Abstract

  Paraquat-induced liver fibrosis involves two factors, direct injury by oxygen free radicals and indirect injury by inflammatory cells and fibroblasts. This study was carried out to examine the prophylactic potential of the Balanites aegyptiaca seeds water extract (BASWE) on paraquat-induced injury in rat. Oral administration of BASWE (100 and 200 mg/kg b.w.) to paraquat treated rats normalize significantly the serum levels of hepatic enzymes AST, ALT and ALP activity as well as liver TBARS, NO, TNF-α and IL-1β. Oral administration of BASWE also exhibited its capacity to replenish the paraquat-induced decreased GSH levels and enhance increase in IL-10 and SOD activity. The present results proved the protective effect of BASWE against paraquat-induced liver fibrosis by suppression of miR-122a and miR-192 gene expression as well as normalized the liver histology.

Keywords: Balanites aegyptiaca;Hepatoprotective; Paraquat; Cytokines;Antioxidant Enzymes; Inflammatory Mediators;miR-122a; miR-192

Abbreviations

  AST: Aspartate Aminotransaminase; ALT:Alanine Aminotransaminase; ALP: Alkaline Phosphatase; TBARS: Thiobarbituric Reactive Substances; NO: Nitric Oxide;TNF-α: Tumor Necrosis Alpha;IL-1β:Interleukin-1β; GSH: Reduced Glutathione; IL-10: Interleukin-10; SOD: Superoxide Dismutase

Introduction

  Paraquat (1, 1'-dimethyl-4, 4' bipyridinium dichloride) is widely used as a nonselective herbicide, but it has toxic effects on various organs, including lung, liver and other organs [1]. Also, oxidative stress of paraquat by redox cycling led to produce superoxide radical [2,3] and cause lung and liver damage and kidney failure [3].

  For over four thousand years Balanites aegyptiaca have been planted in Egypt. In the tombs of the Twelfth Dynasty [4] stones of the fruit were offered as votive offerings.

  Cook.,et al. [5] has indicated the high amount of sugar, protein, fats, minerals and vitamins in the Balanites Aegyptiaca fruit pulp. The total sugar of fruits pulp, as reported by the NRC[6], ranges from 40 to 70%, and contains about 5% proteins and 0.1% fat. Abdulrazak.,et al.[7]have investigated the mineral contents of Balanites aegyptiaca fruit pulp.

  The concentrations of were found to be 24.4, 6.33, 1.58, 0.542, 1.81 and 1.23 g/kg dry basis (DM), respectively [7].

  The fruits of Balanites aegyptiaca are highly rich in saturated acids which can be used as cooking oil. It also contains steroids (saponins, sapogens, diosgenes), usually used for the production of contraceptives, corticoids, anabolic and other sex hormones as the raw materials for the industrial production [8].

  In some skin diseases, Balanites aegyptiaca is also employed in curing leucodermia. In addition, the fruits and leaves are used to treat the syphilis, yellow fever, and bilharzia[9].

  Balanites aegyptiaca contains large amounts of soluble tannins[10], polyphenols [11,12] and flavonoids[13] that excellent source of scavengers of reactive oxygen species and antioxidants. These reports led us to investigate other pharmacological functions of Balanites aegyptiacas. There are no reports on liver toxicity induced by hepatoprotection of Balanites aegyptiaca seeds Extension of our research on neutral products' biological significance [15-18]. In this study, we sought to estimate the preventive effects of Balanites Aegyptiaca seeds water extract for liver injury induced by intraperitoneal injection paraquat.

Materials and Methods

  Paraquat dichloride and vitamin C were purchased from Sigma-Aldrich, USA. Paraquat dichloride was injected intraperitoneally in a dose of 50 mg/kg into intact animals [19].

  Balanites aegyptiaca seeds were brought from the local market in Cairo and characterized by prof. Heba A. Elgezawy, Faculty of Pharmacy, October 6 University.

  This was prepared by extracting 0.5 kg of air-dried crashed Balanites aegyptiaca seeds using hot water in ratio 1:10. The extraction was carried out at 500C for 2h with stirring at regular intervals. It was filtered into a low pressure to give viscous mass and evaporated to dryness. The extract was kept in airtight containers in a deep freeze maintained at 4oC until the time of further use.

  A 30 adult female albino rats (180± 20 gms), were purchased from NCI, Cairo University. The conditions in the animal house were acclimatized. Standard diet and water adlibtium were provided to animals. Rats observed daily throughout the experimental work.

  This experiment was carried out to investigate, repeatedly for 2 weeks, the prophylactic potential of water extracts from Balanitesaegyptiaca seeds against Paraquatinduced hepatotoxicity in vivo, of the Balanitesaegyptiaca seeds. For intragastric intubation of rats a 3g percent suspended solution was developed. Animal groups each of six rats were treated daily for 14 days as follows: For the following groups:

• Group I: Standard control was given 5 mL of saline p.o.
• Group II: Positive control was given 5 mL of saline p.o.
• Group III: WEBAS (100 mg/kg b.w.) was treated with a single daily dose of suspended water [20].
• GroupeIV: WEBAS (200 mg/kg b.w.) was treated with a single daily dose of suspended water.
• Group V:vitamin C (1 g/kg b.w.) was treated with a single daily dose of suspended water [21].

  At day 13, i.e. one day before the last treatment, animals of all groups were fasted for 18h. At day 14, one hour after the last dose of drug treatment, all animals in groups II, III, IV and V received Paraquat dichloride (50 mg/kg.b.w.) [19].

  Serum levels of glutamic-oxaloacetic transaminase (GOT) [22], glutamic-pyruvate transaminase (GPT) [22] and alkaline phosphatase (ALP) [23].

  At the end of the experiment, cervical decapitation sacrificed rats from each group. The liver specimens were quickly retrieved and gently opened with a scrapper, rinsed using ice-cold isotonic saline to remove all blood cell types and clots, then blotted between 2 filter documents and divided one part in biological liver GSH estimations [24], superoxide dismutase (SOD) [25], TBARS [26] and Nitric oxide [27].

  TNF-α[28], interlinkin-1β (IL-1β)[29] and interleukin-10(IL-10)[30] were detected using a Multiskan Ascent UV microplate reader (Thermo Electric Corp., Shanghai, China) enzyme related immune test technique as per instructions from the manufacturer. The enzyme associated immunoassay (ELISA). Added acid stopped the reaction and a microplatform reader measured the absorption at 450 nm.

  A kit column miRNeasy kit (Qiagen, USA) was used to mix the 200-μl serum sample with the 1000 μlQiAzol solution and the microRNA extraction process was carried out in accordance with the manufacturers kit protocol. Finally, the extraction product was kept at -80°C in a freezer for later use.

  According to the manufacturer's instructions, total RNA was prepared with an RNeasy® Mini Kit (QIAGEN, Germany). The integrity of RNA with NanoDrop2000 was verified (1.8-2.0; NanoDrop2000, Thermo, city, state). RNA (1μg), as detailed in the manufacturer's instructions, was transcribed with a miScript II RT (Qiagen, Germany). An FastStart Universal SYBR Green PCR Master (ROX) was performed with a total volume of 10 μL on a MxPro 3000 pp quantitative real-time PCR (qRT-PCR) test used for measuring miR-122a and miR-192 RNA extracted from serum samples (Agilent, Palo Alto, USA). The following conditions were applied: initial denaturation at 95°C for 10 min. 40 cycles of three-step PCR (95°C at 15 sec, 55°C for 30 sec and 72°C for 30 sec) BGI supplied all primers (The Beijing Genomics Institute). For all genes, the primary sequences (5′‐3′′) were shown in table 1.

  Liver samples were isolated and preserved in formalin 10% then routinely processed to be embedded in paraffin. 5-mm thick paraffin sections were cut and stained with hematoxylin-eosin (HE) for light microscopic analysis according to the method of Bancroft and Steven [31].

  All the grouped data were statistically evaluated with SPSS/13 software. Hypothesis testing methods included one way analysis of variance (ANOVA) followed by least significant difference (LSD) test. P values of less than 0.05 were considered to indicate statistical significance. All the results were expressed as mean ± SD for six separate determinations.

Results

  The hepatotoxic, paraquat significantly produced severe liver damage as indicated by a marked increase in serum AST, ALT and ALP as compared with the control group. Treatment with Balanites aegyptiaca seeds water extract (100 and 200 mg/kg) and Vitamin C (1 g/kg b.w.) caused significant reduction AST, ALT and ALP as compared with the positive control group and exhibited a significant hepatoprotective effect (Table 2) (P ≤ 0.05).

  Table 3showed the levels ofliver reduced glutathione (GSH), superoxide dismutase (SOD), thiobarbituric reactive substances(TBARS) and Nitric oxide (NO) of normal and experimental groups of rats. The levels of GSH and SOD in paraquat-treated rats were significantly loweras well as a significantly increase of liver TBARSand NOas compared with the control group (P ≤ 0.05), whereas paraquat-treated rats which treated with the Balanites Aegyptiaca seeds water extract (100 and 200 mg/kg) and Vitamin C (1 g/kg b.w.) restored the altered values to the near normalcy as compared with the positive control group. The effect was more pronounced in the paraquat-treated rats which treated with Balanites Aegyptiaca seeds water extract (200 mg/kg).

  Table 4 showed the levels of liver tumor necrosis alpha (TNF-α),interleukin-1β (IL-1β) and interleukin-10 (IL-10) in liver. The level of hepatic TNF-α, IL-1β and IL-10in paraquat-treated rats was significantly higher than normal rats, whereas paraquat-treated rats which treated with the Balanites Aegyptiaca seeds water extract (100 and 200 mg/kg) and Vitamin C (1 g/kg b.w.) restored the altered values to the near normalcy (P ≤ 0.05) as compared with the positive control group.

  Serum miR-122a and miR-192 gene expression in paraquat-treated rats were higher than those in the control group (P < 0.05). Treatment with Balanites Aegyptiaca seeds water extract (100 and 200 mg/kg) and Vitamin C (1 g/kg b.w.) significantly decreased the expression levels of miR-122a and miR-192as compared toparaquat-treated rats (Figure 1and 2).

  Figure 3a-3eshowedSections stained with hematoxylin and eosin (H&E; 200 X) histological examination of rats livers of different groups compared to control group. (Figure 3a) negative control group Showed section in liver with unremarkable pathological changes. Also, figure 3b showed scattered apoptotic bodies (the black arrows). the portal tracts are expanded by inflammatory cells and fibrosis in group II which received a Paraquat dichloride (50 mg/kg b.w.) for a 15-day period. In addition, figure 3c showed congested dilated blood vessels (the arrow) ingroup III which treated with Balanites aegyptiaca seeds (100 mg/kg b.w.) for a 15-day period. Finally, figure 3d and 3e showed normal architecture with unremarkable pathological changes ingroups IV and V which treated with Balanites aegyptiaca seeds (200 mg/kg b.w.) andVitamin C, respectively.

Discussion and Conclusion

  Paraquat is a widely used broad spectrum herbicide which is toxic to man [32]and laboratory animals [33]. Paraquat toxicity is characterized by delayed development of liver lesions, which progresses to interstitial fibrosis [34]. Paraquat toxicity appeared to result from cyclic reduction-oxidation of the herbicide with subsequent generation of superoxide radicals. Superoxide radicals may nonenzymatically dismutate to singlet oxygen, which reacts with unsaturated lipids in cell membranes to form lipid hydroperoxides. The spontaneous decomposition of lipid hydroperoxides to lipid free radicals initiates the membrane destructive process of lipid peroxidation [35]. Previous studies show that oxidative strain happens during fibrosis and probably contributes to paraquat-induced liver injury [36]. Previous studies show that antioxidants, including N-acetylcysteine, vitamin E, silymarin, and quercetin, decrease lipid peroxidation and partially ameliorate liver injury, but the effects of antioxidants on fibrosis remain controversial [37]. Our results show a significant increase in liver enzyme activity and indicate a deteriorated integrity of the hepatocellular membrane which could end with liver dysfunction. This effect has also been shown by our findings on the liver of treatment rats. As we have confirmed from previous studies, the activation of cell molecular damage on paraquat exposure has been shown to be functional and biochemical changes, which are liver damage [33,34] and increased liver enzymes activity [35].

  From these findings, it is evident that the water extract of Balanites aegyptiaca seeds was able to reduce all the elevated biochemical parameters as a result of hepatotoxin challenge, indicating improvement of the functional status of the liver. Significant change only suggests hepatic impairment, for example in the classical enzymes of AST, ALT and ALP because these are reliable liver toxicity indications[38]. An increase in ALP may be caused by altered skeletal muscle metabolism [39]. ALP levels are, however, useful to evaluate the lysosomal changes in vivo as marker enzymes [37].

  Protective effects due to the treatment of Balanites aegyptiacaseed with water extract have strongly shown the potential for extracts to prevent and/or reduce any leakages of markers, to condition hepatocytes to accelerate parenchymal cell regeneration, to preserve plasma membrane integrity, and thus to restore the levels of these enzymes[37].

  The magnitude of the effects vary greatly between the various plant extracts, depending on oxidative stress biomarkers SOD, GSH, NO and TBARS. The decreasing activity of the paraquat-treated rats, and increased levels of GSH, NO and TBARS in the liver tissue while the use of water extracts from balanites, aegyptiaca, prevented dramatic modifications in paraquat-induced SOD, GSH, NO and TBARS. Balanites aegyptiacaextracts significantly contributed to the intracellular antioxidant defence system through the use of single oxygen and hydroxylic radicals as strong consumers.

  The role of paraquat-induced liver injury is known to be critical for the peroxidation of the lipid[40] and one of their end products is TBARS. TBARS can therefore be used in lipid peroxidation measurements. The content of the liver TBARS was significantly increased by the administration of acute paraquat[37,41]. Pretreatment of the rats with balanite extract aegyptiaca substantially lower the TBARS level of the liver tissue and support its free radical scavenging property and antioxidative effects in the anti-lipid peroxide potential of the Balanites aegyptiaca. It may be due to the presence of polyphenols [11,12] and flavonoids [13] which are excellent reactive scavengers, and which have a promising antioxidant effect [14] that the balanite can have a hepatitis protective effect.

  The normal oxidative stress and elevation of liver TBARS and NO resulting in cell failure and metabolism resulting in ROS. It demonstrates that paraquat poisoning at a concentration of ROS induces cell production and thus promotes the synthesis of active cell activation and releases a large number of pro-inflammatory mediators, proteases and chemokines.

  ROS expression is greatly increased in cells at this time. ROS can cause liver necrosis alpha (TNF-α) and interleukin-1β (IL-1β) releases, infiltrations and activations, and inhibition of interleukin-10(IL10) through NF ŚB, which can accelerate environmental damage to the body and lead ultimately to organ dysfunction and failure. The results of He.,et al.[42] on the effects of paraquat on alveolary epithelial cells, which can support the views of this experiment, are basically consistent with the results of this experiment.

  Balanites aegyptiacaextract significantly reduces both TNF-α and IL-1β and normalises IL-10. Its free radical scavenging, antifirectory and antioxidative properties support the anti-inflammatory potential of Balanites aegyptiaca. Steroid (saponin, sapogenins, diosgenins)[8] can be the cause of the anti-inflammatory effects of Balanites aegyptiaca. Hussein.,et al.[43] have reported the inhibition of some cytokines to anti-inflammatory activity of steroidal saponins in rats.

  Our research has shown that miR-122a and miR-192 were highly expressed in paraquat treated group of rats, in line with previous studies. These results showed that miR-122a and miR-192 changes were previously diagnosed than hepatic markers. The miR-122a and miR-192 have been examined by Antoine.,et al. to identify patients with liver injury admitted to hospital for the first time [44]. They showed that miR-122a is increased in these patients as a highly specific liver biomarker. Significantly inhibited serum miR-122a and miR-192 expression are also Balanites Aegyptiaca extract.

  The activation of nuclear factor kappa induced by Balanites aegyptiacadiosgenin could abrogate tumour necrotic factor alpha (TNFα) -Light-chain enhancer of activated B cells (NF-kB) and of transcription 3 (STAT3) signal transducer induced by interleukin 6 induced by transcription cells (IL-6) [45]. The inhibition of miR-122a and miR-192 through diosgenin administration reported by Yuan Meng.,et al.[46].

  MiR-122a and miR-192 were not reported earlier in my knowledge and this study is perhaps the first such observation. The inhibition of Balanites aegyptiaca extract in paraquat-treated rats.

  The histological findings of the study show, in rats with paraquat-induced liver toxicity, that Balanites aegyptiaca extract affected liver structure recovery. Indeed, in rats treated with Balanites aegyptiacaextract treated groups, the extent of fibrosis and a reduction of star infiltration was significantly reduced compared with that treated with paraquat. The hepatoprotective effect of Balanites aegyptiacawater extract was confirmed by histological results.

  The phytochemical screening of the Aegyptiaca balanitesrevealed that flavonoids existed. Flavonoids are natural products that modulate enzyme activity and affect the behaviour of many cell systems and have significant antihepatotoxic, anti-inflammatory, even antitumor and anti-oxidant activity [47-54].

  Finally, the results of this study show that Balanites aegyptiacahas a powerful liver protection in rat for hepatic damage induced by paraquat. This can be due to the anti-oxidant activity with the ability to scavenge free radicals and inhibit lipid peroxidation, cytokines, miR-122a and miR-192.

Ethics Approval and Consent to Participate

  Ethical approval for the data collection was granted by the Research Ethics Committee at the Faculty of Applied Medical Sciences, October 6 University, Egypt (No. 20201202). No Humans were used studies that are base of this research, in-vivo study using rats only.

Consent for Publication

  The authors gave consent for their data to be used in the article

Competing Interests

  The authors declare no conflict of interest, financial or otherwise.

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Citation

Citation: Mohammed A Hussein., et al. “Hepatoprotective Effect of Balanites aegyptiaca Extract against Paraquat-Induced Liver Toxicity". Acta Scientific Nutritional Health 5.5 (2021): 110-119.

Copyright

Copyright: © 2021 Mohammed A Hussein., et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.