Nephroprotective Effect of Naringenin and Bromelain Against Cisplatin-Induced Renal Toxicity in Rats
DOI:
https://doi.org/10.48048/tis.2025.10681Keywords:
Cisplatin, Nephropathy, Naringenin, Bromelain, N-Acetyl cysteine, Oxidative stress, Nephroprotective agents, Combination therapyAbstract
Cisplatin is a widely used chemotherapeutic agent known for its dose-limiting nephrotoxicity, which significantly hampers its clinical utility. The present study evaluates the nephroprotective potential of Naringenin and Bromelain, natural compounds with established antioxidant and anti-inflammatory properties, administered alone and in combination against cisplatin-induced nephropathy in rats. Adult Wistar rats were divided into eight groups: normal control, cisplatin control, standard treatment with N-acetylcysteine (NAC) and various treatment groups receiving Naringenin and Bromelain at low and high doses, both alone and in combination. Nephropathy was induced using a single intraperitoneal dose of cisplatin (7 mg/kg) at day 0. Treatments were administered orally for 14 consecutive days. Parameters like body and kidney weight, kidney hypertrophy index, serum biochemical markers (urea, creatinine, uric acid), oxidative stress markers (LPO, NO), pro-inflammatory cytokines (TNF-α, IL-6) and histopathological changes in renal tissue were evaluated. Cisplatin administration resulted in significant renal impairment, as indicated by weight alterations, elevated serum biochemical markers, increased oxidative and inflammatory markers and marked renal histological damage. Treatment with NAC and both natural compounds ameliorated these pathological changes. Notably, the combination of high-dose Naringenin and Bromelain demonstrated the most substantial nephroprotective effects, restoring biochemical and inflammatory parameters near normal levels and preserving renal histoarchitecture. These findings suggest a synergistic effect likely mediated through combined antioxidant and anti-inflammatory mechanisms. The study concludes that Naringenin and Bromelain, particularly when administered together at higher doses, exert significant protective effects against cisplatin-induced nephropathy. These natural agents may serve as promising adjunctive therapies to mitigate cisplatin-associated renal damage.
HIGHLIGHTS
- Naringenin and Bromelain, alone and in combination, were evaluated for their nephroprotective effects in a cisplatin-induced rat model of nephropathy.
- Combination therapy significantly attenuated cisplatin-induced elevations in serum urea, uric acid, creatinine, and oxidative stress markers.
- Co-administration of high-dose Naringenin and Bromelain significantly reduced pro-inflammatory cytokines (TNF-α, IL-6) and preserved renal histological architecture.
- The study demonstrates a synergistic antioxidant and anti-inflammatory effect of Naringenin and Bromelain, suggesting their therapeutic potential against cisplatin nephrotoxicity.
GRAPHICAL ABSTRACT
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R Ranasinghe, ML Mathai and A. Zulli. Cisplatin for cancer therapy and overcoming chemoresistance. Heliyon 2022; 8(9), 10608.
F Chun-Yan, L Da-Yong, Z Li-Qin, W Jin-Cheng, B Yang, H Qiao-Jun, W Jia-Jia and Weng Qin-Jie. Natural products: Potential treatments for cisplatin-induced nephrotoxicity. Acta Pharmacologica Sinica 2021; 42(12), 1951-1969.
JN Curry and JA McCormick. Cisplatin-induced kidney injury: Delivering the goods. Journal of the American Society of Nephrology 2022; 33(2), 255-256.
C Tang, MJ Livingston, R Safirstein and Z Dong. Cisplatin nephrotoxicity: New insights and therapeutic implications. Nature Reviews Nephrology 2023; 19(1), 53-72.
MA El-Kader and RI Taha. Comparative nephroprotective effects of curcumin and etoricoxib against cisplatin-induced acute kidney injury in rats. Acta Histochemica 2020; 122(4), 151534.
Z Zeng-Lu, M Jun-Wei, Y Luo, L Gui-Jin, L Shi-Jie, Y Ke-Jin, M Hai-Bing and L Xiu-Juan. Mechanism of dexmedetomidine protection against cisplatin induced acute kidney injury in rats. Renal Failure 2024; 46(1), 2337287.
K Pansare, C Upasani, A Upaganlwar, G Sonawane, C Patil. Lycopene alone and in combination with olive oil ameliorates streptozotocin-induced diabetic nephropathy in rats. Vidyabharati International Interdisciplinary Research Journal 2021; 1(SI), 320-332.
K Pansare, C Upasani, A Upaganlwar, G Sonawane, C Patil. Streptozotocin and alloxan induced diabetic nephropathy: Protective role of natural products. Journal of the Maharaja Sayajirao University of Baroda 2021; 25, 422.
V Ramkumar, D Mukherjea, A Dhukhwa, LP Rybak. Oxidative stress and inflammation caused by cisplatin ototoxicity. Antioxidants 2021; 10(12), 1919.
K Dong-Hyun, C Hoon-In, JS Park, CS Kim, EH Bae, SK Ma and SW Kim. Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes. Redox Biology 2022; 54, 102382.
YJ Lim, NC Tonial, ED Hartjes, A Haig, TJ Velenosi and BL Urquhart. Metabolomics for the identification of early biomarkers of nephrotoxicity in a mouse model of cisplatin-induced acute kidney injury. Biomedicine & Pharmacotherapy 2023; 163, 114787.
NK Alaqeel and MT Al-Hariri. Naringenin ameliorates cyclophosphamide-induced nephrotoxicity in experimental model. Saudi Journal of Biological Sciences 2023; 30(6), 103674.
S Liu, X Gao, Y Yin, J Wang, K Dong, D Shi, X Wu and C Guo. Silk fibroin peptide self-assembled nanofibers delivered naringenin to alleviate cisplatin-induced acute kidney injury by inhibiting mtDNA-cGAS-STING pathway. Food and Chemical Toxicology 2023; 177, 113844.
IF Okkay, U Okkay, C Bayram, B Cicek, S Sezen, IC Aydin, AS Mendil and A Hacimuftuoglu. Bromelain protects against cisplatin-induced ocular toxicity through mitigating oxidative stress and inflammation. Drug and Chemical Toxicology 2023; 46(1), 69-76.
M Hidayat, R Pangastuti, S Prahastuti and K Hasan. Protein hydrolysate of green peas bromelain attenuates kidney fibrosis in cisplatin-induced nephrotoxicity rats: Emphasis on anti-inflammatory activities. HAYATI Journal of Biosciences 2023; 30(2), 347-357.
FA Chermahini, E Raeisi, MH Aazami, A Mirzaei, E Heidarian and Y Lemoigne. Does bromelain-cisplatin combination afford in-vitro synergistic anticancer effects on human prostatic carcinoma cell line, PC3? Galen Medical Journal 2020; 9, 1749.
H Fan, L Jian-Wei, M Sun and Z Jian-Hua. N-acetylcysteine protects septic acute kidney injury by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis. Iranian Journal of Basic Medical Sciences 2024; 27(7), 850-856.
K Okamoto, F Kitaichi, Y Saito, H Ueda, K Narumi, A Furugen and M Kobayashi. Antioxidant effect of ascorbic acid against cisplatin-induced nephrotoxicity and P-glycoprotein expression in rats. European Journal of Pharmacology 2021; 909, 174395.
KA Mapuskar, CF Pulliam, D Zepeda-Orozco, BR Griffin, M Furqan, DR Spitz and BG Allen. Redox regulation of Nrf2 in cisplatin-induced kidney injury. Antioxidants 2023; 12(9), 1728.
S Mirfendereski, M Taghipour, F Yadollahi, H Taghavinejad and M Ahmadnia. Administration of N-acetylcysteine for contrast-induced acute kidney injury; an updated mini-review. Journal of Nephropharmacology 2023; 13(1), 11658.
MO Iqbal, MM Ahmed, S Arshad, U Javaid, IA Khan, M Manzoor, S Andleeb, R Riaz, SH Munawar, Z Manzoor, and A Mumtaz. Nephroprotective effects of Alhagi camelorum against cisplatin-induced nephrotoxicity in albino Wistar rats. Molecules 2022; 27(3), 941.
AM Badr, LA Al-Kharashi, H Attia, S Alshehri, HN Alajami, RA Ali and YF Mahran. TLR4/inflammasomes cross-talk and pyroptosis contribute to N-acetyl cysteine and chlorogenic acid protection against cisplatin-induced nephrotoxicity. Pharmaceuticals (Basel) 2023; 16(3), 337.
AO Bakare and BV Owoyele. Antinociceptive and neuroprotective effects of bromelain in chronic constriction injury-induced neuropathic pain in Wistar rats. The Korean Journal of Pain 2019; 33(1), 13-22.
Z Li, R He, J Liu, X Jin, B Jiang, Y Lao and S Yang. JianPiYiShen formula prevents cisplatin-induced acute kidney injury in mice by improving necroptosis through MAPK pathway. BMC Complementary Medicine and Therapies 2024; 24(1), 101.
FE Ali, EHM Hassanein, AH El-Bahrawy, ZMM Omar, EK Rashwan, BA Abdel-Wahab and TH Abd-Elhamid. Nephroprotective effect of umbelliferone against cisplatin-induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO-3 and NF-kB-p65 signaling pathways. Journal of Biochemical and Molecular Toxicology 2021; 35(5), 22738.
DC Guzmán, NO Brizuela, MO Herrera, AV Peraza, NL Ruíz, HJ Olguín, DS Angel and GB Mejía. N-acetylcysteine attenuates cisplatin toxicity in the cerebrum and lung of young rats with artificially induced protein deficiency. International Journal of Molecular Sciences 2024; 25(11), 6239.
M Naushad, M Urooj, T Ahmad, GM Husain, MH Kazmi and M Zakir. Nephroprotective effect of Apium graveolens L. against cisplatin-induced nephrotoxicity. Journal of Ayurveda and Integrative Medicine 2021; 12(4), 607-615.
SJ Gilani, MN Bin-Jumah, FA Al-Abbasi, MS Nadeem, SI Alzarea, MM Ahmed, N Sayyed and I Kazmi. Rosinidin protects against cisplatin-induced nephrotoxicity via subsiding proinflammatory and oxidative stress biomarkers in rats. International Journal of Environmental Research and Public Health 2022; 19(15), 9719.
W Gong, L Lu, Y Zhou, J Liu, H Ma, L Fu, S Huang, Y Zhang, A Zhang and Z Jia. The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction. American Journal of Physiology-Renal Physiology 2021; 320(4), 608-616.
MA Za’abi, SA Salam, YA Suleimani, M Ashique, P Manoj, A Nemmar and BH Ali. Effects of repeated increasing doses of cisplatin as models of acute kidney injury and chronic kidney disease in rats. Naunyn-Schmiedeberg’s Archives of Pharmacology 2021; 394(2), 249-259.
Z Zhang, B Liang, W Jike, R Li, X Su, J Yu and T Liu. The protective effect of Marsdenia tenacissima against cisplatin-induced nephrotoxicity mediated by inhibiting oxidative stress, inflammation and apoptosis. Molecules 2023; 28(22), 7582.
J Zhou, N Run-Cong, Y Yi-Xin, C Xiao-Xia, D Xie and C Mu-Yan. Protective effect of natural antioxidants on reducing cisplatin‐induced nephrotoxicity. Disease Markers 2022; 2022, 1612348.
T Afsar, S Razak, D Aldisi, M Shabbir, A Almajwal, AAA Kheraif and M Arshad. Acacia hydaspica R. Parker ethyl-acetate extract abrogates cisplatin-induced nephrotoxicity by targeting ROS and inflammatory cytokines. Scientific Reports 2021; 11(1), 17248.
A Elsayed, A Elkomy, R Elkammar, G Youssef, EY Abdelhiee, W Abdo, SE Fadl, A Soliman and M Aboubakr. Synergistic protective effects of lycopene and N-acetylcysteine against cisplatin-induced hepatorenal toxicity in rats. Scientific Reports 2021; 11(1), 13979.
J Stabrauskiene, DM Kopustinskiene, R Lazauskas and J Bernatoniene. Naringin and naringenin: Their mechanisms of action and the potential anticancer activities. Biomedicines 2022; 10(7), 1686.
U Kansakar, V Trimarco, MV Manzi, E Cervi, P Mone and G Santulli. Exploring the therapeutic potential of bromelain: Applications, benefits, and mechanisms. Nutrients 2024; 16(13), 2060.
M Zhang, J Zhang, Y Ma, Y Jin, Y Li and W Xin’an. Nephropathy induced by cisplatin results from mitochondrial disruption, impaired energy metabolism, altered expression of renal transporters and accumulation of urinary toxins. Journal of Trace Elements in Medicine and Biology 2024; 86, 127553.
S Dasari, S Njiki, A Mbemi, CG Yedjou and PB Tchounwou. Pharmacological effects of cisplatin combination with natural products in cancer chemotherapy. International Journal of Molecular Sciences 2022; 23(3), 1532.
N Mehranfard, M Ghasemi, A Rajabian and L Ansari. Protective potential of naringenin and its nanoformulations in redox mechanisms of injury and disease. Heliyon 2023; 9(12), 22820.
Y Hong, A Boiti, D Vallone and NS Foulkes. Reactive oxygen species signaling and oxidative stress: Transcriptional regulation and evolution. Antioxidants 2024; 13(3), 312.
Y Fu, Y Xiang, Y Wang, Z Liu, D Yang, J Zha, C Tang, J Cai, G Chen and Z Dong. The STAT1/HMGB1/NF-κB pathway in chronic inflammation and kidney injury after cisplatin exposure. Theranostics 2023; 13(9), 2757-2773.
X Li, J Shi, Y Teng and Z Liu. The preventative effect of Baihe Gujin Pill on cisplatin-induced acute kidney injury by activating the PI3K/AKT and suppressing the NF-κB/MAPK pathways. Journal of Ethnopharmacology 2024; 318(B), 117071.
L Tonietti, M Esposito, M Cascone, B Barosa, S Fiscale, MT Muscari Tomajoli, T Sbaffi, R Santomartino, G Covone, A Cordonel, A Rotundi and D Giovannelli. Unveiling the bioleaching versatility of acidithiobacillus ferrooxidans. Microorganisms 2024; 12(12), 2407.
J Stabrauskiene, DM Kopustinskiene, R Lazauskas and J Bernatoniene. Naringin and naringenin: Their mechanisms of action and the potential anticancer activities. Biomedicines 2022; 10(7), 1686.
A Colletti, S Li, M Marengo, S Adinolfi and G Cravotto. Recent advances and insights into bromelain processing, pharmacokinetics and therapeutic uses. Applied Sciences 2021; 11(18), 8428.
Z Pei, M Wu, H Yu, G Long, Z Gui, X Li, H Chen, Z Jia and W Xia. Isoliquiritin ameliorates cisplatin-induced renal proximal tubular cell injury by antagonizing apoptosis, oxidative stress and inflammation. Frontiers in Medicine 2022; 9, 873739.
KR McSweeney, LK Gadanec, T Qaradakhi, BA Ali, A Zulli and V Apostolopoulos. Mechanisms of cisplatin-induced acute kidney injury: Pathological mechanisms, pharmacological interventions and genetic mitigations. Cancers 2021; 13(7), 1572.
A Gounipalli and L Yaidikar. Ameliorative activity of bromelain, an active principle of pineapple, against cisplatin-induced nephrotoxicity. Asian Journal of Pharmaceutical and Clinical Research 2025; 15(88), 88422-88430.
SS Khaled, HA Soliman, M Abdel-Gabbar, NA Ahmed, KAHA Attia, HA Mahran, ES El-Nahass and OM Ahmed. The preventive effects of naringin and naringenin against paclitaxel-induced nephrotoxicity and cardiotoxicity in male Wistar rats. Evidence-Based Complementary and Alternative Medicine 2022; 2022, 8739815.
HA Al-Amer, NS Al-Sowayan, HA Alfheeaid, SA Althwab, SA Alrobaish, EM Hamad, KH Musa and HM Mousa. Oral administration of naringenin and a mixture of coconut water and arabic gum attenuate oxidative stress and lipid peroxidation in gentamicin-induced nephrotoxicity in rats. European Review for Medical and Pharmacological Sciences 2023; 27(21), 10427-10437.
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