JAHP_13_4_862-868

Introduction

Hylocereus undatus Extract (HUE) is a herb with a long history of medicinal use reported in history. HUE is rich in flavonoids such as kaempferol, isorhamnetin, and quercetin, which exhibit potent anti-respiratory and therapeutic effects. These compounds contribute significantly to the medicinal efficacy of HUE, which is traditionally used to treat respiratory conditions such as asthma, cough, and pneumonia, as well as digestive issues like constipation (Zhu et al., 2018; Molitorisova et al., 2021; Yaseen et al., 2025; Obaid et al., 2025; Abo-Ser et al., 2024). The dried flower of Hylocereus undatus (Haw.) Britton and Rose, commonly known in China as jianhua, is referred to here as HUE. This flower is nutritionally dense, containing vitamins, trace minerals, dietary fiber, and a wide range of amino acids. Among the 17 amino acids present, leucine is the most abundant and has been shown to support intestinal health by stimulating immunoglobulin secretion (Song et al., 2020; Yaseen et al., 2024; Obaid et al., 2020; Saleh et al., 2025).

HUE is also a source of essential trace elements such as potassium, zinc, and iron, which are vital for numerous physiological and metabolic functions. Its water-soluble dietary fiber absorbs water to form gel-like substances in the intestines, which can help prevent intestinal cancer (Fritsch et al., 2021; Obaid et al., 2020; Kareem and Hussain, 2023; Tawfic et al., 2024). One key fiber component, pectin, plays a protective role in the intestinal mucosa, contributing to the regulation of gut microbiota and slowing the progression of colitis (Wei et al., 2016; Altemeemi et al., 2021; Saleh et al., 2022). In addition, HUE contains a unique, sticky, gelatinous substance known as phytoalbumin, which forms a protective film over the gastrointestinal lining after digestion, offering further gut protection.

HUE is widely considered safe for consumption, as it is traditionally used as a vegetable in culinary dishes and soups across China, Japan, and Korea (Li et al., 2013; Al-Khuzaay et al., 2024; Tawfic et al., 2024). The Lingnan herbal collection and the handbook of commonly used Chinese herbs describe HUE as effective in clearing heat, eliminating toxins, relieving discomfort, treating coughs and asthma, and preventing colon cancer. Notably, HUE has demonstrated a protective effect against the nephrotoxicity and general toxicity induced by Ehrlich Ascites Carcinoma (EAC) in mice, highlighting its potential as a functional and preventive medicinal herb (Wahyuni et al., 2023; Song et al., 2016).

Ehrlich’s ascites carcinoma (EAC) is one of the most widely studied and aggressive experimental tumor models, known for its rapid proliferation and ability to spread until it reaches the ascitic stage. EAC closely resembles certain types of human malignant tumors, making it a useful model for cancer research. The use of natural resources as alternative cancer therapies has shown significant promise in combating malignancies (Hameed et al., 2024; Al-Maliki et al., 2025). In recent years, combination drug therapies and multidrug-loaded delivery systems have emerged as advanced strategies in cancer treatment (Hasan et al., 2024). Notably, the integration of targeted peptide-based nanoformulations with conventional chemotherapeutic agents has demonstrated substantial potential in improving therapeutic outcomes (Hameed et al., 2024; Razooki et al., 2025).

Despite considerable advances in our understanding of cancer biology and pharmacology, cancer remains a major global health concern. Metastasis the process by which abnormal, rapidly growing cells spread to surrounding tissues and distant organs continues to be the leading cause of cancer-related deaths (Al-Dulimia et al., 2022; Razooki et al., 2019; Hasan et al., 2024; Saleh et al., 2024). The development of cancer is influenced by a range of factors, including environmental exposures, diet, genetics, and personal health history. Current treatment options primarily include chemotherapy, radiation, and surgery. However, chemotherapy often presents severe side effects that limit its long-term use and patient compliance (Islam et al., 2012; Razooki et al., 2020).

Cancer is characterized by uncontrolled cell proliferation and disrupted differentiation due to failure of the normal cell cycle. It can develop in nearly any organ at any time (Hasan et al., 2024). The Ehrlich tumor, a form of adenocarcinoma, can be induced in almost all mouse strains, further highlighting its relevance in experimental oncology (Al-Khuzaay et al., 2024). The use of medicinal plants and their active compounds is an emerging approach in oncology, offering both cytotoxic effects on tumor cells and chemopreventive properties that inhibit the carcinogenesis process (Hasan et al., 2023).

The aim of this research is to evaluate the protective effect of Hylocereus undatus leaf extract against nephrotoxicity induced by Ehrlich ascites carcinoma in female mice.

Materials and Methods

Induction of EAC in female mice

EAC cells were initially obtained from the National Cancer Institute in Cairo, Egypt, for the purpose of the first transplantation. To maintain the cells in vivo, Swiss albino mice were given serial intraperitoneal (I.P.) injections of 2 × 10⁶ EAC cells every 14 days, following the method described by Hasan et al. (2024) (Figure 1).

Experimental animals

Swiss albino mice (female 25-30 g weight) were acquired from Giza, Egypt’s Abo Rawash culture. Mice were housed in cages made of steel mesh. With a 12:12 light/dark cycle and unlimited access to food and drink, mice were housed in pathogen-free, and climate-controlled animal house.

Study design

Forty mature female Swiss albino mice, weighing between 20–30 g, were used in this study. The mice were randomly divided into four groups, with ten mice in each group. Group 1 (G1) served as the control group and received no treatment. Group 2 (G2) received Hylocereus undatus extract (HUE) at a dose of 200 mg/kg body weight. The HUE was prepared using an aqueous extraction method and administered orally via gavage once daily for 14 days, following the method described by Kanchana et al. (2018). Group 3 (G3) was the EAC group, in which mice were intraperitoneally (I.P.) injected with 1 × 10⁶ Ehrlich Ascites Carcinoma (EAC) cells, following the protocol of Medhat et al. (2017). Group 4 (G4) was the treatment group; mice were first injected with 1 × 10⁶ EAC cells (I.P.) and then administered HUE (200 mg/kg) orally once daily for 14 consecutive days.

At the end of the experimental period (day 15), all animals were euthanized for blood and tissue collection.

Blood sampling

Each mouse’s inferior vena cava was used to draw blood samples, which were then centrifuged at 3000×g for 15 minutes after being left to clot for 30 minutes at room temperature. Centrifugation was used to extract serum, which was then kept at -60 °C.

Tissue sampling

After extraction and rinsing in cold saline, 0.8 g of kidney tissue was collected. The remaining portion was preserved in 10% neutral buffered formalin for histological analysis.

Biochemical assays

The Biuret approach was used to measure kidney function and electrolytes, as shown by Abd El-Rahmana et al. (2024) and Ezz et al. (2023).

Tumor markers

Carcinoembryonic antigen (CEA) and serum alpha-fetoprotein (AFP) levels were measured using the MyBioSource Mouse Carcinoembryonic Antigen ELISA Kit, a quantitative sandwich immunoassay (MyBioSource, San Diego, USA), according to the method described by Hasan et al. (2024).

Histopathological investigations

Kidney specimens were preserved in 10% neutral buffered formalin for 48 hours. Tissue sections were then cut at a thickness of 7 microns, cleaned, dried, and embedded in paraffin. The sections were subsequently stained with hematoxylin and eosin (H & E) following the procedure described by Hasan et al. (2024) and Yahya et al. (2024).

Statistical analysis

All statistical analyses were performed using SPSS software version 14.0 for Microsoft Windows (SPSS Inc.). Numerical data are presented as mean ± standard error (SE). Analysis of variance (ANOVA) was used to assess differences in marker levels among the groups. A p-value of less than 0.05 was considered statistically significant.

Results

Effect of EAC or HUE on mice body and kidney weights

Figure 2 illustrates the variations in body and kidney weights across the different experimental groups. Mice injected with EAC showed significantly increased body and kidney weights compared to the control group (P<0.05). However, treatment with HUE resulted in a substantial reduction in both body and kidney weights in EAC-bearing mice as compared to EAC group (P<0.05).

Effect of HUE on kidney functions and electrolytes

Figure 3 shows that, compared to the control group, EAC caused a significant decrease in sodium and calcium ion levels, along with a marked increase in urea, creatinine, potassium, and chloride ions (P<0.05). Conversely, treatment with HUE (EAC + HUE) significantly increased sodium and calcium levels and decreased urea, creatinine, potassium, and chloride levels compared to the EAC group (P<0.05).

Effect of HUE on tumor markers

Figure 4 shows that, compared to the control group, EAC induced a significant increase in AFP and CEA levels (P<0.05). However, treatment with HUE (EAC + HUE) led to a marked and significant reduction in these tumor markers compared to the EAC group (P<0.05).

Kidney histopathology

Figure 5 illustrates the histological and morphometric changes in kidney tissues across all treatment and control groups. Kidney sections from the control group exhibited a normal histological structure, with clearly defined renal cortex and medulla. The renal cortex contained multiple renal corpuscles, each comprising a glomerulus surrounded by Bowman’s capsule with a normal filtration space between them. These corpuscles were encircled by a network of convoluted tubules, reflecting typical kidney architecture (Figure 5A). Similarly, kidneys from mice treated with HUE showed normal glomerular and tubular structures comparable to the control group (Figure 5A, B).

In contrast, kidney samples from the EAC group displayed various pathological changes, including severe renal tissue damage, extensive cellular infiltration, and significant degradation of renal structures. The Malpighian corpuscles exhibited loss of their normal shape due to glomerular atrophy (Figure 5C). Treatment with HUE in EAC-injected mice led to moderate histological improvement and tissue organization. Notably, the glomeruli showed remarkable restoration, while the renal tubules demonstrated partial recovery from atrophy and damage (Figure 5D).

Discussion

Chemotherapy is effective against several cancer types; however, its use is often limited by adverse side effects and complications. Cancer remains the second leading cause of death worldwide (Sharma et al., 2023; Jasim et al., 2025; Teaima et al., 2022). EAC was initially described as an autonomous breast cancer model, mimicking characteristics of common breast cancer (Zahran et al., 2024). EAC cell invasion into internal organs leads to mitochondrial damage and inflammatory cell aggregation (El-Zahed et al., 2021; Naik et al., 2021). Similar to human cancers, EAC is undifferentiated, rapidly growing, and responsive to therapy (Rizzk et al., 2024; Aldayel et al., 2023).

Cytological analysis of ascitic fluid in the EAC + HUE group revealed numerous apoptotic bodies and fewer viable EAC cells, while untreated EAC samples showed increased ascitic fluid volume alongside abundant EAC and mitotic cells. These findings agree with Elbeshlawy et al. (2022), who reported significantly increased ascitic fluid volume, tumor cell count, body weight, and abdominal circumference in EAC-bearing mice.

The current study observed elevated levels of urea, creatinine, potassium (K⁺), and chloride (Cl⁻) ions, alongside decreased sodium (Na⁺) and calcium (Ca²⁺) ions, indicating renal dysfunction induced by EAC. This disruption in kidney function likely results from renal tissue damage caused by EAC, supporting findings from Zahan et al. (2021), who documented similar changes following EAC induction.

Treatment with HUE significantly improved renal function and electrolyte balance in EAC-bearing mice, consistent with Shafiq et al. (2022), who demonstrated renal benefits from HUE administration. Histologically, EAC caused significant glomerular and tubular cell shrinkage and degeneration, echoing the kidney damage reported by Makiyah et al. (2021).

Previous studies (Ibrahim and Baker, 2024; Sonu et al., 2025; Wahyuni et al., 2023; Li et al., 2023; Antar et al., 2024) have confirmed that HUE enhances physiological, tissue, and immune functions due to the high antioxidant content and vital bioactive compounds present in the plant’s leaves.

Conclusions

We conclude from our study that EAC cells induce toxicity in kidney cells, evidenced by altered levels of urea, creatinine, sodium, potassium, calcium, chloride, AFP, and CEA, as well as histological kidney damage. Treatment with HUE significantly improves these biochemical parameters and restores kidney tissue integrity in mice. We recommend further research to explore the therapeutic potential of HUE.

Acknowledgement

Thanks only to the authors for their full support to make the article as good and wonderful as it appears upon publication.

Novelty Statement

This study demonstrates the protective effects Hylocereus undatus Leaf Extract against laboratory mice with Ehrlich Ascites Carcinoma through oncological, histological, and biochemical assays.

Author’s Contribution

The authors contributed equally to the manuscript, including coordination, writing, costs, study design, and statistical analysis.

Ethical approval

This research was conducted with approval from the Biotechnology Research Center at Al-Nahrain University, under ethical approval number E.B.B.30, dated August 2, 2024.

Generative AI and AI-assisted technology statement

No artificial intelligence tools were used in the manuscript, and the authors bear all responsibility for any future consequences thereof.

Conflict of interest

The authors have declared no conflict of interest.

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