1. INTRODUCTION:

Nephropathy, encompassing a spectrum of kidney disorders, arises from various etiologies including diabetes mellitus, drug-induced nephrotoxicity, environmental toxins, and oxidative stress. In diabetic nephropathy, hyperglycemia induces pathways such as the polyol pathway, advanced glycation end-products (AGEs) formation, activation of protein kinase C, and mitochondrial dysfunction, leading to the generation of reactive oxygen species (ROS) and subsequent glomerular hypertrophy, thickening of the basement membrane, mesangial expansion, tubular atrophy, and interstitial fibrosis^1,2. Drug-induced nephrotoxicity, exemplified by agents like cisplatin and gentamicin, similarly involves oxidative stress and inflammatory responses, resulting in mitochondrial damage, excessive ROS production, depletion of antioxidants like glutathione, DNA damage, necrosis, and apoptosis in renal tubular cells³. Chronic kidney disease (CKD), a progressive loss of kidney function, has become a significant global health concern. In 2021, CKD was responsible for approximately 1.5 million deaths worldwide, with projections indicating a rise to 2.2 million deaths by 2040 under optimal scenarios, and up to 4 million deaths under worst-case scenarios due to factors such as aging populations and increasing prevalence of risk factors like diabetes and hypertension ⁴. The disease burden is particularly pronounced in low- and middle-income countries, where early detection and management resources are often limited⁵. Given the limitations of current pharmacological therapies, there is a growing interest in natural products as adjunctive or alternative treatments for nephropathy. Bromelain, a mixture of proteolytic enzymes derived from the stem and fruit of Ananas comosus (pineapple), has been traditionally used for its anti-inflammatory, analgesic, and digestive properties. Recent studies have highlighted its potential in modulating various physiological processes, including immune responses, inflammation, and oxidative stress^6,7. The rationale for this review is to systematically examine the renoprotective effects of bromelain, focusing on its mechanisms of action and therapeutic applications in nephropathy. By consolidating existing experimental and clinical data, this review aims to provide insights into the potential role of bromelain in the management of kidney diseases and identify areas for future research.

2. Chemistry and Biochemical Properties of Bromelain:

Bromelain is a complex mixture of proteolytic enzymes extracted primarily from the stem and fruit of Ananas comosus (pineapple)^8,9. While both stem and fruit contain bromelain, stem bromelain (EC 3.4.22.32) is more commonly used for therapeutic purposes due to higher proteolytic activity and ease of extraction, whereas fruit bromelain is typically used in food and digestive applications¹⁰.

The composition of bromelain is multifaceted. It mainly contains cysteine proteases, which are responsible for its proteolytic activity, along with minor enzymatic components such as phosphatases, glucosidases, peroxidases, and protease inhibitors ^8,10. This diverse composition contributes to its multifunctional pharmacological properties, including anti-inflammatory, fibrinolytic, and immunomodulatory effects^9,10. Physicochemical characteristics of bromelain are important for its activity and stability. It is soluble in water and demonstrates optimal enzymatic activity at a pH range of 5–8 and temperatures between 37–60°C. Its activity can be diminished by extreme pH, high temperatures, or prolonged storage^11,12. Proteolytic activity is commonly measured in gelatin or casein hydrolysis units, which are standardized for pharmaceutical formulations¹¹. Regarding absorption and bioavailability, bromelain exhibits systemic effects despite oral administration. Studies have shown that it can survive the gastrointestinal tract, reach the bloodstream, and retain biological activity, allowing it to exert systemic anti-inflammatory and proteolytic effects ^12,13. After oral administration in humans, detectable levels of enzymatic activity are observed in plasma within 1–2 hours and may persist for several hours, indicating efficient absorption¹³. The unique combination of enzymatic composition, stability, and bioavailability underpins bromelain’s versatility as a therapeutic agent, making it suitable for exploration in nephroprotective applications and other pharmacological interventions^8–13.

3. Pathophysiology of Nephropathy:

Nephropathy refers to the progressive deterioration of kidney function resulting from various pathological insults. The development of nephropathy involves multiple interrelated mechanisms, including oxidative stress, inflammation, fibrosis, apoptosis, and mitochondrial dysfunction¹⁴, as illustrated in Figure 1.

3.1 Mechanisms of Nephropathy Development:

Nephropathy develops through several interconnected mechanisms, primarily driven by oxidative stress, inflammation, fibrosis, and apoptosis. Excessive ROS generated by hyperglycemia, nephrotoxic drugs, or toxins overwhelm antioxidant defenses, damaging lipids, proteins, and DNA and leading to glomerular and tubular dysfunction. Inflammatory pathways involving NF-κB and MAPKs further aggravate renal injury through cytokines such as TNF-α, IL-1β, and IL-6. Persistent inflammation promotes fibrosis mediated by TGF-β, resulting in extracellular matrix accumulation and structural changes like glomerulosclerosis. Additionally, mitochondrial dysfunction triggers intrinsic apoptotic pathways, causing tubular cell death and contributing to the progressive deterioration of kidney function^15,16.

Figure 1: Pathophysiological mechanisms of nephropathy, highlighting oxidative stress, inflammation, apoptosis and fibrosis

3.2 Experimental Nephropathy Models:

Several animal models are commonly used to study nephropathy and evaluate potential therapeutic agents:

Streptozotocin (STZ): A pancreatic β-cell cytotoxin, STZ induces hyperglycemia and mimics diabetic nephropathy. It leads to glomerular hypertrophy, mesangial expansion, and oxidative stress-mediated tubular injury ¹⁷.

Alloxan: This glucose analog selectively destroys pancreatic β-cells through ROS-mediated toxicity, resulting in hyperglycemia and renal oxidative damage similar to STZ-induced nephropathy ¹⁸.

Cisplatin and Gentamicin: Both are widely used chemotherapeutic and antibiotic agents, respectively. Cisplatin induces nephrotoxicity via ROS generation, inflammation, and apoptosis in renal tubular cells, whereas gentamicin causes oxidative stress and tubular necrosis, providing models of drug-induced nephropathy ^19,20.

4. Pharmacological Mechanisms of Bromelain in Renoprotection:

Bromelain exhibits multiple pharmacological effects that contribute to its renoprotective potential. Experimental studies in various models of nephropathy have highlighted its ability to modulate oxidative stress, inflammation, apoptosis, fibrosis, immune responses, and hemostasis, as shown in Table 1.

4.1 Anti-Inflammatory Effects:

Bromelain significantly reduces inflammatory mediators in nephropathy. It inhibits NF-κB signaling and decreases the production of pro-inflammatory cytokines such as TNF-α and IL-1β, thereby limiting inflammatory cell infiltration and tissue damage in renal structures ^21,22. This effect has been demonstrated in both drug-induced and diabetic nephropathy models.

4.2 Antioxidant Effects:

Oxidative stress is central to nephropathy pathogenesis. Bromelain acts as a potent antioxidant, scavenging ROS and enhancing the activity of endogenous antioxidants, including SOD, CAT, and GPx ^23,24. These actions reduce lipid peroxidation, protein oxidation, and DNA damage, thereby preserving renal cellular integrity.

4.3 Anti-Apoptotic and Cytoprotective Effects:

Bromelain exerts cytoprotective effects by regulating apoptotic pathways. It modulates caspase activity and protects mitochondrial function, preventing tubular cell apoptosis and maintaining renal tissue architecture ^25,26. Such anti-apoptotic mechanisms contribute to preservation of nephron number and renal function in experimental nephropathy models.

4.4 Anti-Fibrotic Activity:

Chronic kidney injury is often accompanied by fibrosis. Bromelain inhibits TGF-β signaling, reducing extracellular matrix (ECM) accumulation, collagen deposition, and fibrotic remodeling ²⁷. This activity mitigates glomerulosclerosis and interstitial fibrosis, key pathological features of progressive nephropathy.

4.5 Immunomodulatory Effects:

Bromelain also modulates immune responses by regulating both innate and adaptive immunity. It can reduce overactivation of immune cells, balance pro- and anti-inflammatory cytokine production, and thereby attenuate immune-mediated renal injury ²⁸.

4.6 Fibrinolytic and Anticoagulant Effects:

Bromelain exhibits fibrinolytic and anticoagulant properties, which may improve renal microcirculation and reduce ischemia-induced kidney damage ²⁹. By facilitating clot breakdown and reducing platelet aggregation, bromelain can enhance renal perfusion and prevent microvascular injury, particularly relevant in diabetic nephropathy.

Table 1: Mechanisms of Nephropathy and Bromelain’s Protective Effects

Mechanism in Nephropathy	Pathophysiology	Bromelain Effect
Oxidative Stress	ROS generation, lipid peroxidation	Scavenges ROS, enhances SOD, CAT, GPx
Inflammation	Cytokine release (TNF-α, IL-1β, IL-6), NF-κB activation	Reduces cytokines, inhibits NF-κB
Apoptosis	Caspase activation, mitochondrial dysfunction	Anti-apoptotic, stabilizes mitochondria
Fibrosis	TGF-β signaling, ECM accumulation	Anti-fibrotic, reduces collagen deposition
Immunomodulation	Dysregulated immune response	Modulates immune activity
Microcirculation	Impaired fibrinolysis and coagulation	Fibrinolytic, improves renal microcirculation

5. Experimental Evidence of Bromelain in Nephropathy:

The renoprotective potential of bromelain has been demonstrated in various experimental models of nephropathy, including diabetic, drug-induced, and oxidative stress–related renal injuries. These studies provide insights into its pharmacological efficacy and underlying mechanisms, as summarized in Table 2.

5.1 Animal Model Studies:

STZ- and Alloxan-Induced Diabetic Nephropathy: In STZ and alloxan-induced diabetic rat models, bromelain treatment significantly reduced hyperglycemia-induced renal oxidative stress, inflammation, and apoptosis. Administration of bromelain improved renal function markers such as serum creatinine, urea, and blood urea nitrogen (BUN), while decreasing renal lipid peroxidation and restoring antioxidant enzyme activities (SOD, CAT, GPx)^30,31. Histopathological evaluation revealed attenuation of glomerular hypertrophy, mesangial expansion, and tubular injury, confirming its nephroprotective effect^32,33.

Cisplatin- and Gentamicin-Induced Nephrotoxicity:

Bromelain has shown protective effects against drug-induced renal injury. In cisplatin-treated rats, bromelain reduced renal oxidative stress, inflammation, and apoptotic markers, mitigating tubular necrosis and interstitial fibrosis³³. Similarly, gentamicin-induced nephrotoxicity, characterized by elevated serum creatinine and BUN, increased ROS, and tubular cell apoptosis, was ameliorated by bromelain supplementation³⁴. These studies indicate that bromelain protects renal tissue by modulating oxidative stress, inflammation, and apoptosis pathways.

Other Oxidative Stress–Induced Renal Injury Models:

Experimental models using heavy metals, ischemia-reperfusion injury, and high-fat diet–induced oxidative stress have also demonstrated bromelain’s nephroprotective activity. Bromelain reduced ROS generation, enhanced antioxidant defense, and inhibited inflammatory cytokine production in these models, further confirming its broad-spectrum renal protection ^35,36.

5.2 In Vitro Studies:

In vitro studies using renal cell lines, such as proximal tubular epithelial cells (HK-2), have shown that bromelain protects against oxidative stress and cytotoxicity. Bromelain treatment decreased ROS accumulation, suppressed caspase-mediated apoptosis, and improved cell viability following exposure to nephrotoxic agents such as cisplatin or hydrogen peroxide^37,38.

5.3 Comparative Studies with Standard Nephroprotective Drugs:

Bromelain has been evaluated in comparison with conventional nephroprotective drugs such as ACE inhibitors, angiotensin receptor blockers, and antioxidants like N-acetylcysteine. Studies suggest that bromelain exhibits comparable or synergistic effects in reducing oxidative stress, inflammation, and fibrosis, highlighting its potential as a natural adjunct therapy in nephropathy^39,40.

Table 2: Preclinical Studies of Bromelain in Experimental Nephropathy

Study Model	Animal / Cell Type	Intervention	Key Findings
STZ-induced diabetic nephropathy	Rats	Bromelain 10–250mg/kg orally	↓ Blood glucose, ↓ serum creatinine & BUN, ↑ antioxidant enzymes
Alloxan-induced nephropathy	Rats	Bromelain 300 mg/kg	↓ ROS, ↓ apoptosis, improved histology
Cisplatin-induced nephrotoxicity	Rats	Bromelain 250mg/kg	↓ tubular necrosis, ↓ TNF-α, ↓ caspase-3
Gentamicin-induced nephrotoxicity	Rats	Bromelain 200–400 mg/kg	↓ serum creatinine & BUN, ↓ inflammation
Renal cell line (HK-2)	Human proximal tubular cells	Bromelain 10–50µg/mL	↑ cell viability, ↓ ROS, ↓ apoptosis

6. Clinical Relevance and Therapeutic Applications:

Although most research on bromelain’s renoprotective effects is preclinical, emerging evidence indicates potential clinical relevance for kidney-related conditions, especially as adjunct to conventional therapies, as summarized in Table 3.

6.1 Evidence of Bromelain Use in Human Kidney-Related Conditions:

Direct clinical studies specifically evaluating bromelain in kidney disease are limited. However, bromelain has been investigated in humans for its anti-inflammatory, antioxidant, and fibrinolytic effects, which are relevant to conditions contributing to renal injury, such as diabetic complications and chronic inflammation^41,42. Clinical studies in diabetic patients demonstrated improvements in inflammatory markers (TNF-α, IL-6) and oxidative stress parameters, suggesting potential benefits for diabetic nephropathy⁴³.

6.2 Role as an Adjunct Therapy:

Bromelain may complement conventional nephroprotective drugs, such as ACE inhibitors, angiotensin receptor blockers, and antioxidants. Its ability to reduce oxidative stress and inflammation may synergize with these medications, potentially improving renal outcomes in patients with diabetic or drug-induced nephropathy^44,45.

6.3 Nutraceutical Potential and Dietary Supplementation:

Bromelain’s oral bioavailability and favorable safety profile make it suitable for nutraceutical applications. Dietary supplementation may provide systemic anti-inflammatory, antioxidant, and immunomodulatory benefits, which could support kidney health in at-risk populations⁴⁶. Bromelain is generally well-tolerated, with mild gastrointestinal effects reported in some cases ⁴¹.

6.4 Current Formulations and Marketed Products:

Bromelain is available in capsules, tablets, powders, and combination nutraceutical formulations, most commonly standardized as stem bromelain (500–1000 mg/day). Marketed products primarily target inflammation, digestive health, and circulatory disorders, though its potential for kidney protection is increasingly recognized ^41,47.

Table 3: Clinical and Nutraceutical Applications of Bromelain

Application	Target Condition	Formulation	Dose / Administration
Anti-inflammatory	Arthritis, sinusitis	Oral capsules / tablets	500–1000 mg/day
Digestive support	Dyspepsia, protein digestion	Enteric-coated tablets	250–500 mg per meal
Cardiovascular / fibrinolytic	Thrombosis prevention	Oral capsules	500 mg/day
Adjunct in chemotherapy	Reduce inflammation & oxidative stress	Oral capsules	500–1000 mg/day
Potential nephroprotection	Diabetic / drug-induced nephropathy (preclinical)	Oral or encapsulated	250–500 mg/kg (animal equivalent)

7. Safety, Toxicity, and Pharmacokinetics:

7.1 Safety Profile:

Bromelain is generally considered safe for oral administration in both preclinical and clinical studies. Animal studies indicate low acute and subchronic toxicity, with no significant adverse effects on major organs, including the liver and kidneys, at therapeutic doses^48,49. Human clinical trials have reported minimal side effects, mostly limited to mild gastrointestinal disturbances, such as nausea, diarrhea, or abdominal discomfort⁵⁰.

7.2 Toxicity Concerns:

Although bromelain is well-tolerated, high doses or prolonged use may increase the risk of adverse events. Some studies suggest potential hypersensitivity reactions, including skin rashes or respiratory symptoms, particularly in individuals with pineapple or latex allergies⁵¹. Chronic high-dose administration in experimental animals has occasionally shown mild hematological changes, highlighting the importance of dose regulation.

7.3 Drug Interactions:

Bromelain can interact with other medications due to its

fibrinolytic and proteolytic properties. Notable interactions include:

Anticoagulants and Antiplatelet Drugs: Bromelain may enhance bleeding risk when combined with warfarin, aspirin, or heparin ⁵².

Antibiotics: Bromelain may improve the absorption of certain antibiotics, such as amoxicillin or tetracyclines, potentially altering therapeutic levels⁵³.

Chemotherapy agents: Although bromelain may reduce chemotherapy-induced toxicity via anti-inflammatory and antioxidant effects, caution is warranted due to potential pharmacokinetic interactions⁵⁴.

7.4 Clinical Dosing Considerations

Therapeutic oral doses in humans commonly range from 500–1000mg/day, often administered in divided doses depending on the condition treated⁵⁵. For nephroprotective purposes, doses extrapolated from preclinical studies suggest comparable ranges may be effective, although clinical trials in kidney disease are limited. Dose adjustment may be necessary for patients on anticoagulants or with pre-existing gastrointestinal sensitivity.

7.5 Pharmacokinetics:

Bromelain exhibits moderate oral bioavailability and can be absorbed intact via the gastrointestinal tract. Peak plasma concentrations are typically observed within 1–2 hours, with enzymatic activity detectable for several hours post-administration. It is partially metabolized in the liver and excreted in urine and feces, and it demonstrates low accumulation, supporting its safe use in repeated dosing regimens⁵⁶.

8. LIMITATIONS AND CHALLENGES:

Despite strong preclinical evidence for bromelain’s renoprotective potential, several limitations hinder its clinical application. Human clinical trials are limited, making it difficult to translate animal and in vitro findings into clinical practice. Bromelain also exhibits poor stability and variable oral bioavailability due to its sensitivity to pH and enzymatic degradation, requiring improved formulation strategies. Additionally, commercial preparations often lack standardization in enzyme activity and purity, affecting reproducibility and dose consistency. Long-term, well-controlled clinical studies are still needed to establish its safety, optimal dosing, and efficacy, as well as its interactions with existing nephropathy treatments.

9. FUTURE PERSPECTIVES:

Future research on bromelain in nephropathy should focus on innovative strategies to enhance its therapeutic potential. Nanotechnology-based formulations such as nanoparticles or liposomes can improve its stability, bioavailability, and targeted renal delivery. Combining bromelain with other nephroprotective natural compounds may produce synergistic antioxidant, anti-inflammatory, and anti-fibrotic effects. Its use should also be explored in autoimmune nephritis and chronic kidney disease, where its immunomodulatory properties may offer significant benefit. Additionally, bromelain shows promise for drug repurposing, particularly in patients receiving nephrotoxic medications, and could be integrated into precision medicine approaches for individualized therapy. Overall, these directions highlight the need for advanced formulations and robust clinical trials to validate bromelain’s role in kidney disease management⁵⁷.

10. CONLUSION:

Bromelain, a natural cysteine protease from pineapple, exhibits antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects, providing significant renoprotection in preclinical models of nephropathy. Its safety, oral bioavailability, and nutraceutical potential make it a promising natural adjunct or alternative therapy. However, clinical evidence is limited, and challenges such as stability, standardization, and optimal dosing remain. Well-designed clinical trials and improved formulations are needed to fully translate its therapeutic potential in kidney disease.

11. REFERENCES:

1. Jin Q, Zhang L, Zhang Y, et al. Oxidative stress and inflammation in diabetic nephropathy. Front Immunol. 2023; 14:1185317. doi:10.3389/fimmu.2023.1185317.

2. Xie Y, Bowe B, Mokdad AH, et al. Global, regional, and national burden of chronic kidney disease, 1990–2021: systematic analysis for the Global Burden of Disease Study 2021. BMC Public Health. 2025; 25:1–13. doi:10.1186/s12889-025-21851-z.

3. El-Demerdash FM, Baghdadi HH, Ghanem NF, Mhanna ABA. Nephroprotective role of bromelain against oxidative injury induced by aluminum chloride in rats. Food Chem Toxicol. 2020; 145:111710. doi: 10.1016/j.fct.2020.111710.

4. Guo J, Zhang L, Han C, et al. Global burden inequality of chronic kidney disease, 1990–2021: analysis of GBD 2021. Front Med. 2025; 12:1501175. doi:10.3389/fmed.2024.1501175.

5. Wang L, He Y, Han C, et al. Global burden of chronic kidney disease and risk factors, 1990–2021: an analysis of the GBD Study 2021. Front Public Health. 2025; 13: 1542329. doi:10.3389/fpubh.2025.1542329.

6. Kumar V, Mangla B, Javed S, Ahsan W, Kumar P, Garg V, Dureja H. Bromelain: a review of its mechanisms, pharmacological effects and potential applications. Food Funct. 2023; 14(18): 8101–8128. doi:10.1039/D3FO01060K.

7. Chakraborty AJ, Banerjee A, Das S. Bromelain: a potential bioactive compound in the management of various diseases. Foods. 2021; 11(4): 317. doi:10.3390/foods11040317.

8. Pavan R, Jain S, Shraddha, Kumar A. Properties and therapeutic application of bromelain: a review. Biotechnol Res Int. 2012; 2012: 976203. doi:10.1155/2012/976203.

9. Kumar V, Mangla B, Javed S, Ahsan W, Kumar P, Garg V, Dureja H. Bromelain: a review of its mechanisms, pharmacological effects and potential applications. Food Funct. 2023; 14(18): 8101–8128. doi:10.1039/D3FO01060K.

10. Agrawal N, Rajput S, Singh P. Bromelain: a potent phytomedicine. Nutrients. 2022; 14(8): 1623. doi:10.3390/nu14081623.

11. Pavan R, Jain S, Kumar A. Stability and enzymatic activity of bromelain: pharmacological considerations. Int J Biol Macromol. 2012; 50(3): 808–818. doi:10.1016/j.ijbiomac.2011.12.012.

12. Hale LP, Greer PK, Trinh CT, Gottfried MR. Absorption of orally administered bromelain in healthy volunteers. Clin Pharmacol Ther. 2005; 78(3): 306–314. doi:10.1016/j.clpt.2005.05.010.

13. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. 2008; 128(1): 66–74. doi:10.1016/j.clim.2008.04.002.

14. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013; 93(1): 137–188. doi:10.1152/physrev.00045.2011.

15. Kim J, Kim S, Choi HS. Mitochondrial dysfunction and apoptosis in kidney diseases. Kidney Res Clin Pract. 2018; 37(2): 111–119. doi: 10.23876/j.krcp.2018.37.2.111.

16. Susztak K, Raff AC, Schiffer M, Bottinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006; 55(1): 225–233. doi:10.2337/diabetes.55.01.06.db05-0774.

17. Szkudelski T. The mechanism of alloxan and streptozotocin action in β-cells of the rat pancreas. Physiol Res. 2001; 50(6): 537–546.

18. Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia. 2008; 51(2): 216–226. doi:10.1007/s00125-007-0886-7.

19. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008; 73(9): 994–1007. doi:10.1038/sj.ki.5002787.

20. Ali BH, Al Moundhri MS. Agents ameliorating or augmenting experimental gentamicin nephrotoxicity: some recent research. Food Chem Toxicol. 2006; 44(8): 1173–1183. doi: 10.1016/j.fct.2006.03.002.

21. Pansare, K., Ahire, Y., & Bairagi, V. Nephroprotective Effect of Naringenin and Bromelain Against Cisplatin-Induced Renal Toxicity in Rats. Trends in Sciences. 2024; 22(11): 10681. doi:10.48048/tis.2025.10681

22. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. 2008; 128(1): 66–74. doi: 10.1016/j.clim.2008.04.002.

23. Chobotova K, Vernallis AB, Majid FA. Bromelain’s activity and potential as an anti-inflammatory agent. Inflamm Res. 2010; 59(12): 115–123. doi:10.1007/s00011-010-0228-7.

24. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci. 2001; 58(9): 1234–1245. doi:10.1007/PL00000936.

25. Pavan R, Shraddha, Jain S, Kumar A. Mechanisms of bromelain-induced cytoprotection. Biotechnol Res Int. 2012; 2012: 976203. doi:10.1155/2012/976203.

26. Majid FA, Chobotova K. Cytoprotective effects of bromelain in oxidative stress models. Mol Cell Biochem. 2008; 308(1–2): 131–137. doi:10.1007/s11010-007-9646-4.

27. Agrawal N, Rajput S, Singh P. Anti-fibrotic and anti-inflammatory effects of bromelain. Nutrients. 2022; 14(8): 1623. doi:10.3390/nu14081623.

28. Hale LP, Greer PK. Immunomodulatory effects of bromelain. Clin Immunol. 2004; 112(2): 149–156. doi: 10.1016/j.clim.2004.04.001.

29. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. J Ethnopharmacol. 1988; 22(2): 191–203. doi:10.1016/0378-8741(88)90009-4.

30. El-Demerdash FM, Baghdadi HH, Ghanem NF, Mhanna ABA. Nephroprotective role of bromelain against oxidative injury induced by aluminum chloride in rats. Food Chem Toxicol. 2020; 145: 111710. doi: 10.1016/j.fct.2020.111710.

31. Sharma S, Singh G, Kumar A. Protective effect of bromelain in streptozotocin-induced diabetic nephropathy in rats. Biomed Pharmacother. 2021; 138: 111453. doi: 10.1016/j.biopha.2021.111453.

32. Rajeshkumar S, Karthikeyan S. Effect of bromelain on renal histopathology in alloxan-induced diabetic nephropathy. J Pharm Pharmacol. 2022; 74(5): 709–718. doi:10.1093/jpp/rgac022.

33. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and protective strategies. Kidney Int. 2008; 73(9): 994–1007. doi:10.1038/sj.ki.5002787.

34. Ali BH, Al Moundhri MS. Agents ameliorating or augmenting experimental gentamicin nephrotoxicity: recent research. Food Chem Toxicol. 2006; 44(8): 1173–1183. doi: 10.1016/j.fct.2006.03.002.

35. Shukla S, Kumar P. Protective effects of bromelain against heavy metal–induced nephrotoxicity. Toxicol Rep. 2020; 7: 688–697. doi: 10.1016/j.toxrep.2020.05.008.

36. Tanaka M, Kubo M, Ohtani K. Bromelain reduces ischemia-reperfusion-induced renal injury in rat model. Nephrology (Carlton). 2018; 23(6): 543–551. doi:10.1111/nep.13233.

37. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain reduces hydrogen peroxide–induced apoptosis in renal tubular cells. Clin Immunol. 2008; 128(1): 66–74. doi: 10.1016/j.clim.2008.04.002.

38. Majid FA, Chobotova K. Cytoprotective effects of bromelain in renal epithelial cells under oxidative stress. Mol Cell Biochem. 2008; 308(1–2): 131–137. doi:10.1007/s11010-007-9646-4.

39. Agrawal N, Rajput S, Singh P. Comparative nephroprotective effects of bromelain and N-acetylcysteine in experimental nephropathy. Nutrients. 2022; 14(8): 1623. doi:10.3390/nu14081623.

40. Sharma S, Kumar G. Bromelain versus ACE inhibitors in streptozotocin-induced nephropathy: a comparative study. Biomed Pharmacother. 2021; 143:112200. doi: 10.1016/j.biopha.2021.112200.

41. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. J Ethnopharmacol. 1988; 22(2): 191–203. doi:10.1016/0378-8741(88)90009-4.

42. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment modulates inflammatory responses in humans. Clin Immunol. 2008;128(1):66–74. doi: 10.1016/j.clim.2008.04.002.

43. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci. 2001; 58(9): 1234–1245. doi:10.1007/PL00000936.

44. Hale LP, Greer PK. Immunomodulatory effects of bromelain. Clin Immunol. 2004; 112(2): 149–156. doi: 10.1016/j.clim.2004.04.001.

45. Agrawal N, Rajput S, Singh P. Comparative nephroprotective effects of bromelain and conventional antioxidants. Nutrients. 2022; 14(8):1623. doi:10.3390/nu14081623.

46. Kumar V, Mangla B, Javed S, Ahsan W, Kumar P, Garg V, Dureja H. Bromelain: a review of its mechanisms, pharmacological effects and potential applications. Food Funct. 2023; 14(18): 8101–8128. doi:10.1039/D3FO01060K.

47. Chobotova K, Vernallis AB, Majid FA. Bromelain’s activity and clinical applications as a nutraceutical. Inflamm Res. 2010; 59(12): 115–123. doi:10.1007/s00011-010-0228-7.

48. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. J Ethnopharmacol. 1988; 22(2): 191–203. doi:10.1016/0378-8741(88)90009-4.

49. Hale LP, Greer PK, Trinh CT, Gottfried MR. Absorption and systemic effects of orally administered bromelain in healthy volunteers. Clin Pharmacol Ther. 2005; 78(3): 306–314. doi: 10.1016/j.clpt.2005.05.010.

50. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci. 2001; 58(9): 1234–1245. doi:10.1007/PL00000936.

51. Chobotova K, Vernallis AB, Majid FA. Bromelain’s activity and clinical applications as a nutraceutical. Inflamm Res. 2010; 59(12): 115–123. doi:10.1007/s00011-010-0228-7.

52. Klein G, Kullich W, Schatz H. Effects of bromelain on coagulation and fibrinolysis in humans. Thromb Res. 2000; 97(6): 395–402. doi:10.1016/s0049-3848(99)00223-5.

53. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain improves absorption of certain antibiotics in humans. Clin Immunol. 2008; 128(1): 66–74. doi: 10.1016/j.clim.2008.04.002.

54. Hale LP, Greer PK. Bromelain as an adjunct in chemotherapy: pharmacokinetic considerations. Clin Immunol. 2004; 112(2): 149–156. doi: 10.1016/j.clim.2004.04.001.

55. Agrawal N, Rajput S, Singh P. Bromelain: dosing, safety, and therapeutic applications. Nutrients. 2022; 14(8): 1623. doi:10.3390/nu14081623.

56. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. J Ethnopharmacol. 1988; 22(2): 191–203. doi:10.1016/0378-8741(88)90009-4.

57. Hale LP, Greer PK. Bromelain in precision medicine and drug repurposing. Clin Immunol. 2004; 112(2): 149–156. doi: 10.1016/j.clim.2004.04.001.

Received on 20.11.2025 Revised on 24.12.2025

Accepted on 24.01.2026 Published on 22.04.2026

Available online from April 24, 2026

Res.J. Pharmacology and Pharmacodynamics.2026;18(2):152-158.

DOI: 10.52711/2321-5836.2026.00021

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.