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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 55
| Issue : 4 | Page : 243-250 |
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Protective effects of ginsenosides in cisplatin-induced kidney injury: A systematic review, meta-analysis
Xinyi Luo1, Dengpiao Xie2, Ziwei Chen3, Qing Ji3
1 Chengdu Medical College, Chengdu, Sichuan, China
2 Department of Kidney, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
3 Department of Kidney, Chengdu First People's Hospital, Chengdu, Sichuan, China
| Date of Submission | 01-May-2023 |
| Date of Decision | 26-Jul-2023 |
| Date of Acceptance | 08-Aug-2023 |
| Date of Web Publication | 11-Sep-2023 |
Correspondence Address:
Qing Ji
Chengdu First People's Hospital, Chengdu, Sichuan
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.ijp_251_23
Although evidence suggests ginsenosides, the primary active and distinctive components of ginseng, have beneficial effects in cisplatin-induced nephrotoxicity, their efficacy and protective mechanisms remain unclear. The aim of the current meta-analysis is to study the effectiveness and mechanisms of ginsenosides in a model of nephrotoxicity induced by cisplatin. Preclinical investigations were conducted in the search of various databases including Medline, Web of Science, Google, CNKI, Embase, and the Wanfang database. 12 studies with 216 animals were included in this review. Stata 15.0 and RevMan 5.3 were used for statistical analyses. The pooled results showed that ginsenosides significantly improved kidney function, and inhibited histological damage. The protective mechanism of ginsenosides is associated with its antioxidative stress, anti-inflammation, anti-apoptosis, and anti-autophagy. The results of our study indicate that ginsenosides have the potential to mitigate nephrotoxicity induced by cisplatin through the modulation of various targets and pathways. Consequently, ginsenosides hold promise as therapeutic agents for the clinical management and prevention of cisplatin-induced nephrotoxicity.
Keywords: Cisplatin, ginsenosides, kidney injury, meta-analysis, preclinical study
How to cite this article:
Luo X, Xie D, Chen Z, Ji Q. Protective effects of ginsenosides in cisplatin-induced kidney injury: A systematic review, meta-analysis. Indian J Pharmacol 2023;55:243-50 |
How to cite this URL:
Luo X, Xie D, Chen Z, Ji Q. Protective effects of ginsenosides in cisplatin-induced kidney injury: A systematic review, meta-analysis. Indian J Pharmacol [serial online] 2023 [cited 2023 Sep 30];55:243-50. Available from: https://www.ijp-online.com/text.asp?2023/55/4/243/385496 |
| » Introduction | |  |
Cisplatin is an important chemotherapy drug and is widely used in the management of various types of tumors, including testicular,[1] small cell lung,[2] head and neck,[3] cervical,[4] bladder,[5] and esophageal cancers.[6] However, cisplatin-induced nephrotoxicity significantly hinders its clinical application. It has been demonstrated that cisplatin can selectively accumulate in the kidney, especially in tubular cells.[7] The common adverse effect of cisplatin is nephrotoxicity, and 30%–40% of patients suffer from renal loss when using cisplatin.[8] Cisplatin-induced nephrotoxicity mainly manifests as acute kidney injury (AKI),[9] and typical histological changes include tubular dilation, cellular necrosis, interstitial inflammatory cells infiltration, and loss of brush border in tubular cells. Numerous molecular pathways and mechanisms were involved in cisplatin-induced nephrotoxicity. Apoptosis and necrosis of kidney cells have been demonstrated to be crucial in cisplatin-induced nephrotoxicity.[9],[10] In addition, abnormal production of inflammation and oxidative stress are also important in renal injury induced by cisplatin.[11] The prevention or alleviation of cisplatin-induced nephrotoxicity includes hydration with intravenous saline, magnesium supplementation, and forced diuresis with mannitol.[12] However, these treatments cannot achieve satisfactory outcomes. Therefore, it is urgent to find a novel strategy to reduce cisplatin-induced nephrotoxicity in the treatment of tumors.
Ginseng is a traditional Chinese herb clinically used in Asia for thousands of years. It possesses many therapeutic properties, such as health promotion, regulating the immune system, improving chronic diseases, as well as anti-stress.[13] Recently, Ginseng has been used to alleviate fatigue symptoms in cancer patients with chemotherapy treatment.[14] Ginsenosides, the important components in ginseng, have many pharmacological effects, encompassing anti-diabetic, anti-apoptotic, anti-inflammatory, and anti-tumor properties.[15] Recent studies have shown that ginsenosides can alleviate cisplatin-induced nephrotoxicity. However, these animal studies have limitations of sample size, leading to a lack of statistical power to evaluate the true benefit of the studies. Animal models are valuable tools to predict the effectiveness of therapeutic strategies in clinical studies and help us to understand the mechanisms and etiology of human diseases. Preclinical meta-analyses are important for supporting the development and translation of new drugs.[16] Since no meta-analysis is conducted to assess the effect of ginsenosides on cisplatin-induced nephrotoxicity, it aims to perform a meta-analysis to assess the protective effect and potential mechanisms of ginsenosides on cisplatin-induced nephrotoxicity.
| » Methods | | |
The current review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses.[17]
Data sources and search strategies
A thorough search was conducted in the following databases to identify relevant studies up until January 2022: Medline, Web of Science, Embase, Google, CNKI, and Wanfang Database. The search was done using the following keywords: “Cisplatin,” “cis-Diamminedichloroplatinum,” “kidney injury,” “nephrotoxicity,” “ginseng,” “ginsenoside,” “mice,” “rat,” and “animal.” The inclusion criteria for language were restricted to Chinese and English only. References lists of similar studies or reviews also were screened to search for potential studies.
Inclusion and exclusion criteria
The inclusion criteria were: (1) Kidney injury model was induced by cisplatin in animals. (2) The model and treatment groups were given the same regimen with cisplatin. (3) The treatment group received ginsenosides, including all types of ginsenosides. (4) Primary outcomes encompassed serum creatinine (Scr) and blood urea nitrogen (BUN) levels. (5) Secondary outcomes were histological changes and potential mechanisms of ginsenosides protected against cisplatin-induced nephrotoxicity, such as markers of oxidative stress, inflammatory markers, apoptosis, and the change of protein levels in the kidney.
The exclusion criteria were: (1) Reviews, case reports, comments, in vitro studies, and clinical studies. (2) Other kidney injury models. (3) The treatment group received other interventions. (4) Studies with no primary outcome indicators.
Study selection, data extraction, and quality assessment
Two investigators assessed titles, abstracts, and full-text versions of potentially eligible studies. A third investigator was consulted for disagreement. The data in each eligible trial were systematically extracted and recorded in a spreadsheet. Two reviewers independently collected the following information: (1) First author's name and publication year. (2) The specific characteristics of the animals, including sex and species of animals. (3) The regimen of cisplatin to induce nephrotoxicity (including administration route, and cisplatin dose). (4) Intervention scheme of the treatment group (including the types of ginsenosides, ginsenosides dose, administration route, and treatment course). (5) The index of primary and secondary outcomes. If outcomes were measured more than once in the study, data were extracted at the last time. When data were displayed in a graphical format, the corresponding author was responsible for contacting the author of the study to get more information. If no response was received, data were extracted from the graphs by digital ruler software. The assessment was conducted by two reviewers, and any discrepancies can be resolved by the third investigator. The corresponding author took responsibility for acquiring any missing information and unpublished data. The study quality was evaluated by the risk of bias tool of laboratory animal study.[18]
Data synthesis and analysis
For continuous outcomes, the effect size was evaluated using either weighted mean differences (WMD) or standardized mean difference (SMD) along with a 95% confidence interval (CI). A random-effects model was applied to the pooled effect. When the outcomes were assessed on different scales, SMD was applied to assess the pooled effect; otherwise, WMD was used in this review. I2 statistic was assessed to study the degree of heterogeneity.[19]
Publication bias and sensitivity analysis
To study the potential publication bias regarding Scr and BUN, an assessment was applied using both a visual examination of the funnel plot and the Egger's regression test. Sensitivity analysis was done by systematically excluding one study at a time to assess its impact on the overall results and by changing it to a fixed-effects model for the primary outcome. The trim-and-fill method was employed to identify and address potential publication bias. Stata 15.0 (StataCorp., Texas, The United States) and RevMan 5.3 (RevMan v5.3, The Cochrane. Collaboration, Oxford, UK) were used for statistical analyses. A level of P < 0.05 was deemed statistically significant.
Additional analysis
Subgroup analyses were performed based on different animal species (mice or rats), and doses of cisplatin (<20 mg/kg or ≥20 mg/kg).
| » Results | | |
Literature selection and study characteristics
The initial search across six databases yielded a total of 315 relevant studies, out of which 78 duplicate studies were eliminated. Subsequently, the remaining 237 studies underwent a thorough evaluation based on titles and abstracts, and 180 studies were removed. Finally, 57 full-text studies were subjected to a detailed assessment, resulting in the exclusion of 45 studies based on the following criteria: (1) reviews or meta-analysis, (2) treatment was unrelated drugs, (3) model group was not eligible, (4) in vitro studies, and (5) clinical studies. Finally, 12 studies met the inclusion criteria.[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] [Figure 1] shows the study selection procession.
A detailed presentation of the study characteristics is shown in [Table 1]. Twelve studies with 216 animals were included in the current review. Ten studies were published in English,[20],[22],[23],[24],[25],[26],[28],[29],[30],[31] and two studies were published in Chinese.[21],[27] All studies used male animals. Two studies used Sprague–Dawley rats.[20],[22] Two studies used LWH: Wistar rats.[30],[31] Seven studies used Institute of Cancer Research mice.[21],[23],[24],[27],[28],[29],[32] Two studies used C57BL/6 mice.[24],[25] All experimental models were created by injection of cisplatin, and the dose of cisplatin varied from 5 mg/kg body weight[20] to 25 mg/kg body weight.[23] Eleven studies were orally administered ginsenosides.[20],[21],[22],[23],[25],[26],[27],[28],[29],[30],[32] One study was administered ginsenosides by intraperitoneal injection.[24] The ginsenosides used in these studies included ginsenosides-Rk3, ginsenosides-Rh4, ginsenosides-Re, ginsenosides-RT5, ginsenosides-Rg5, ginsenosides-Rg1, ginsenosides-Rg3, ginsenosides-Rk1, ginsenosides-Ck, ginsenosides-Rb3, ginsenosides-Rd, and ginsenosides-Rh2. The doses of ginsenosides varied from 1 mg/kg[30],[31] to 40 mg/kg body weight.[27] The control group received the same solution as the intervention and model groups. The duration of studies varied from 6[20],[24] to 35 days.[30],[31]
Study quality
Two studies got 2 points.[24],[32] Ten studies got 4 points.[20],[21],[22],[23],[25],[26],[27],[28],[29],[30],[31] Seven studies reported the randomized allocation of animals.[20],[21],[24],[26],[27],[28],[29] However, no studies reported the sequence generation. The rest of the 6 studies did not report the randomized allocation.[22],[23],[25],[30],[31],[32] All studies have the results of baseline characteristics. No studies reported the allocation concealment, random housing, performance of blinding methods, and random outcome assessment. Two studies were considered to have risks of incomplete data and selective outcomes.[24],[32] No studies exhibited additional sources of bias. A comprehensive evaluation of the included studies, providing detailed quality assessments, can be found in [Table 2].
Primary outcomes
Serum creatinine
The results of Scr were included in 11 studies. In the pooled analysis, the use of ginsenosides could significantly decrease Scr in the treatment group compared with the model group [SMD, −2.67; 95% CI, −3.55 to −1.80; P < 0.00001; I2 = 71%, [Figure 2]]. | Figure 2: Forest plot for assessing the effect of ginsenosides on serum creatinine
Click here to view |
Blood urea nitrogen
The results of BUN were included in 11 studies. In the pooled analysis, the use of ginsenosides could significantly decrease BUN [SMD, −3.01; 95% CI, −3.86 to −2.16; P < 0.00001; I2 = 70%, [Figure 3]]. | Figure 3: Forest plot for assessing the effect of ginsenosides on blood urea nitrogen
Click here to view |
Secondary outcomes
Histological tubular damage
The results of histological changes were included in three studies. The degree of tubular necrosis was classified based on the following scale: 0 indicated no damage, 1 indicated 0%–10% necrosis, 2 indicated 11%–25% necrosis, 3 indicated 26%–45% necrosis, 4 indicated 46%–75% necrosis, and 5 indicated necrosis exceeding 75%. In the pooled analysis, the use of ginsenosides could significantly reduce tubular necrosis scores [WMD, −1.53; 95% CI, −1.74 to −1.32; P < 0.00001; I2 = 0%, [eFigure 1]].
Oxidative stress index
In the pooled analysis of superoxide dismutase (SOD), the use of ginsenosides could significantly improve SOD [SMD, 2.91; 95% CI, 1.78 to 4.05; P < 0.00001; I2 = 74%, [eFigure 2]].
In the pooled analysis of glutathione (GSH), the use of ginsenosides could significantly improve GSH [SMD, 4.38; 95% CI, 2.06 to 6.71; P = 0.0002; I2 = 93%, [eFigure 3]].
In the pooled analysis of catalase (CAT), the use of ginsenosides could significantly improve CAT [SMD, 1.83; 95% CI, 1.14 to 2.52; P < 0.00001; I2 = 31%, [eFigure 4]].In the pooled analysis of malondialdehyde (MDA), the use of ginsenosides could significantly reduce MDA [SMD, −2.17; 95% CI, −3.12 to − 1.21; P < 0.00001; I2 = 76%, [eFigure 5]].
Apoptosis-associated protein expression
In the pooled analysis of Bax, the use of ginsenosides could significantly reduce Bax [WMD, −1.61; 95% CI, −2.46 to −0.77; P = 0.0002; I2 = 99%, [eFigure 6]].
In the pooled analysis of Bcl2, the use of ginsenosides could significantly improve Bcl2 [WMD, 0.36; 95% CI, 0.30 to 0.42; P < 0.00001; I2 = 34%, [eFigure 7]].
In the pooled analysis of Cleaved-caspase-3, the use of ginsenosides could significantly reduce Cleaved-caspase-3 [WMD, −0.91; 95% CI, −1.10 to − 0.73; P < 0.00001; I2 = 90%, [eFigure 8]].
Apoptosis detected by TUNEL staining
In the pooled analysis of apoptosis percentage of renal cells, the use of ginsenosides could significantly reduce apoptosis of renal cells [WMD, −34.96; 95% CI, −46.98 to −22.93; P < 0.00001; I2 = 98%, [eFigure 9]].
Inflammatory markers: Tumor necrosis factor-α, interleukin-1β
In the pooled analysis of tumor necrosis factor (TNF)-α, the use of ginsenosides could significantly reduce TNF-α [SMD, −5.51; 95% CI, −9.18 to −1.84; P = 0.003; I2 = 87%, [eFigure 10]].
In the pooled analysis of interleukin (IL)-1β, the use of ginsenosides could significantly reduce IL-1β [SMD, −5.24; 95% CI, −8.92 to −1.56; P = 0.005; I2 = 88%, [eFigure 11]].
Additional analysis
Primary outcomes were analyzed based on different subgroups. Subgroup analysis was conducted, taking into account the species (rat or mouse) and the dose of cisplatin administered (<20mg/kg or ≥20mg/kg). For pooled results of Scr and BUN, the subgroup of the rat group and mouse group were same as the overall results. For pooled results of Scr and BUN, both subgroups of cisplatin dose <20 mg/kg and cisplatin dose ≥20 mg/kg were same as the overall results.
Sensitivity analysis and publication bias
Leave-one-out approach and changing random-effects model to the fixed-effects model for primary outcomes were performed to assess sensitivity analysis. Both methods showed that the pooled result of Scr and BUN did not significantly change.
Egger's tests (P < 0.05) detected publication bias in this meta-analysis for Scr and BUN. Similarly, funnel plot analysis of Scr and BUN showed asymmetry by visual inspection [Figure 4]. However, the trim-and-fill approach demonstrated that adjusted outcome showed that publication bias did not change the pooled result of the primary outcome. | Figure 4: Summary mechanisms of ginsenosides protect against cisplatin-induced nephrotoxicity
Click here to view |
| » Discussion | | |
The present study evaluated the protective effect and potential mechanisms of ginsenosides against cisplatin-induced kidney injury. The pooled results demonstrated that ginsenosides can significantly improve cisplatin-induced kidney dysfunction and histological damage. In addition, this review revealed that the protective effect of ginsenosides is associated with its anti-oxidative stress, anti-inflammation, anti-apoptosis, and inhibiting autophagy.
The possible mechanisms that ginsenosides protect against cisplatin-induced nephrotoxicity are summarized in [Figure 4] and described as follows: First, ginsenosides can overexpress SOD, CAT, GSH, and decrease the expression of MDA, reactive oxygen species in cisplatin-treated kidneys. Second, ginsenosides inhibited cisplatin-induced inflammation as evidenced by the decreased expression of TNF-α and IL-1β by blocking the activation of NF-κB and iNOS. Third, ginsenosides reduced cisplatin-induced renal cellular apoptosis as shown by reducing expression of Bax, Cleaved-caspase-3, and increasing expression of Bcl2 through suppressing PI3K/caspase-9, and JNK/P53 pathway. Fourth, ginsenosides can inhibit cisplatin-induced autophagy in the kidney by suppressing the AMPK/mTOR pathway. Fifth, ginsenosides can inhibit cisplatin-induced DNA fragmentation. In consistent with our review, these studies found that inhibiting oxidative stress, inflammation, apoptosis, and autophagy alleviated cisplatin-induced nephrotoxicity.[10],[33],[34],[35]
Ginseng has been traditionally employed as a tonic to enhance the stamina and vitality of individuals, including those with cancer or kidney disease. In traditional Chinese medicine, chemotherapy is often associated with Qi deficiency, which is characterized by fatigue, shortness of breath, dizziness, and loss of appetite.[36],[37] Ginseng is the most widely used Chinese herb to replenish Qi for patients.[38] Therefore, cancer patients undergoing chemotherapy are often prescribed ginseng to improve symptoms of Qi deficiency in China.[39] In a randomized trial, it was demonstrated that the administration of ginseng improved the quality of life in colorectal cancer patients undergoing chemotherapy, specifically in terms of fatigue-related aspects and stress levels.[40] In addition, consumption of ginseng has kidney protective effects, including reducing proteinuria, and Scr.[41] Therefore, the use of ginseng may not only alleviate cisplatin-induced nephrotoxicity but improve the Qi-deficiency-related quality of life caused by cisplatin.
Ginsenosides as the main active components in ginseng were widely studied and constitute a minimum of 4% of the dry weight of ginseng roots. Ginsenosides share a similar backbone structure, which consists of a four-ring, hydrophobic steroid-like structure. Different areas of the backbone have different sugar molecules producing a specific type of ginsenosides.[15] In this review, the included studies used different types of ginsenosides, and these ginsenosides all showed a protective effect in cisplatin-induced nephrotoxicity, which might due to their similar backbone structure. Although many studies have shown that ginsenosides improved kidney damage in the various models of kidney disease, however, most studies are limited to in vitro or vivo studies.[42],[43],[44],[45] Only one clinical study was conducted and showed that ginsenoside reduced Scr, BUN in early chronic kidney disease.[46] Based on the pooled results in this review, we recommend that clinical trials on the protective effect of ginsenosides on cisplatin-induced nephrotoxicity should be conducted in the future. The concern is also raised whether ginsenosides, which inhibit cisplatin-induced nephrotoxicity, would reduce the anti-tumor effect. The included studies all use mice without bearing tumors, therefore, this review did not assess whether ginsenosides affect the anti-tumor effect of cisplatin. However, other studies showed that the use of ginsenosides improved anti-tumor effect of cisplatin. Jiang et al. found that ginsenosides attenuated cisplatin resistance in the treatment of lung cancer by regulating the immune system and downregulating programmed death-ligand 1,[47] which explains that the use of ginseng is associated with a decrease in cancer incidence.[48],[49]
Limitations
(1) No included studies assess the toxicity of ginsenosides on animals; therefore, our review also has no information on toxicology, which poses a challenge in the translation of clinical use. (2) Significant heterogeneity was observed in some pooled results, such as Scr, BUN, and the heterogeneity might be related to the different types, dose, duration use of ginsenosides, regimen of cisplatin in inducing kidney injury, and animal species. However, we only perform some subgroups to search the causes of heterogeneity. (3) We only searched publications restricted to English, and Chinese, however studies of ginseng are also popular in some Asian countries, such as Korea, and Japan, which might publish the studies in their language. (4) Publication bias was found in this review, indicating that studies with negative results might not have been published, potentially leading to an overestimation of our findings. (5) Certain results from the included studies were presented in graphical form, and attempts were made to reach out to the authors for additional information. However, no response was received. Consequently, digital ruler software was employed to collect the necessary data, which might have a slight impact on accurate data we collected.
| » Conclusion | | |
Ginsenosides, the active and unique components of ginseng, alleviate cisplatin-induced nephrotoxicity by acting on multiple targets and pathways. Therefore, ginsenosides hold promise as therapeutic agents for the clinical management and prevention of cisplatin-induced nephrotoxicity. This review also suggested that ginseng is recommended to use in the treatment of cancer with cisplatin.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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