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BY 4.0 license Open Access Published by De Gruyter Open Access September 19, 2022

A focusing study on radioprotective and antioxidant effects of Annona muricata leaf extract in the circulation and liver tissue: Clinical and experimental studies

  • Ozlem Elmas EMAIL logo , Havva Hande Keser Sahin , Berrak Guven , Mohamed M. Abuzaid , Wiam Elshami , Ghada ALMisned , Hesham M. H. Zakaly EMAIL logo , Antoaneta Ene EMAIL logo and Huseyin Ozan Tekin EMAIL logo
From the journal Open Chemistry



This study investigates the effect of Annona muricata (AM) leaf extract against irradiation-induced damage by the evaluation of hepatic tissue and the levels of oxidative and inflammatory stress in the circulation.


An experimental study with 37 female Wistar albino rats randomized into four groups (controls and three intervention groups) was performed. The first interventional group (group 2) received 300 mg/kg of AM leaf extract by oral gavage once a day for 9 days, group 3 received a single dose of whole-body radiation (8.3 Gy) after a 9-day oral gavage treatment with saline, and the last group received the same irradiation of 8.3 Gy after being treated with 300 mg/kg of AM leaf extract by oral gavage once a day for 9 days.


Radiation was found to elevate reactive oxygen species parameters, and AM administration before irradiation was found to decrease total oxidant status (TOS), increase caspase 9, and improve hepatic damage when compared with the group that received only irradiation.


The damage caused by irradiation may be ameliorated by the use of the AM extract, which appears to be effective in preventing oxidative stress and inflammatory activity.

1 Introduction

Radiation therapy, also called radiotherapy is the application of ionizing radiation to avoid the proliferation of cancer cells and then induce cell death. Despite the radiation risks, radiotherapy has proven to be effective in the treatment of localized cancer in 50% of cancer patients [1,2]. Radiotherapy produces reactive oxygen species (ROS), which increases oxidative stress and frequently leads to an imbalance in which the antioxidant system is unable to respond to excessive oxidative stress. Under the influence of ROS, numerous forms of injury may develop, including alterations in cellular metabolism, DNA damage, lipid peroxidation, protein oxidation, and cumulative long-term changes in stable macromolecules, which result in various pathological changes at the systemic and tissue level [3]. These changes may progress in conjunction with inflammatory activation and could result in the development or worsening of cardiovascular diseases, ischemic injury, atherosclerosis, hypertension, cardiomyopathies, and stroke [4]. The liver is one of the organs that is severely affected by irradiation and radiation-related disorders because it plays a critical role in metabolism that affect the entire body. The problems in DNA repair and anti-oxidative capabilities may result in necroinflammation, fibrosis, and many other pathological changes in the liver [5,6]. Annona muricata (AM), generally known as Graviola, is a tropical broadleaf edible fruit tree with a long history of traditional use. It has been used as a traditional medicine for various diseases, such as neuralgia, arthritis, diarrhea, abscess, and parasitic infections [7]. Various studies confirmed the anticancer, antiphrastic, anti-arthritic, and hepatoprotective effects of AM. In vitro and in vivo investigations have been conducted to investigate and verify the biological activities, which have revealed remarkable features, including anticancer [8,9] antidiabetic [10], anti-inflammatory [11,12], and antioxidant activities [13]. About 200 chemical components have been found and extracted from AM. The most important of them are alkaloids, phenols, and acetogenins, all of which are thought to have anti-inflammatory and antioxidant properties [6]. According to reports, the plant’s seeds and leaves contain enzymatic antioxidants, such as catalase and superoxide dismutase, and nonenzymatic antioxidants, such as vitamins C and E, which regulate oxidative stress [7,13]. As determined by biochemical and histological tests, the hepatoprotective effects of AM leaf extracts were efficient in the normalization of function after liver damage [14]. We expected that using AM leaf extracts before radiotherapy would have systemic and hepatic protective benefits, based on the oxidative stress generated by radiation and the documented antioxidant capacities of the AM leaf extract. To investigate the probable protective effect of the AM leaf extract against radiation-induced oxidative stress and tissue damage in rats, as well as the antioxidant and anti-inflammatory activities of this plant extract, the present research was conducted. The results of this study may help the minimization of serious adverse effects caused by excessive radiation exposure in radiotherapy patients and act as a substantial drive for additional evaluations.

2 Methods

2.1 Animals

The study was approved by Bulent Ecevit University’s research ethics committee, and the animal (see Figure 1) experiments were carried out in compliance with the institution’s guidelines. (Decision no: 2020/06, Decision date: 02/07/2020). A total of 37 adult female Wistar Albino rats weighing 140 ± 20 g and having similar physiological characteristics were used. The animals were initially randomized into four groups: one control group and three interventional groups. Throughout the experimental period, all animals were fed ad libitum with laboratory tap water and pellet chow containing 21% crude protein. The environment was constantly kept under optimum laboratory conditions (22 ± 1°C, 45–55% humidity, and 12 h of automated light/dark cycle).

Figure 1 
                  Positioning of rat on the treatment couch.
Figure 1

Positioning of rat on the treatment couch.

2.2 Irradiation Procedure

Whole-body irradiation procedures were carried out in the Radiation Oncology Department of Zonguldak Bulent Ecevit University, Faculty of Medicine (see Figure 2). Subsequently, the required dose of irradiation to create measurable radiation damage was calculated. Figure 3 depicts the planning procedure along with the given doses and treatment details. Using a linear accelerator device, a total dose of 8.3 Gy X-rays was applied to the whole body, fixed in the supine position in a single fraction.

Figure 2 
                  Treatment room and Varian Clinac IX – Radiation Oncology Department of Bulent Ecevit University Faculty of Medicine.
Figure 2

Treatment room and Varian Clinac IX – Radiation Oncology Department of Bulent Ecevit University Faculty of Medicine.

Figure 3 
                  Planning procedure along with the given doses and treatment details.
Figure 3

Planning procedure along with the given doses and treatment details.

2.3 Preparation of AM extract

Due to the fruit’s sour and sweet flavor, AM is often known as soursop. It is also known as prickly custard apple because of its flavor. Locals refer to the fruit as durian belanda. In Indonesia, the plant is known as sirsak or nangka belanda, while in Portugal and Latin America, it is known as graviola and guanabana, respectively [15]. Figure 4 depicts the appearance of AM extracts along with the leaves extract obtained from the dried leaves of the AM plant by ethanol-based filtration. The powdered leaves of A. muricata (3 kg) were macerated three times with ethyl acetate (32,500 mL) at room temperature. At 40°C, the solvent for extraction was decanted and concentrated to dryness using a rotating vacuum evaporator. The yield percentage after extraction was 3.9% (117 g). To create 250 and 500 mg/kg stocks for future investigations, the extract was diluted in 10% Tween-20. The rats were given this extract as the active component.

Figure 4 
                  Appearance of A. muricata extract along with the leaves.
Figure 4

Appearance of A. muricata extract along with the leaves.

2.4 Experimental design

This study was carried out as follows: (a) a total of 0.01 mL/kg distilled water was administered orally once daily for 9 days to the control group of 13 rats. (b) A total of 300 mg/kg AM leaf extract was given orally once daily for 9 days to the AM group of 12 rats. (c) A dose of 0.01 mL/kg of physiologic serum (saline) was given orally once daily for 9 days to the ionizing radiation (IR) group of four rats, along with a single dose of whole-body radiation (8.3 Gy) applied 1 hour after the last gavage. The animals were sacrificed 96 h after the last treatment, under anesthesia with intraperitoneal 90 mg/kg ketamine and 10 mg/kg xylazine. Blood samples and tissues from all animals were collected and stored accordingly for the analysis.

2.5 Biochemical analysis

Using an autoanalyzer and the supernatant portion of homogenates and serum samples, the total oxidant status (TOS) of serum was determined. Interleukin (IL)-6 and caspase levels were measured by ELISA kits (Cloud-Clone Corp., Wuhan, China).

2.6 Histopathological evaluation

All liver tissues (n = 37) that had been stored for histopathological evaluation were fixed in 10% formalin for 12 h and then embedded in paraffin blocks. The blocks were sliced to a thickness of 4 µm before being stained with hematoxylin and eosin. In four distinct groups, four markers for centrilobular hepatic necrosis, fatty alteration, ballooning degeneration, and lymphocyte infiltration in liver tissue were evaluated. The histomorphology characteristics of tissues and cells are evaluated. Each criterion was assigned a score between 0 and 3 (0 = normal, 1 = mild, 2 = moderate, and 3 = severe).

2.7 Statistical analysis

All analyses were conducted using SPSS v21 (SPSS Inc., Chicago, IL, USA). For testing normalcy, the Kolmogorov–Smirnov test was used. The data for continuous variables are shown as median (first to third quartiles) and frequency with percentage values for categorical variables. Using the Kruskal–Wallis test, continuous variables were examined. By using the Bonferroni correction technique, pairwise comparisons (for the post hoc analysis of >2 group comparisons) were conducted. Pearson’s Chi-square test was used to examine categorical data. p < 0.05 values were accepted as statistically significant results.

3 Results

3.1 Histopathological findings

A light microscopic examination of the control group’s liver parenchyma showed a normal appearance with undamaged hepatocytes and sinusoids. Rats in the IR group exhibited considerable lymphocyte infiltration and ballooning degeneration. In AM receivers (the AM and AM + IR groups), these modifications happened to a lesser extent (mild). In terms of ballooning degeneration and infiltrating lymphocytes, there were statistically significant differences between the groups (p < 0.001 for each) (Table 1). Centrilobular hepatic necrosis and fatty changes were not found in any of the animals (see Figure 5).

Table 1

Histomorphological and biochemical findings according to treatment groups

Treatment groups
Control (n = 13) AM (n = 12) IR (n = 4) AM + IR (n = 8) p
Centrilobular hepatic necrosis
 Normal 13 (100.0) 12 (100.0) 4 (100.0) 8 (100.0)
Fatty change
 Normal 13 (100.0) 12 (100.0) 4 (100.0) 8 (100.0)
Ballooning degeneration
 Normal 13 (100.0) 0 0 0 <0.001
 Light 0 12 (100.0) 0 8 (100.0)
 Medium 0 0 4 (100.0) 0
Infiltrating lymphocytes
 Normal 13 (100.0) 0 0 0 <0.001
 Light 0 12 (100.0) 0 8 (100.0)
 Medium 0 0 4 (100.0) 0

Data were given as frequency (percentage).

AM: A. muricata, IR: irradiation.

Figure 5 
                  Histopathological changes in liver sections (H&E 200) of (a) control; (b) IR Group; (c) IR + AM group; (d) AM group. HV, hepatic vein; PT, portal tract; horizontal arrow: balooning degeneration; vertical arrow: infiltrating lymphocytes.
Figure 5

Histopathological changes in liver sections (H&E 200) of (a) control; (b) IR Group; (c) IR + AM group; (d) AM group. HV, hepatic vein; PT, portal tract; horizontal arrow: balooning degeneration; vertical arrow: infiltrating lymphocytes.

3.2 Biochemical analyses

The highest levels of TOS were found in the group that had received irradiation after saline gavage, which showed a significant difference compared with the control and AM groups (p = 0.036 and p = 0.045, respectively; Table 2).

Table 2

Biochemical findings according to treatment groups

Treatment groups
Control (n = 13) AM (n = 12) IR (n = 4) AM + IR (n = 8) p
Total oxidant status
µmol H2O2 Eq/L 18.76 (17.84–19.66) 18.88 (17.93–20.17) 22.79 (21.99–26.58)a,b 21.12 (18.19–23.97) 0.024
IL-6 (pg/mL) 305.56 (283.46–405.22) 321.54 (272.58–388.86) 340.24 (299.1–362) 373.9 (261.7–499.02) 0.914
Caspase 3 (ng/mL) 7.89 (7.28–8.38) 7.93 (6.36–8.62) 6.33 (5.36–7.28) 7.74 (7–8) 0.357
Caspase 9 (ng/mL) 4.51 (3.59–4.88) 5.71 (4.4–6.07) 3.56 (3.46–3.86)bc 5.31 (4.51–6.31) 0.022
Caspase 8 (ng/mL) 7.59 (6.34–8.61) 9.08 (8.14–10.69) 6.63 (6.2–6.94) 7.34 (6.01–9.51) 0.219

Data were given as median (1st quartile – 3rd quartile).

a,b,cSignificantly different from the control, AM, AM + IR group, respectively.

AM: A. muricata, IR: irradiation.

In terms of IL-6 levels, although there was no statistically significant difference, an increase relative to the other groups was observed in the AM + IR group. The levels of caspase 3 and caspase 8 were similar in all groups (p > 0.05); however, the caspase 9 level was significantly decreased in the IR group when compared to the AM and AM + IR groups (p = 0.039; Table 2).

4 Discussion

The overproduction of superoxide radicals by the mitochondrial electron transport chain is caused by oxidative stress, which plays an important role in the pathophysiology of irradiation-related problems [16,17]. The production of oxidative stress appears to be an unavoidable side effect of radiotherapy, which is a critical modality in the treatment of cancer. Irradiation causes the production of ROS, which can be spread through the circulatory system and cause harm to the hematological, gastrointestinal, and central nervous systems depending on the radiation dose [18]. When free radicals are created as a result of radiation exposure, radioprotective drugs may be used to counteract these effects [19]. AM is currently one of the most extensively studied phytotherapeutic substances, with antioxidant, anti-inflammatory, and anticarcinogenic activities [20]. All the rats in this research were irradiated, and their TOS levels increased significantly. The AM + IR group received AM leaf extract, which decreased their TOS levels. According to this finding, using AM before irradiation may be useful in lowering oxidative stress in radiotherapy patients, which is consistent with earlier research demonstrating AM’s antioxidant effects [13,20]. Previous studies showed anticarcinogen, antiulcerogenic, antifungal, immunomodulator, antibacterial, and wound healing effects [21,22,23]. There are few studies that look at the impact of AM on the secondary inflammatory response triggered by radiation and oxidative damage caused by ROS in various tissues. Radioprotective properties of AM have been demonstrated in previous studies in both liver and kidney tissues [24], skin tissue [25], and liver tissue alone [26]. Extrinsic (type I apoptosis) and intrinsic (type II apoptosis) pathways of apoptosis, both of which are caspase dependent, are activated by external or internal cues [27]. Since 1990, radiation-induced apoptosis has been observed in many animal studies and cell tumor lines [28]. Radiation-induced apoptosis is activated by the internal pathway that is associated with the permeability of the outer mitochondrial membrane. The activation of caspase 9 is directly linked to the activation of this pathway, which elevates and releases pro-apoptotic molecules in the cytosol. Once active, caspase 9 can directly cleave caspase 3 and caspase 7, resulting in the progression of apoptosis [29,30]. Other important characteristics of apoptosis include morphological changes and DNA fragmentation, both of which have been associated with oxidative stress [29]. In the current study, caspase 9 levels showed a decrease in the IR group, which correlates with the increased levels of TOS in this group. However, there was no statistical difference in caspase 3 levels between the groups, even though it was observed that caspase 3 levels were somewhat lower in the IR group. Caspase 9 is able to release cytochrome c while preventing changes in mitochondrial shape and ROS generation, according to Brentnall et al. We may infer that caspase 9 is necessary for mitochondrial morphological alterations and ROS generation from these data. Furthermore, caspase 3 limits ROS formation after activation by caspase 9 despite the fact that caspase 3 is required for successful apoptosis execution [30]. In the current study, AM admiration before irradiation inhibited radiation-induced apoptosis. In an interesting study, according to Moghadamtousi et al., an ethyl acetate extract of AM leaves was able to trigger apoptosis in colon and lung cancer cells via the mitochondria-mediated pathway [31,32]. Taken together, these findings suggest that AM extracts may have tumor-specific toxicity. IL-6 is an effective pleiotropic pro‐inflammatory cytokine due to its strong immunomodulatory influence and wide range of biological effects [33]. Under normal physiological conditions, serum levels of IL-6 are extremely low [34]. There was no significant difference in IL-6 levels between the experimental groups in this study, which is consistent with the bulk of cancer-related studies that look at IL-6 levels when using radiotherapy. According to Nakajima et al., a radiation dose of at least 10 Gy should be employed to detect serum IL-3 and gain inflammation-related responses [5]. The 8.3 Gy dose in this study seems to be insufficient to produce changes in IL-6 levels. It is also possible that the duration of our experiment and other factors could have affected the (in) activation of inflammation-related pathways. Other similar designed studies confirm that significant changes are not common for the majority of proinflammatory cytokines, suggesting that radiotherapy does not alter cytokine levels [35]. The liver histopathological findings revealed that a single dose of 8.3 Gy irradiation caused ballooning degeneration and infiltrating lymphocytes at a moderate level in the IR group. Studies reveal that inflammatory processes in the liver are initiated early after irradiation, as seen by hematoxylin and eosin staining, especially after large acute doses of irradiation, which is consistent with our findings [6]. An 8 Gy single-dose abdominal irradiation can cause hemorrhage, dilation of the central vein, and degeneration of hepatocytes (with perinuclear vacuolization) in the liver, when analyzed 36 h after exposure [35]. The preradiation administration of AM appears to ameliorate these changes, as determined by mild histopathological findings in the AM + IR group. Although determining the mechanism of this effect was not within the scope of the current study, it is worth suggesting the AM as an antioxidant and anti-inflammatory substance.

5 Conclusion

Radiation-protective medicines have been demonstrated to reduce DNA damage in vitro, in vivo, and in human randomized clinical trials. DNA damage and lipid peroxidation may be reduced in clinical medicine to prevent cancer and teratogenesis and improve morbidity and death rates among patients. The present study demonstrates that a single dose of 8.3 Gy irradiation elevated oxidative stress markers and caused moderate liver injury in rats. Pretreatment with 300 mg/kg concentrations of AM leaf extract before irradiation was found to decrease TOS and restore the liver structure. These findings suggest that AM has a radioprotective effect, possibly owing to its antioxidative and anti-inflammatory effects. Treatments using AM extracts seem to be promising as methods of radioprotection in patients receiving radiotherapy; however, much research is required to identify the mechanisms of these effects and their value in humans.

  1. Funding information: The work of Antoaneta ENE and the APC were supported by Dunarea de Jos University of Galati, Romania through the grant no. RF 3621/2021.

  2. Author contributions: O.E., H.H.K.S., H.O.T.: conceptualization and methodology; M.A., W.E., G.A.: validation; G.A. and H.M.H.Z.: formal analysis; O.E., H.H.K.S., B.G., H.O.T.: writing and review; O.E., H.H.K.S., B.G., A.E., M.A., W.E.: investigation; A.E.: funding acquisition through APC by “Dunarea de Jos” University of Galati, Romania through the grant no. RF 3621/2021.

  3. Conflict of interest: There are no conflict of interest.

  4. Ethical approval: Ethical Approval of this study has been obtained from Bulent Ecevit University, Animal Experiments Local Ethical Committee (2020-17-02/07).

  5. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.


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Received: 2022-06-08
Revised: 2022-08-14
Accepted: 2022-08-24
Published Online: 2022-09-19

© 2022 Ozlem Elmas et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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