopathology. The portion used for biochemical analysis was homogenized in a buffer solution using a rotor-stator homogenizer (USA). The homogenates were centrifuged, separated, and stored until used at −80°C.

2.11. Biochemical Study

2.11.1. Oxidative Stress Parameters

The oxidative stress markers (TAC, GSH, GR, GPx, GST, NO, SOD, CAT, and TBARS) were measured in the liver tissue homogenate by readymade kits purchased from Bio Diagnostic Co. for research kits, Egypt.

2.11.2. Inflammatory Markers

The tumor necrosis (TNF-α) was measured in the liver tissue homogenate using methods outlined in the ELISA kit (Catalog No: MBS2507393, MyBioSource, Inc. San Diego, USA). The interleukin-6 (IL-6) was measured in the liver tissue homogenate using methods outlined in the ELISA kit (Catalog No: E-EL-R0015, Elabscience Biotechnology, Inc., Texas, USA).

2.11.3. Apoptotic Biomarkers Estimation

The P53/tumor protein (p53/TP53) was measured in the liver tissue homogenate using methods outlined in the ELISA kit (Cusabio Technology LLC, Houston, USA).

2.11.4. Liver Function Tests

The liver parameters (AST, ALT, TBIL, GGT, TP, albumin, globulin, A/G ratio, and tissue ALP) were estimated by readymade kits purchased from Bio Diagnostic Co. for research kits, Egypt.

2.11.5. The Liver Tissue Histological Study

After the dissection of rats, the liver tissues were excised, washed in saline, fixed, processed (in alcohol series), sectioned (5 μm), and stained (HX & E) following the micro techniques outlined in Bancroft and Gamble [27].

2.12. Statistical Analysis

The data analysis (SPSS/PC program) was conducted using ANOVA one-way followed by LSD post hoc. The results were shown as mean ± SE. The significance level was at .

3. Results

3.1. The Effects of the FOD on the Oxidative Stress Markers of the Liver Tissue of Male Rats Treated with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days

The FOD and FOD-SiO₂NPs-treated groups showed insignificant changes in oxidative stress markers compared with control values (Table 1).

The SiO₂NPs-, Al₂O₃NPs-, and ZnONPs-treated groups showed a significant decrease in the TAC (11.76%, 29.58%, and 35.42%, respectively), GSH (16.49%, 37.36%, and 39.01%, respectively), GR (10.43%, 39.89%, and 43.26%, respectively), GPx (15.69%, 56.18%, and 59.54%, respectively), GST (16.05%, 42.58%, and 45.00%, respectively), CAT (11.88%, 23.30%, and 26.80%, respectively), and SOD (10.09%, 22.28%, and 24.07%, respectively), in the liver tissue in contrary to a significant increase in the NO (26.39%, 48.27%, and 57.97%, respectively), and TBARS (19.24%, 52.70%, and 58.26%, respectively) as compared with the control (Table 1).

Similarly, the groups treated with the FOD-Al₂O₃NPs, and FOD-ZnONPs recorded a significant decrease in the TAC (17.18%, and 24.12%, respectively), GSH (28.35%, and 31.64%, respectively), GR (20.12%, and 23.31%, respectively), GPx (12.86%, and 15.49%, respectively), GST (11.20%, and 11.51%, respectively), and CAT (15.02%, and 16.97%, respectively) SOD (8.05%, and 13.45%, respectively), in the liver tissue in contrary to a significant increase in the NO (16.51%, and 12.43%, respectively), and TBARS (26.53%, and 38.71%, respectively) as compared with the control group (Table 1).

The groups treated with the FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs recorded a significant increase in the TAC, GSH, GR, GPx, GST, CAT, and SOD in the liver tissue; on the contrary to a significant decrease in the NO, TBARS as compared with the groups treated with the SiO₂NPs, Al₂O₃NPs, and ZnONPs, respectively (Table 1).

3.2. The Effects of the FOD on the Hepatic Tumor Suppressor p53 and Inflammatory Markers of Male Rats Administered with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days

Compared with the control, the FOD and FOD-SiO2NPs-treated groups show insignificant changes in the hepatic p53 and the measured inflammatory markers (Figures 2–4).

The groups treated with the SiO₂NPs, Al₂O₃NPs, and ZnONPs recorded a significant increase in the hepatic p53 (29.66%, 51.53%, and 52.14%, respectively), hepatic TNF-α (21.17%, 90.96%, and 140.50%, respectively), and hepatic IL-6 (11.11%, 25.50%, and 21.39%, respectively) as compared with the control group (Figures 2–4).

Similarly, the groups treated with the FOD-Al₂O₃NPs and FOD-ZnONPs recorded a significant increase in the hepatic p53 (42.85%, and 45.44%, respectively), hepatic TNF-α (74.83%, and 122.43%, respectively), and hepatic IL-6 (13.17%, and 10.53%, respectively) compared with the control group (Figures 2–4).

The groups treated with the FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs recorded a significant decrease in the hepatic p53, hepatic TNF-α, and hepatic IL-6 as compared with the groups treated with the SiO₂NPs, Al₂O₃NPs, and ZnONPs, respectively (Figures 2–4).

3.3. The Effects of FOD on the Liver Markers of Male Rats Treated with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days

The FOD and the FOD-SiO₂NPs-treated groups showed insignificant changes in ALP, AST, ALT, TBIL, GGT, TP, albumin, and globulin in the serum compared with the control group (Table 2).

The groups treated with the SiO₂NPs, Al₂O₃NPs, and ZnONPs recorded a significant increase in the ALP (21.69%, 39.81%, and 45.86%, respectively), AST (14.24%, 25.99%, and 29.30%, respectively), ALT (14.58%, 31.12%, and 34.30%, respectively), TBIL (68.42%, 101.75%, and 128.07%, respectively), GGT (39.27%, 72.25%, and 76.28%, respectively), in the serum in contrary to a significant decrease in the TP (21.49%, 41.85%, and 48.50%, respectively), albumin (15.39%, 38.39%, and 39.28%, respectively), and globulin (28.25%, 45.69%, and 58.72%, respectively) in the serum compared with the control group (Table 2).

Similarly, the groups treated with the FOD-Al₂O₃NPs, and FOD-ZnONPs recorded a significant increase in the ALP (16.24%, and 24.67%, respectively), AST (13.58%, and 15.40%, respectively), ALT (21.21%, and 26.36%, respectively), TBIL (54.39%, and 63.16%, respectively), GGT (30.39%, and 45.22%, respectively), in the serum, in contrary to a significant decrease in the TP (27.61%, and 33.28%, respectively), albumin (18.88%, and 28.03%, respectively), and globulin (37.28%, and 39.09%, respectively) in the serum as compared with the control group (Table 2).

The groups treated with the FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs recorded a significant decrease in the serum ALP, AST, ALT, TBIL, and GGT in contrast to a significant increase in the TP and albumin in the serum as compared with the SiO₂NPs-, Al₂O₃NPs-, and ZnONPs-treated groups, respectively (Table 2).

The groups treated with the FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs recorded insignificant changes in the serum globulin compared with the groups treated with the SiO₂NPs, Al₂O₃NPs, and ZnONPs, respectively (Table 2).

3.4. The Effects of the FOD on the Liver Histopathological Characters of Male Rats Treated with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days

The control liver showed a normal morphological appearance. However, the antioxidant-treated NPs administered groups (FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs) recorded significantly ameliorated liver histopathological characters as compared with values in the nonantioxidant-treated NPs administered groups (SiO₂NPs, Al₂O₃NPs, and ZnONPs, respectively) as indicated in Table 3 and Figure 5.

Figure 5

The effects of fig with olive oil and date-palm fruit extracts (FOD) on the microscopic histological appearance of livers treated with different nanoparticles (NPs) for 75 days. (a) Higher power view of the control liver showing average central veins (CV) and average hepatocytes in peri-venular area (black arrow) with average blood sinusoids (Si); (b) FOD-treated group showing average portal tracts (PT) with average portal veins (PV), average bile ducts (BD), and average hepatocytes in peri-portal area (black arrow); (c) SiO₂NPs-treated group showing portal tracts with mild portal inflammatory infiltrate (black arrow), average portal vein (PV), and scattered apoptotic hepatocytes in peri-portal area (blue arrow); (d) FOD-SiO₂NPs-treated group showing average central veins (CV) and average hepatocytes in peri-venular area (black arrow); (e) Al₂O₃NPs-treated group showing portal tracts with mild portal inflammatory infiltrate (black arrow) with mildly dilated congested portal veins (PV), average bile ducts (BD), and average hepatocytes in peri-portal area (blue arrow); (f) FOD-Al₂O₃NPs-treated group showing average portal tracts (PT) with average portal veins (PV), average bile ducts (BD), and average hepatocytes in peri-portal area (black arrow); (g) ZnO NPs-treated group showing mildly edematous portal tracts (PT) with markedly dilated congested portal veins (PV), average bile ducts (BD), and moderate apoptotic hepatocytes in peri-portal area (black arrow); (h) FOD-ZnO NPs-treated group showing mildly edematous portal tracts (PT) with mildly dilated portal veins (PV), average hepatic artery (HA), and few scattered apoptotic hepatocytes in peri-portal area (black arrow).

4. Discussion

With the progress in the nanotechnology field, there may be an increase in the exposure of humans to various nanoparticles, so further urgent studies are required to study the possibility of any detrimental health impacts and their mechanisms [28, 29]. Nanoparticles can be translocated from the entry portals into the blood circulation and the lymphatic system and then to body organs and tissues. They can cause irreversible cell damage by oxidative stress and organelle injuries because of their sizes and structures, leading to severe cytotoxicities [30]. Body organ dysfunction may result from distributing these nanoparticles to other organs [23].

Our study confirmed the subchronic hepatic toxicity of rats treated with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 days of oral administration as agreed with other studies [31, 32], which indicated that the liver toxicity due to NPs administration might be due to induction of lipid peroxidation, oxidative stress, systemic inflammation, and hepatic toxicity.

In the present study, regarding the liver oxidative stress markers, the subchronic oral administration of the SiO₂NPs, Al₂O₃NPs, and ZnONPs for consecutive 75 days recorded a significant reduction in the TAC, GSH, GR, GPx, GST, SOD, and CAT in contrast to a considerable elevation in the NO, and TBARS compared with their corresponding control values. That agrees with previous studies [3, 23, 32] that recorded a significant decrease in the antioxidants after SiO₂NPs, Al₂O₃NPs, or ZnONPs administration. In addition, Li et al. [33] and Yousef et al. [23] reported that nanoparticles such as SiO₂NPs, Al₂O₃NPs, or ZnONPs could generate many deleterious ROS that led to their toxic effects, cellular dysfunction, and cell death. The ROS interact with and cause damage to the cellular molecules [34].

The oxidative damage to cells caused an alteration in both lipid bilayer fluidity and permeability properties [35]. In agreement with the present results, there was a directly proportional relationship between TBARS and the oxidative stress that caused biochemical alterations in different parameters [36, 37]. The increased TBARS after SiO₂NPs, Al₂O₃NPs, or ZnONPs administration could be attributed to the produced ROS that interacts with the phospholipids portion of the cell membrane and initiates the lipid peroxidation chain reaction [23, 32].

The GSH maintains the normal reduced status of the cells and counteracts oxidative stress by conjugation with GPx and GST [29, 38]. In addition, GSH is a major endogenous antioxidant. Therefore, it is used as a marker for counteracting a variety of toxicants and can function as an antioxidant in many ways [39]. The present data confirmed the previous reports of Wu et al. [40] and Bashandy et al. [37], who revealed that the glutathione deficiency contributed to oxidative stress due to its diffusion or inhibition of GSH synthetase/reductase enzymes.

The antioxidant enzymes (SOD and CAT) play a vital role in antioxidant defense. The SOD utilizes free radicals as a substrate. The CAT is an index of increased H₂O₂ production and transforms it into water [41]. As in the present study, the depletion of these enzymes may be due to an enhanced radical production during SiO₂NPs, Al₂O₃NPs, or ZnONPs administration [4, 5, 23].

The oxidative stress due to NPs administration causes increased NO production, which reacts with superoxide to form peroxynitrite (ONOO⁻) and peroxynitrous acid that initiates the cascade of lipid peroxidation and accelerate cell toxicity [3].

The present study demonstrated that the antioxidant-treated NPs administered groups (FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs) treated for two weeks before and during the administration of the nanoparticles (75 days) recorded significantly ameliorated hepatic oxidative stress markers when compared with the nonantioxidant-treated NPs administered groups (SiO₂NPs, Al₂O₃NPs, and ZnONPs, respectively). The FOD treatment counteracted the free radical toxicity in the present study due to many antioxidants [37, 42]. Our results showed that FOD effectively reduced oxidative stress induced by the NP administration. More attention has been paid to natural antioxidants due to their protective effects against metals-induced toxicity, especially when reactive oxygen species are involved. Olive oil is among these natural antioxidants [43]. Moreover, the antioxidant component cyanidin-3-rhamnoglucoside (C3R) present in the fig fruit may reduce oxidative stress and improve liver function [44]. In addition, it has been demonstrated by several phytochemical studies that date-palm fruits contain many antioxidants that act as free radical scavengers [45].

Regarding the inflammatory markers, the SiO₂NPs, Al₂O₃NPs, and ZnONPs-treated groups for consecutive 75 days as subchronic oral administration recorded significant elevation in the hepatic TNF-α and hepatic IL-6 compared with the control values. The liver can accumulate more than 90% of nanoparticles. Activation of Kupffer cells due to NPs administration elicits the release of different mediators such as TNF-α, IL-Iβ, and IL-6 [46]. When administrated to rats, NPs such as SiO₂NPs, Al₂O₃NPs, or ZnONPs entering the body cause changes in inflammatory cytokines. It causes the elevation of proinflammatory cytokines (IL-1β and IL-6) [23, 47]. In line with these data, amorphous silica (SiO₂NPs) nanoparticles significantly increased transient inflammatory response after intratracheal instillation [47] and induced proinflammatory responses such as IL-6, IL-Iβ, and TNF-α release. Moreover, Faddah et al. [48] found that ZnONPs administration can elevate the inflammatory markers in the blood. In addition, Hou et al. [49] described that exposure to Al₂O₃NPs stimulates the immune system and altered cytokine levels.

Understanding the effects of nanoparticles on the cellular genome is very important to evaluate the extent of toxicity [50]. In the present study, regarding the tumor suppressor p53, the SiO₂NPs, Al₂O₃NPs, and ZnONPs administered groups recorded a significant elevation in the p53 compared with the control group. That elevation may participate in inducing hepatocytes apoptosis in response to the NP’s administration, as agreed by Yousef et al. [23]. Nanoparticles may also aggravate stress-induced apoptosis in the liver, suggesting that they may be dangerous to liver disease patients [51]. In addition, Vurusaner et al. [52] described the activation of p53 in response to oxidative stress, which performs antioxidant functions.

The present study demonstrated that the antioxidant-treated subchronic NPs administered groups (FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs) treated for two weeks before and during the administration of the nanoparticles (75 days) significantly ameliorated hepatic p53 and inflammatory markers when compared with the nonantioxidant-treated NPs administered groups (SiO₂NPs, Al₂O₃NPs, and ZnONPs, respectively). In agreement, FOD has been studied as a potential antioxidant and anti-inflammatories because of their polyphenol contents which stimulate apoptosis and inhibit cell proliferation [53, 54]. Reporter assays indicated that many plants possessed antitoxic activity for different cell lines, including the colon, ovary, liver, kidney, central nervous system, and gastric cells treated with various toxic agents [55, 56]. These authors related this effect to the antiproliferative activity of these plants. In addition, the antitumor efficacy of FOD may ascribe to the synergies between them [18, 37, 57]. In addition, oleuropein (major phenol for olive products) and hydroxytyrosol (one of the most potent antioxidants in olive oil) may also act through the modulation of oncogenic signaling pathways, leading to cell apoptosis [58]. In addition, few studies demonstrate that the different components of FOD could block and suppress tumor growth and inflammation [57, 59].

Any disruption of the function of hepatic cells can lead to alteration in the blood serum constituents and enzyme functions [55, 60]. The current study showed that SiO₂NPs, Al₂O₃NPs, or ZnONPs as subchronic oral administrations for 75 days have adverse influences on the liver and cause a significant effect on the liver function parameters, which was consistent with other studies [23, 61]. Changes in serum biochemical parameter levels directly indicate the pathological status of the liver. In clinical practice, high serum AST, ALT, and ALP levels produced from damaged hepatic cells in the circulation are related to severe liver dysfunctions [62, 63]. This finding suggests that the retention of nanoparticles injured hepatocytes. Many studies reported that SiO₂NPs, Al₂O₃NPs, or ZnONPs caused dose-dependent liver injury in rodents [23, 47].

The changes in AST, ALT, GGT, and ALP, besides the increase of TBIL, were markers of liver injury and indicated cellular leakage and impaired cell membranes [64]. The GGT is a hepatocyte plasma membrane enzyme found mainly in the canalicular domain and is considered the best indicator of liver damage. The increased serum GGT in response to the NPs administration in the present study indicates damage to the hepatic cells and liver injury, as agreed with other studies [63, 65]. The elevation in ALP activity and TBIL in NPs administration groups might be attributed to liver diseases or the bile duct obstruction that led to the release of this enzyme in the blood [23].

The serum proteins were synthesized and secreted by several cell types and function in the osmotic regulation of body fluids. In agreement, some studies [23, 66] suggested that decreased serum albumin in the SiO2NPs, Al₂O₃NPs, or ZnONPs administrated rats might be due to liver damage or changes in the permeability of liver cell membranes. The decreased albumin might also be due to the slower rate of its synthesis [4, 67].

The antioxidant-treated NPs administered groups (FOD-SiO₂NPs, FOD-Al₂O₃NPs, and FOD-ZnONPs) for two weeks before and during the administration of the nanoparticles (75 days) significantly ameliorated liver functions compared with the nonantioxidant-treated NPs administered groups (SiO₂NPs, Al₂O₃NPs, and ZnONPs, respectively). Our results showed that FOD effectively reduced the increased liver function parameters induced by the NP administration, which could be attributed to the many antioxidants and polyphenolic compounds found in FOD and responsible for hepatoprotective impacts of FOD against many toxins. In addition, the amelioration in the NP-administrated groups treated with FOD might be attributed to the existence of chemical components in the extract and the antihepatotoxic effects of FOD. [17, 68]. The reversal of plasma enzyme activity elevation in NPs-induced hepatotoxicity revealed that FOD could lower hepatocyte death. Thus, it probably effectively ameliorates NPs induced liver injury [69]. In addition, in the present work, the possible mechanism of hepatoprotection of FOD may be attributed to the antioxidant activity of its components [25, 70].

The current results are consistent with Domitrovic et al. [71], who stated that oleuropein decreased transaminases in a dose-dependent manner at carbon tetrachloride-induced liver damage in mice. In addition, the result of the current study was also in agreement with those of Amiri et al. [72], who stated that the administration of virgin olive oil to mice significantly decreases liver enzymes in the serum. Also, the results of the present study were similar to those of Al-Seeni et al. [73], who observed that rats injected with carbon tetrachloride (CCl₄) and cotreated with olive oil recorded significantly decreased liver enzymes, in contrast, to significantly increased total protein and albumin as compared with the control group. This improvement could be explained by Bulotta et al. [54], who stated that virgin olive oil contains natural antioxidants such as hydroxytyrosol and oleuropein that act as free radical scavengers. In agreement, Singhal et al. [74] and Bashandy et al. [37] reported that the fig fruit extract was responsible for improving various antioxidant and liver function parameters in irradiated rats. In agreement, the treatments with the fruit extract of the date palm ameliorate liver functions [75, 76].

As agreed with the present study, the liver damage caused by SiO₂NPs, Al₂O₃NPs, or ZnONPs is further confirmed by histopathological examination, which showed many pathological features, including necrosis, dilation of central veins, and their congestion with blood, edema, and degeneration of the hepatocytes [23, 61].

The antioxidant-treated NPs groups in the current work recorded significantly ameliorated histopathological characteristics when compared with the nonantioxidant-treated NPs groups. The protection of the liver in response to FOD administration may be due to decreased or prevented lipid peroxidation and protein oxidation [37, 77].

5. Conclusion

The FOD treatments in the NPs administered groups are protective against different NPs-induced subchronic hepatotoxicity in male Wistar albino rats. The present findings also revealed the ameliorative effects of FOD in the treatment of NPs toxicity by modulating oxidative stress, inflammation, apoptosis, and toxification hazards. In addition, the administration of FOD revealed a synergistic effect between their components.

Data Availability

The data supporting the current study are available from the corresponding author upon request.

Ethical Approval

The Research Ethical Committee approved the study protocol, Faculty of Pharmacy, Ain Shams University, and conducted it according to the regulations and recommendations of the ethical guidelines and complied with the guide for the care and use of laboratory animals.

All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

This work was carried out in collaboration with all authors. All authors read and approved the final manuscript.

Acknowledgments

The authors would like to thank all Animal House Facility Department staff, Faculty of Pharmacy, Ain shams University for their kind cooperation in completing the present study. The authors are profoundly grateful to Prof. Dr. Sayed Abdel Raheem, Professor of Histopathology, Al-Azhar Faculty of Medicine, Cairo, for his kind help during the histopathological investigation of liver tissues.

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Copyright © 2023 Abdallah H. Fathy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Journal of Food Quality

Antioxidant and Hepatoprotective Effects of Fig Fruit Extract with Olive Oil and Date-Palm Fruit Extract on Hepatic Toxicity of Oral Subchronic Exposure to Some Nanoparticles in Wistar Rats

Abstract

1. Introduction

2. Materials and Methods

2.1. Chemicals

2.1.1. Reagents

2.2. Nanoparticles

2.3. Preparation of Nanoparticle (NPs) Treatments

2.4. Plant Materials and Authorities

2.5. Preparation of Crude Extracts

2.6. Preparation of the Antioxidant Treatments

2.7. The Experimental Animals

2.8. Animal Welfare

2.9. Experimental Design

2.10. Preparation of Samples

2.11. Biochemical Study

2.11.1. Oxidative Stress Parameters

2.11.2. Inflammatory Markers

2.11.3. Apoptotic Biomarkers Estimation

2.11.4. Liver Function Tests

2.11.5. The Liver Tissue Histological Study

2.12. Statistical Analysis

3. Results

3.1. The Effects of the FOD on the Oxidative Stress Markers of the Liver Tissue of Male Rats Treated with SiO2NPs, Al2O3NPs, or ZnONPs for 75 Days

3.2. The Effects of the FOD on the Hepatic Tumor Suppressor p53 and Inflammatory Markers of Male Rats Administered with SiO2NPs, Al2O3NPs, or ZnONPs for 75 Days

3.3. The Effects of FOD on the Liver Markers of Male Rats Treated with SiO2NPs, Al2O3NPs, or ZnONPs for 75 Days

3.4. The Effects of the FOD on the Liver Histopathological Characters of Male Rats Treated with SiO2NPs, Al2O3NPs, or ZnONPs for 75 Days

4. Discussion

5. Conclusion

Data Availability

Ethical Approval

Consent

Conflicts of Interest

Authors’ Contributions

Acknowledgments

References

Copyright

3.1. The Effects of the FOD on the Oxidative Stress Markers of the Liver Tissue of Male Rats Treated with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days

3.2. The Effects of the FOD on the Hepatic Tumor Suppressor p53 and Inflammatory Markers of Male Rats Administered with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days

3.3. The Effects of FOD on the Liver Markers of Male Rats Treated with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days

3.4. The Effects of the FOD on the Liver Histopathological Characters of Male Rats Treated with SiO₂NPs, Al₂O₃NPs, or ZnONPs for 75 Days