Ginger (Zingiber officinale Rosc.), a perennial medicinal plant from the Zingiberaceae family, is widely cultivated in Southeast Asia. The name "Zingiber" is derived from the Greek word "Zingiberi" and the Sanskrit term "Singabera," both meaning "horn," referencing the rhizome's resemblance to a deer antler. The term "Officinale" originates from the Latin word "Officina," indicating its historical use in medicine or pharmacy. Ginger rhizomes are processed into various forms, including fresh Ginger, dried Ginger, ginger powder, ginger paste, essential oil, and oleoresin, highlighting its versatility [1] Traditionally, Ginger has been valued for its medicinal properties, particularly in managing gastrointestinal disorders such as nausea, vomiting, dyspepsia, constipation, and diarrhea. It has also been used to address colic, rheumatism, and diabetes.[2] Modern studies have expanded its therapeutic profile, identifying bioactive compounds such as gingerols, shogaols, and gingerones, which exhibit antioxidant, anti-inflammatory, anti-diabetic, anti-cancer, and antiviral activities. These compounds effectively neutralize free radicals, reduce lipid peroxidation, and prevent the pathogenesis of various diseases [3,4]

Malignant tumors are the second most common cause of mortality globally. While a lot of efforts achieved toward cancer treatment and management, substantial gaps and opportunities for improvement persist. Chemotherapy, while effective, is often associated with various dangerous side effects. Natural therapies, particularly the use of plant-derived compounds, have shown potential in decrease these effects. However, several plant-based products are utilized in cancer treatment. [5]

Because the kidneys are the most common organs affected by the toxic of chemotherapy and result in Acute kidney injury (AKI), which defined as a clinical condition characterized by a sudden decline in kidney function tests, typically occurring within hours to days. It results in elevated serum creatinine levels, oliguria or anuria, and electrolyte imbalances. If unresolved for more than three months, AKI can progress to chronic kidney disease (CKD).[6,7]

Therefore, any efforts goals to reduce this toxicity are valuable and may aid in enhancing the life quality of millions of patients with cancer. However, numerous studies have demonstrated that Ginger contains active compounds with diverse bioactive properties, including antioxidant, in addition to anti-diabetes mellitus, anti-inflammatory, anti-tumor, and anti-viruses effects. Importantly, Ginger is a rich source of antioxidants and is crucial in mitigating lipid peroxidation, thereby inhibiting the progression of various diseases. The antioxidant activity of Ginger is partially attributed to its high content of polyphenolic compounds and ginger-specific flavonoids, such as gingerols, shogaols, and gingerones, which are known to reduce the production of free radicals[8]. Therefore, the current study is designed to investigate ginger extract's role in attenuating chemotherapy's side effects through several doses.

At first, the current study was approved by the scientific and ethical committee in the Medical Laboratory Department, College of Medical and Health Techniques, University of  Bilad Alrafidain (approval No. 38 in 2023/5/3). The study achieved during the period continued from January 2023 to April 2024 in a medical lab. In our college. 

Ginger (Zingiber officinale) was purchased from a local market in Muqdadiyah, Diyala, Iraq. The dried rhizomes were ground using a 2 mm diameter mesh grinder. Five hundred grams of the resulting dry powder were then stored in a tightly sealed container until used.

Subjects

Forty-eight male Rattus norvegicus rats, aged 8-10 weeks, weighing 200-250 grams, were included in the current study. The rats were brought from an animal house in Tikrit University, Iraq. The experimental study was conducted at the University of Bilad Alrafedian, Iraq. Therefore, within 10 days of the study, the rats were placed in the animal house in BAUC to conditioning with the temperature (25-28C°) and 12-hour light-dark cycle as standard environment situations. The rats were divided into 6 groups; the Control Group included 10 rats administered intubation acetate 100 mg/kg and saline. The second group included eight rats administered Cisplatin only at a dose of 5 mg/kg. The third group also included 8 rats who were administered intubation. Ginger extracts were 500 mg/kg, and 5 mg/kg cisplatin was considered low-dose administration. The fourth group included 8 rats who were administered intubation. Ginger extracts 750 mg/kg and 5 mg/kg cisplatin were considered moderate dose administration. The fifth group considered high-dose administration included eight rats who were administered intubation, Ginger extracts 1000 mg/kg, and 5 mg/kg Cisplatin. To eliminate the possible toxicity associated with the Ginger, the sixth group included 8 rats intubated with Ginger at only 400 mg/kg. The intubation was twice a week for six consecutive weeks.

Cisplatin administration at a dose of 5 mg/kg can lead to AKI, as described previously in [9]. All chemicals in the present study were of analytical grade, products of Sigma (US), Merck (Germany), and BDH (England). 

Plant extraction

Preparation of the various extracts 

The dried medicinal plant materials were ground using a grinder equipped with a 2 mm mesh sieve. Approximately 500 g of the resulting dry powder from each plant was subjected to sequential extraction with petroleum ether, chloroform, diethyl ether, methanol, and water using the percolation method, with each solvent applied for a duration of 72 hours. The solvents were subsequently removed under reduced pressure to obtain the dried extracts. The extract method is well described in previous studies [10,11]. This can summarized as the dried and powdered rhizome was subjected to sequential extraction using a Soxhlet apparatus (Toshiba, India) with solvents of increasing polarity: petroleum ether (40–60°C), chloroform, and 95% ethanol. Each solvent extraction was conducted for 72 hours. The solvents were subsequently removed under reduced pressure, and the extracts were dried at 40°C, yielding semisolid residues with percentages of 1.3%, 0.80%, and 2.35% w/w, respectively. All chemicals used in the current study were of analytical grade, products of Sigma in the United States of America.

Animals sacrificing

An anaesthetizing mixture of xylazine 0.1 ml and ketamine 0.5 ml was used on rats, as described in a previous study. [12]

Sample collection 

After the animals were sacrificed, the blood sample was collected by direct heart puncture with a needle and collected at about 5 ml. Then, the organs were collected in a suitable container with formalin. After washing, the organs were with normal saline and punctured with a needle to enhance the infiltration of the fixative inside the tissues and, therefore, enhance the fixation. 

Laboratories examinations

Histopathological Examination: Euthanize rats at the end of the study. Kidney organs were collected for histopathological analysis to assess the extent of kidney injury and inflammation and the healing in response to ginger extract treatment. The kidneys were collected and fixed in formalin, and then these tissues enrolled in tissue processing to reach the final slide preparation. The tissue processing was done as well as described in [13,14]

Biochemical Analysis: Measure levels of inflammatory cytokines TNF-α, IL-6 and urea and creatinine to monitor the Kidney function test in serum.

Statistical analysis

The current study's data was processed with GraphPad Prism (version 8.0). ANOVA test was used and followed by post-hoc tests to analyze differences between groups. Report results as mean ± standard deviation (SD). P-values < 0.01 Considered as statistically significant.

The mean values of the biomarkers analyzed in the current study across the various groups are shown in Table 1. In the Control Group, the mean urea level was 26.75 mmol/L (SD: 1.49), while creatinine levels averaged 0.77 mg/dL (SD: 0.27). Tumour Necrosis Factor-alpha (TNF-α) levels were 29.5 pg/mL (SD: 1.2), and Interleukin-6 (IL-6) levels averaged 51 pg/mL (SD: 2.83). Caspase-9 levels were 3.75 ng/mL (SD: 2.25), malondialdehyde (MDA) levels averaged 5.13 nmol/mL (SD: 0.83), and glutathione (GSH) levels were 74.63 µmol/mL (SD: 3.46).

In the Cisplatin-only Group, urea levels significantly increased to 76 mmol/L (SD: 10.1), and creatinine levels rose to 3.54 mg/dL (SD: 0.18). TNF-α levels were elevated to 63.38 pg/mL (SD: 2.62), and IL-6 levels increased markedly to 91.38 pg/mL (SD: 4.72). Caspase-9 levels averaged 24.5 ng/mL (SD: 4.07), MDA levels rose to 15.13 nmol/mL (SD: 1.36), and GSH levels increased to 160.63 µmol/mL (SD: 15.82).

In the Cisplatin + Low Dose Ginger Group, urea levels averaged 60.38 mmol/L (SD: 5.1), and creatinine levels were reduced to 2.69 mg/dL (SD: 0.15). TNF-α levels were 57.13 pg/mL (SD: 1.46), and IL-6 levels averaged 81.25 pg/mL (SD: 3.2). Caspase-9 levels were 20.38 ng/mL (SD: 2.07), MDA levels were 12.13 nmol/mL (SD: 1.25), and GSH levels were 131.88 µmol/mL (SD: 5.91).

In the Cisplatin + Moderate Dose Ginger Group, urea levels decreased to 56 mmol/L (SD: 2.67), and creatinine levels were further reduced to 1.81 mg/dL (SD: 0.19). TNF-α levels averaged 46.88 pg/mL (SD: 1.81), while IL-6 levels averaged 62.13 pg/mL (3.56). Caspase-9 levels decreased to 17.25 ng/mL (SD: 2.71), MDA levels averaged 10.25 nmol/mL (SD: 1.04), and GSH levels were 102.63 µmol/mL (SD: 5.83).

In the Cisplatin + High Dose Ginger Group, urea levels were further reduced to 44.88 mmol/L (SD: 3.36), and creatinine levels decreased to 1.35 mg/dL (SD: 0.19). TNF-α levels were 41.25 pg/mL (SD: 2.12), and IL-6 levels averaged 56.88 pg/mL (SD: 3.27). Caspase-9 levels were 11.63 ng/mL (SD: 1.69), MDA levels were 7.88 nmol/mL (SD: 0.83), and GSH levels averaged 80.38 µmol/mL (SD: 6.12).

In the Ginger-only Group, urea levels were comparable to the control group, averaging 27.63 mmol/L (SD: 2.33). Creatinine levels were slightly elevated at 0.84 mg/dL (SD: 0.18). TNF-α levels were 30.88 pg/mL (SD: 2.8), and IL-6 levels averaged 57.63 pg/mL (SD: 1.51). Caspase-9 levels were 3.63 ng/mL (SD: 1.19), MDA levels averaged 6.13 nmol/mL (SD: 1.13), and GSH levels were 78.5 µmol/mL (SD: 4.14).

Table 1 shows the means (SD) of the biomarkers included in the current study.

The levels of caspase-9 among the study groups are presented in the figure 1. The caspase-9 level in the cisplatin-treated group was significantly higher compared to the control group (p < 0.0001), the Cisplatin + low-dose ginger group (p < 0.001), the Cisplatin + moderate-dose ginger group (p < 0.001), the Cisplatin + high-dose ginger group (p < 0.001), and the ginger-only treatment group (p < 0.001). Furthermore, a significant difference was observed between the Cisplatin + high-dose Ginger and ginger-only treatment groups (p = 0.001). However, no significant difference was found between the control and ginger-only treatment groups (p > 0.01).

Figure 1. shows the level of caspase nine ng/ml among the study group.

Figure No.2 shows the levels of IL-6 among the study groups. The IL-6 level in the cisplatin-treated group was significantly higher compared to the control group (p < 0.0001), the cisplatin + low-dose ginger group (p < 0.01), the Cisplatin + moderate-dose ginger group (p < 0.001), the Cisplatin + high-dose ginger group (p < 0.001), and the ginger-only treatment group (p < 0.001). However, no significant difference was observed between the control and ginger-only treatment groups (p > 0.01).

Figure 2 shows the IL-6 pg/ml level among the study group.

Figure No. 3 reveals the levels of TNF-α among the study groups. The TNF-α level in the cisplatin-treated group was significantly higher compared to the control group (p < 0.0001), the cisplatin + low-dose ginger group (p < 0.01), the Cisplatin + moderate-dose ginger group (p < 0.01), the Cisplatin + high-dose ginger group (p < 0.001), and the ginger-only treatment group (p < 0.001). A significant difference was observed between the Cisplatin + high-dose ginger group and the ginger-only treatment group (p < 0.01). However, no significant difference was noted between the control and ginger-only treatment groups (p > 0.01).

Figure 3 shows the TNF-a pg/ml level among the study group.

Figure No.4 represents the levels of MDA across the study groups. A significantly elevated level of MDA was observed in the cisplatin-treated group compared to the control group (p < 0.0001), the cisplatin + low-dose ginger group (p < 0.001), the Cisplatin + moderate-dose ginger group (p < 0.001), the Cisplatin + high-dose ginger group (p < 0.001), and the ginger-only treatment group (p < 0.0001). A significant difference was also noted between the Cisplatin + high-dose ginger group and the ginger-only treatment group (p = 0.01). Conversely, no significant difference was detected between the control and ginger-only treatment groups (p > 0.01).

The figure illustrates the levels of GSH among the study groups. The GSH level in the cisplatin-treated group was significantly higher compared to the control group (p < 0.0001), the cisplatin + low-dose ginger group (p < 0.01), the Cisplatin + moderate-dose ginger group (p < 0.001), the Cisplatin + high-dose ginger group (p < 0.001), and the ginger-only treatment group (p < 0.001). However, no significant difference was observed between the control and ginger-only treatment groups (p > 0.01). Similarly, no significant difference was noted between the Cisplatin + high-dose ginger and ginger-only treatment groups (p > 0.01).

Figure No.5 shows urea levels (mmol/L) across various study groups. The cisplatin-treated group (Cis-only) exhibited a markedly higher urea level than the control group. Co-treatment with Ginger at low, moderate, and high doses significantly reduced the urea levels compared to the Cis-only group, demonstrating a dose-dependent trend. The group treated with Ginger alone displayed urea levels comparable to those of the control group, indicating no significant impact of Ginger on urea levels in the absence of Cisplatin. These findings suggest that ginger supplementation effectively mitigates the cisplatin-induced elevation in urea levels.

Figure 5. shows the distribution of urea level mmol/ml among the study group.

Figure No. 6 shows the levels of creatinine (mg/dL) across the study groups. The cisplatin-treated group (Cis-only) showed a significantly elevated creatinine level compared to the control group. Co-administration of Ginger at low, moderate, and high doses resulted in a significant reduction in creatinine levels relative to the Cis-only group, with a clear dose-dependent effect. The ginger-only treatment group exhibited creatinine levels similar to those of the control group, indicating that Ginger alone had no significant influence on creatinine levels in the absence of Cisplatin. These results indicate that ginger supplementation effectively attenuates cisplatin-induced elevations in creatinine levels.

Figure 6 shows the creatinine level mmol/ml distribution among the study group.

Figures 7-15 show the normal tissue and pathological changes in tissues of rats treated with Cisplatin and different doses of Ginger. 

Figure 7. shows normal healthy tissue of rat kidney.

Figure 8. Shows a normal kidney tissue in Ginger alone treated group

Figure 9. shows kidney tubules with simple edema (an aspect of inflammation) in Cisplatin with a high dose of ginger(1000mg/kg)

Figure 10. shows kidney tubules with simple oedema (pointed section) in a cisplatin-moderate dose of ginger (750 mg/kg)

Figure 11. shown that kidney tubules with simple dilation and apoptosis are aspects of inflammation in low doses of ginger (500 mg/kg).

Figure 12. shows the aggregate of inflammatory cells(pointed parts) in the wall of kidney tubules in Cisplatin with a low dose of ginger extract (500 mg/kg).

Figure 14. shows a high aggregate of inflammatory cells and apoptosis (500 mg/kg)(pointed parts) in the wall of kidney tubules in the Cisplatin-treated group only (400 mg/kg).

Figure 15. shows only a high aggregate of inflammatory cells in the cisplatin-treated group (400 mg/kg).

Cisplatin is a widely used chemotherapeutic agent for the treatment of various solid tumors. However, its clinical application is significantly limited by its side effects on normal tissues. Cisplatin exhibits nephrotoxicity, leading to acute kidney injury and chronic kidney disease [15]. The toxicity associated with cisplatin is primarily attributed to its covalent interaction with DNA purine bases, as well as its indirect induction of oxidative stress, which overwhelms cellular scavenging systems and results in the formation of stable adducts with the drug. Organs most commonly affected by cisplatin toxicity include the liver, heart, kidneys, auditory system, and peripheral nerves [16]. To reduce these toxic effects, various natural products have been investigated for their protective properties against drug- or chemical-induced damage. Among these, Zingiber officinale (commonly known as ginger) has shown considerable potential [17]

Ginger (Zingiber officinale Rosc.) is a plant belonging to the Zingiberaceae family. The name "Zingiber" is derived from the Greek word "Zingiberi" and the Sanskrit term "Singabera," both meaning "horn," referencing the ginger rhizome's resemblance to deer antlers. The term "Officinale" originates from the Latin word "Officina," indicating its historical use in medicine and pharmacy. Ginger rhizomes are widely utilized in food and beverages due to their distinctive spicy flavor, which imparts a savory sensation. In addition to its culinary applications, ginger is valued for its functional properties attributed to its bioactive compounds. Notably, ginger enhances the immune system through its non-nutritional compounds with antioxidant activity. These antioxidants play a critical role in neutralizing free radicals, thereby preventing cellular damage to the immune system. By protecting immune cells from oxidative stress, antioxidants also contribute to optimizing immune function and enhancing immunostimulatory activity [18]. Therefore, the current study is designed to evaluate the role of Ginger in reducing the nephrotoxicity of Cisplatin as tumor chemotherapy. 

Cisplatin treatment alone resulted in marked toxicity, as shown by elevated urea and creatinine levels, indicating renal dysfunction. High levels of TNF-a and IL-6 highlighted significant systemic inflammation, while increased Caspase-9 and MDA indicated enhanced apoptosis and oxidative stress. The elevated GSH levels suggested a compensatory antioxidant response but were insufficient to mitigate the oxidative damage caused by Cisplatin. These findings are consistent with [16], which documented that a cisplatin is a commonly used as chemotherapeutic agent for the treatment of various carcinomas and sarcomas. Its efficacy in improving clinical outcomes for cancer patients is well-documented, primarily due to its mechanism of action, which involves crosslinking DNA purine bases. This crosslinking disrupts DNA repair processes in cancer cells, ultimately causing DNA damage and triggering apoptosis. The observed elevation of caspase-9 levels in the current study indicates an increased rate of apoptosis within the system.

Co-treatment with a low dose of a protective agent led to partial improvement. Biomarkers such as urea, creatinine, TNF-a, IL-6, Caspase-9, and MDA were reduced compared to the cisplatin-only group, reflecting decreased nephrotoxicity, inflammation, apoptosis, and oxidative stress. However, GSH levels remained elevated, suggesting persistent oxidative stress. Moreover, in moderate-dose co-treatment provided greater protection. Urea and creatinine levels approached healthier values, while TNF-a and IL-6 levels showed significant reductions, indicating improved nephroprotection and decreased inflammation. Decreased Caspase-9 and MDA levels reflected reduced cell death and oxidative damage. GSH levels, although still elevated, were lower than in the low-dose group, signalling better antioxidant regulation. High-dose co-treatment demonstrated the most substantial protective effects. Urea and creatinine levels were nearly normalized, and TNF-a and IL-6 levels showed robust declines, indicating effective suppression of inflammation. Caspase-9 and MDA levels were markedly reduced, suggesting enhanced cellular protection and oxidative stress mitigation. GSH levels showed a downward trend, indicating a gradual normalization of antioxidant activity. These results indicate the role of Ginger in reducing these markers in a dose-dependent manner, and perfect results were shown in a group with a high dose; these results are in line with  Another study that found that Ginger extract supplementation significantly increased GSH levels, which refers to confirming Ginger's efficacy in enhancing antioxidant capacity. [8] Another study found that cisplatin treatment significantly increased inflammatory cytokines IL-6 and TNF-α, indicating heightened inflammation. Ginger supplementation effectively reduced these cytokines to near-control levels, particularly at 750 mg/kg and 1000 mg/kg doses. This demonstrates Ginger's potential as an anti-inflammatory agent for mitigating cisplatin-induced nephrotoxicity by modulating the inflammatory response. [19] Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are key cytokines used as indicators to monitor inflammation. Elevated levels of IL-6 and TNF-α are associated with acute and chronic inflammatory responses, reflecting the body's immune response to injury or infection. These cytokines play crucial roles in the inflammatory cascade, promoting the recruitment of immune cells to sites of inflammation and mediating the acute phase response. Also, these studies found that Ginger reduces oxidative stress markers such as malondialdehyde (MDA) and enhances the activity of antioxidant enzymes like superoxide dismutase (SOD) in renal tissues [9,20]

The current study found a significant elevation in urea levels in the cisplatin-treated group compared to the control group, indicating acute kidney injury. However, treatment with Zingiber officinale (Ginger) decreased urea levels, demonstrating its protective effect on renal function. Notably, the group receiving a dose of 1000 mg/kg of Ginger showed the most significant improvement, with urea levels approaching those of the control group. This suggests that Ginger, particularly at higher doses, effectively mitigates the nephrotoxic effects of Cisplatin by reducing oxidative stress and inflammation, thereby preserving kidney function. These findings support the potential therapeutic role of Ginger in protecting against cisplatin-induced renal damage and improving overall renal health. [9,20] These results completely agree with the current results.

The ginger-only group showed minimal biomarker changes compared to control levels, underscoring its safety and protective properties. Biomarkers like urea, creatinine, TNF-a, IL-6, Caspase-9, and MDA remained stable, reflecting an absence of nephrotoxicity, inflammation, or oxidative damage. GSH levels were close to control values, reinforcing Ginger's antioxidant role. Generally, these groups were designed to show if any toxic effects of Ginger, such as a synergistic effect, may interfere with the cis-platin. These findings align with previous studies, showing that histopathological evaluations demonstrate ginger treatment preserves kidney tubular structure, reduces necrosis, and promotes cellular regeneration. Such protective effects position ginger as a promising adjunct therapy for preventing and managing acute kidney injury induced by nephrotoxic agents like Cisplatin [9,20] 

Co-treatment with protective agents, particularly at moderate and high doses, mitigated cisplatin-induced toxicity effectively. Ginger demonstrated potential as a safe and beneficial agent for countering oxidative stress and inflammation.

The current study may aid in understanding the dose-dependent protective effects of Ginger against cisplatin-induced acute kidney injury and contribute to developing adjunct therapies for patients undergoing cisplatin chemotherapy.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the University of Diyala, Baqubah, Iraq

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