What is bromelain

Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple 1. However, bromelain is usually referred to the pineapple stem bromelain. Pineapple is the common name of Ananas comosus (Ananas sativus, Ananassa sativa, Bromelia ananas, Bromelia comosa). Pineapple is the leading edible member of the family Bromeliaceae, grown in several tropical and subtropical countries including Philippines, Thailand, Indonesia, Malaysia, Kenya, India, and China. Pineapple has been used as a medicinal plant in several native cultures 2 and these medicinal qualities of pineapple are attributed to bromelain, which is a crude extract from pineapple.

Bromelain concentration is high in pineapple stem, thus necessitating its extraction because, unlike the pineapple fruit which is normally used as food, the stem is a waste byproduct and thus inexpensive 3.

Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase and several protease inhibitors. In vitro (test tubes) and in vivo (animal) studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. Bromelain also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death.


Bromelain enzyme

Bromelainis a mixture of different thiol endopeptidases and other components like phosphatases, glucosidase, peroxidases, cellulases, glycoproteins, carbohydrates, and several protease inhibitors 4. Stem bromelain is different from fruit bromelain 5. Proteinases are considered to be the most active fraction, which comprise ~2% of the total proteins 6. Bromelain enzymatic activities comprise a wide spectrum with pH range of 4.5 to 9.5 7. Nowadays, bromelain is prepared from cooled pineapple juice by centrifugation, ultrafiltration, and lyophilization 8. The process yields a yellowish powder, the enzyme activity of which is determined with different substrates such as casein, gelatin (gelatin digestion units), or chromogenic tripeptides 9.

The composition of bromelain varies based on the method of purification and the source; stem bromelain contains high quantities of protease content when compared with bromelain derived from the fruit 10. It was demonstrated that the majority of the physiological activity of bromelain may not be due to single proteolytic fraction and it is likely that the beneficial effects of bromelain are due to multiple factors 9. Bromelain has not only been used to treat various health problems, it is also popular as a nutritional supplement to promote health. Bromelain is absorbed into the human intestines and remains biologically active with a half-life of ~6–9 hours 11. The highest concentration of bromelain was identified in the blood one hour after administration 12. Bromelain increases bioavailability and reduces the side effects that are associated with various antibiotics 13. Furthermore, bromelain acts as an immunomodulator, is anti-metastatic, anti-edematous, anti-thrombotic and anti-inflammatory 14. These findings indicate that bromelain may present as a promising candidate for the development of future anticancer therapeutic strategies. Notably, although numerous studies have been conducted regarding bromelain there are limited reviews that document the complete anticancer activity of bromelain.

Absorption and Bioavailability of Bromelain

The body can absorb significant amount of bromelain; about 12 gm/day of bromelain can be consumed without any major side effects 10. Bromelain is absorbed from the gastrointestinal tract in a functionally intact form; approximately 40% of labeled bromelain is absorbed from intestine in high molecular form 15. In a study carried out by Castell et al. 10 bromelain was detected to retain its proteolytic activity in plasma and was also found linked with alpha 2-macroglobulin and alpha1-antichymotrypsin, the two antiproteinases of blood. In a recent study, it was demonstrated that 3.66 mg/mL of bromelain was stable in artificial stomach juice after 4 hrs of reaction and also 2.44 mg/mL of bromelain remained in artificial blood after 4 hrs of reaction 16.

Bromelain benefits

A wide range of therapeutic benefits have been claimed for bromelain, such as reversible inhibition of platelet aggregation, sinusitis, surgical traumas 17, thrombophlebitis [inflammation of the wall of a vein with associated blood clot], pyelonephritis [inflammation of the kidney as a result of bacterial infection], angina pectoris [condition marked by severe pain in the chest due to blocked artery to the heart muscle], bronchitis [inflammation of the mucous membrane in the bronchial tubes] 18, and enhanced absorption of drugs, particularly of antibiotics 9. Several studies have been carried out indicating that bromelain has useful phytomedical application. However, these results are yet to be amalgamated and critically compared so as to make out whether bromelain will gain wide acceptance as a phytomedical supplement 19. Bromelain acts on fibrinogen giving products that are similar, at least in effect, to those formed by plasmin 20. Experiment in mice showed that antacids such as sodium bicarbonate preserve the proteolytic activity of bromelain in the gastrointestinal tract 21. Bromelain is considered as a food supplement and is freely available to the general public in health food stores and pharmacies in the USA and Europe 22. Existing evidence indicates that bromelain can be a promising candidate for the development of future oral enzyme therapies for cancer patients 23. Bromelain can be absorbed in human intestines without degradation and without losing its biological activity 23.

Bromelain on Rhinosinusitis

Chronic rhinosinusitis in adults is defined as sinonasal inflammation persisting for >12 weeks. Chronic rhinosinusitis in adults is characterized by nasal obstruction/congestion/blockage, anterior or posterior nasal mucopurulent, facial pain/pressure/fullness, and decreased/loss of sense of smell. Symptoms must be accompanied by objective findings including positive nasal endoscopy (purulence, edema) or positive imaging findings such as inflammation or mucosal changes within the sinuses. A systematic review 24 of the evidence indicates that bromelain is helpful in relieving symptoms of acute nasal and sinus inflammation when used in combination with standard medications. In a study 25 to quantity bromelain in rhinosinusal mucosa of patients with chronic rhinosinusitis and individuals without nasal and paranasal pathology. It was found that patients taking Bromelain 500 mg tablet twice daily was administered for 30 days has significant distribution of bromelain in the ethmoid sinus and nasal turbinates mucus of patients with chronic rhinosinusitis, indicating that Bromelain could be exploited for use as an anti-inflammatory agent in nasal and sinusal pathologies.

Anti-inflammatory activity of bromelain

Inflammation is pivotal in the development of cancer during cellular transformation, proliferation, angiogenesis, invasion and metastasis. It has been demonstrated that suppression of chronic inflammation may reduce the cancer incidence and also inhibit cancer progression 26. Cyclooxigenase-2 (COX-2) is an important component of cancer-associated inflammation that is involved in the synthesis of prostaglandin E2 (PGE-2). PGE-2 is a pro-inflammatory lipid that also acts as an immunosuppressant, as well as a promoter of tumor progression 27. COX-2 converts arachidonic acid into PGE-2 and promotes tumor angiogenesis and cancer progression 28. It has been shown that bromelain downregulates COX-2 and PGE-2 expression levels in murine microglial cells and human monocytic leukemia cell lines 29. Bromelain activates the inflammatory mediators, including interleukin (IL)-1β, IL-6, interferon (INF)-γ and tumor necrosis factor (TNF)-α in mouse macrophage and human peripheral blood mononuclear cells 30. These results indicated that bromelain potentially activates the healthy immune system in association with the rapid response to cellular stress. Conversely, bromelain reduces IL-1β, IL-6 and TNF-α secretion when immune cells are already stimulated in the condition of inflammation-induced over production of cytokines 31. Studies have shown that bromelain reduced the expression of INF-γ and TNF-α in inflammatory bowel disease 32. A study demonstrated that bromelain diminished the cell damaging effect of advanced glycation end products by proteolytic degradation of receptor of advanced glycation end products 32 and controlled the inflammation 32. The cell surface marker, cluster of differentiation (CD)44 is expressed by cancer and immune cells directly involved in cancer growth and metastasis. Furthermore, CD44 regulates lymphocyte requirement at the site of inflammation 33. Bromelain was shown to reduce the level of CD44 expression on the surface of mouse and human tumor cells, and regulate lymphocyte homing and migration to the sites of inflammation 34. Furthermore, bromelain modulates the expression of transforming growth factor (TGF)-β, one of the major regulators of inflammation in patients affected by osteomyelofibrosis and rheumatoid arthritis 35. There are various studies that report the immunomodulatory effect of bromelain 36. Bromelain activates natural killer cells and augments the production of granulocyte-macrophage-colony stimulating factor, IL-2, IL-6 and decreases the activation of T-helper cells 37. Thus, bromelain decreases the majority of inflammatory mediators and has demonstrated a significant role as an anti-inflammatory agent in various conditions 38.

Anticancer activity of bromelain

Recent studies have shown that bromelain has the capacity to modify key pathways that support malignancy. Presumably, the anticancerous activity of bromelain is due to its direct impact on cancer cells and their micro-environment, as well as on the modulation of immune, inflammatory, and hemostatic systems 39. Most of the in vitro (test tubes) and in vivo (animals) studies on anticancer activity of bromelain are concentrated on mouse and human cells, both cancerous and normal, treated with bromelain preparations. In an experiment conducted by Beez et al 40 chemically induced mouse skin papillomas were treated with bromelain and they observed that it reduced tumor formation, tumor volume and caused apoptotic cell death. In one study related to bromelain treatment of gastric carcinoma Kato III cell lines, significant reduction of cell growth was observed 41 while in another study bromelain reduced the invasive capacity of glioblastoma cells and reduced de novo protein synthesis 42. Bromelain is found to increase the expression of p53 and Bax in mouse skin, the well-known activators of apoptosis 43. Bromelain also decreases the activity of cell survival regulators such as Akt and Erk, thus promoting apoptotic cell death in tumours. Different studies have demonstrated the role of NF-κB, Cox-2, and PGE2 as promoters of cancer progression. Evidence shows that the signaling and overexpression of NF-κB plays an important part in many types of cancers 44. Cox-2, a multiple target gene of NF-κB, facilitates the conversion of arachidonic acid into PGE2 and thus promotes tumour angiogenesis and progression 45. It is considered that inhibiting NF-κB, Cox-2, and PGE2 activity has potential as a treatment of cancer. Bromelain was found to downregulate NF-κB and Cox-2 expression in mouse papillomas 43 and in models of skin tumourigenesis 46. Bromelain was also shown to inhibit bacterial endotoxin (LPS)-induced NF-κB activity as well as the expression of PGE2 and Cox-2 in human monocytic leukemia and murine microglial cell lines 47. Bromelain markedly has in vivo antitumoural activity for the following cell lines: P-388 leukemia, sarcoma (S-37), Ehrlich ascetic tumour, Lewis lung carcinoma, and ADC-755 mammary adenocarcinoma. In these studies, intraperitoneal administration of bromelain after 24 hours of tumour cell inoculation resulted in tumour regression 43.

Antimicrobial activity

Bromelain supplementation protects animals against diarrhea caused by bacterial enterotoxins from Escherichia coli and Vibrio cholerae 48. Bromelain acts as anti-adhesion agent by modifying the receptor attachment sites and influences the intestinal secretory signaling pathways 49. In addition to its ability to counter certain effects of particular intestinal pathogens and its synergism with antibiotics, these two mechanisms are indicative of the benefits of bromelain against specific infections. In vitro evidence also suggests that bromelain exerts antihelminthic activity against the gastrointestinal nematodes, Trichuris muris and Heligmosomoides polygyrus 50. Conversely, bromelain acts as an anti-fungal agent by stimulating phagocytosis and respiratory burst killing of Candida albicans when incubated with trypsin in vitro 51. Pityriasis lichenoides chronica is an infectious skin disease and bromelain reportedly caused complete resolution of this condition 52. Bromelain has been documented to increase blood and urine levels of certain antibiotics in humans 53. Combined bromelain and antibiotic therapy was shown to be more effective than antibiotics alone in pneumonia, bronchitis, cutaneous Staphylococcus infection, thrombophlebitis, cellulitis, pyelonephritis, and in perirectal and rectal abscesses 54, sinusitis 55 and urinary tract infections 56. A combination of bromelain, trypsin, and rutin has been administered as an adjuvant therapy in combination with antibiotics for children with sepsis 53. A combination of bromelain with enzymes derived from Aspergillus niger improved protein utilization in elderly nursing home patients 57. Another study demonstrated that bromelain, in combination with sodium alginate, sodium bicarbonate and essential oils, significantly improved dyspeptic symptoms 58. In addition, bromelain has been administered successfully as a digestive enzyme to treat intestinal disorders, pancreatectomy and exocrine pancreas insufficiency 59. Finally, the combination of ox bile, pancreatin, and bromelain is effective in lowering stool fat excretion in patients with pancreatic steatorrhea, resulting in symptomatic improvements in pain, flatulence and stool frequency 60.

Bromelain on Cardiovascular and Circulation

Bromelain prevents or minimizes the severity of angina pectoris and transient ischemic attack (TIA). It is useful in the prevention and treatment of thrombophlebitis. It may also break down cholesterol plaques and exerts a potent fibrinolytic activity. A combination of bromelain and other nutrients protect against ischemia/reperfusion injury in skeletal muscle 61. Cardiovascular diseases (CVDs) include disorders of the blood vessels and heart, coronary heart disease (heart attacks), cerebrovascular disease (stroke), raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, heart failure, and congenital heart disease 62. Stroke and heart disease are the main cause of death, about 65% of people with diabetes die from stroke or heart disease. Bromelain has been effective in the treatment of cardiovascular diseases as it is an inhibitor of blood platelet aggregation, thus minimizing the risk of arterial thrombosis and embolism 63. King et al. 64 reported that administration of medication use to control the symptoms of diabetes, hypertension, and hypercholesteromia increased by 121% from 1988–1994 to 2001–2006 and was greater for patients with fewer healthy lifestyle habits. Bromelain supplement could reduce any of risk factors that contribute to the development of cardiovascular disease. In a recent research, Bromelain was found to attenuate development of allergic airway disease, while altering CD4+ to CD8+T lymphocyte populations. From this reduction in allergic airway disease outcomes it was suggested that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders 65. In another study, carried out by Juhasz et al., Bromelain was proved to exhibit the ability of inducing cardioprotection against ischemia-reperfusion injury through Akt/Foxo pathway in rat myocardium 66.

Bromelain on Osteoarthritis

Osteoarthritis is the most common form of arthritis in Western countries; in USA prevalence of osteoarthritis ranges from 3.2 to 33% dependent on the joint 67. A combination of bromelain, trypsin, and rutin was compared to diclofenac in 103 patients with osteoarthritis of the knee. After six weeks, both treatments resulted in significant and similar reduction in the pain and inflammation 68. Bromelain is a food supplement that may provide an alternative treatment to nonsteroidal anti-inflammatory drug (NSAIDs) 69. It plays an important role in the pathogenesis of arthritis 70. Bromelain has analgesic properties which are thought to be the result of its direct influence on pain mediators such as bradykinin 71. The earliest reported studies investigating bromelain were a series of case reports on 28 patients, with moderate or severe rheumatoid or osteoarthritis 72.

In conclusion, bromelain appears to have potential for the treatment of knee osteoarthritis. However it is important to note that there are a number of methodological issues that are common to the studies reported, including the possibility of inadequate power, inadequate treatment periods, inadequate or non-existent follow-up to monitor possible adverse drug reactions. Furthermore, the optimum dosage for this condition remains unclear. A phase II clinical trial would be beneficial to identify the optimal dosage and to systematically monitor safety issues before a definitive efficacy study could be completed.

Bromelain on Immune System

Bromelain has been recommended as an adjuvant therapeutic approach in the treatment of chronic inflammatory, malignant, and autoimmune diseases 73. In vitro experiments have shown that Bromelain has the ability to modulate surface adhesion molecules on T cells, macrophages, and natural killer cells and also induce the secretion of IL-1β, IL-6, and tumour necrosis factor α (TNFα) by peripheral blood mononuclear cells 74. Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory cytokine and increased TNF-α production is found in serum, stools, and bowel mucosa in both inflammatory bowel disease (IBD) patients and inflammatory bowel disease (IBD) models 75. Anti-TNF therapy has been confirmed to alleviate symptoms, heal mucosal ulcers, spare corticosteroid treatment, and decrease hospitalization costs. TNF-α leads to the activation of nuclear factor kappa B (NF-κB), which can transmigrate into the nucleus, and it binds to DNA response elements in gene promoter regions to control transcription of genes, such as inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2), and myosin light chain kinase 76. Both iNOS and COX2 are pro-inflammatory mediators which play crucial roles in inflammatory responses 76. The expression and activity of myosin light chain kinase is increased in human inflammatory bowel disease (IBD) and associated with histological evidence of disease activity 77. Myosin light chain kinase-induced phosphorylation of perijunctional actomyosin mediates tight junction loss, which triggers the initiation and development of inflammatory bowel disease (IBD) 78. TNF-α exerts its biological function by binding to two kinds of TNF-α receptors (TNFRs), including TNFR1 and TNFR2. Epithelial TNFR1 and TNFR2 are relatively under-examined, but they have been implicated in epithelial apoptosis, proliferation, migration, and tight junction regulation 79. Oral administration of bromelain relieved IBD symptoms 80; however, the effect of bromelain on intestinal inflammation induced by chemical damage and its underlying mechanisms are still not fully understood.

Bromelain can block the Raf-1/extracellular-regulated-kinase- (ERK-) 2 pathways by inhibiting the T cell signal transduction 81. Treatment of cells with bromelain decreases the activation of CD4 (+) T cells and reduce the expression of CD25 82. Moreover, there is evidence that oral therapy with bromelain produces certain analgesic and anti-inflammatory effects in patients with rheumatoid arthritis, which is one of the most common autoimmune diseases 83.

Bromelain on Blood Coagulation and Fibrinolysis

Bromelain influences blood coagulation by increasing the serum fibrinolytic ability and by inhibiting the synthesis of fibrin, a protein involved in blood clotting 84. In rats, the reduction of serum fibrinogen level by bromelain is dose dependent. At a higher concentration of bromelain, both prothrombin time (PT) and activated partial thromboplastin time (APTT) are markedly prolonged 85. In vitro and in vivo studies have suggested that bromelain is an effective fibrinolytic agent as it stimulates the conversion of plasminogen to plasmin, resulting in increased fibrinolysis by degrading fibrin 86.

Bromelain on Diarrhea

Evidence has suggested that bromelain counteracts some of the effects of certain intestinal pathogens like Vibrio cholera and Escherichia coli, whose enterotoxin causes diarrhoea in animals. Bromelain appears to exhibit this effect by interacting with intestinal secretory signaling pathways, including adenosine 3′ : 5′-cyclic monophosphatase, guanosine 3′ : 5′-cyclic monophosphatase, and calcium-dependent signaling cascades 87. Other studies suggest a different mechanism of action. In E. coli infection, an active supplementation with bromelain leads to some antiadhesion effects which prevent the bacteria from attaching to specific glycoprotein receptors located on the intestinal mucosa by proteolytically modifying the receptor attachment sites 88.

Bromelain in Surgery

Administration of bromelain before a surgery can reduce the average number of days for complete disappearance of pain and postsurgery inflammation 89. Trials indicate that bromelain might be effective in reducing swelling, bruising, and pain in women having episiotomy 90. Nowadays, bromelain is used for treating acute inflammation and sports injuries 69.

Bromelain in Debridement Burns

The removal of damaged tissue from wounds or second/third degree burns is termed as debridement. Bromelain applied as a cream (35% bromelain in a lipid base) can be beneficial for debridement of necrotic tissue and acceleration of healing. Bromelain contains escharase which is responsible for this effect. Escharase is nonproteolytic and has no hydrolytic enzyme activity against normal protein substrate or various glycosaminoglycan substrates. Its activity varies greatly with different preparations 91. In two different enzymatic debridement studies carried out in pig model, using different bromelain-based agents, namely, Debriding Gel Dressing (DGD) and Debrase Gel Dressing showed rapid removal of the necrotic layer of the dermis with preservation of the unburned tissues 92, 93. In another study on Chinese landrace pigs, enzymatic debridement using topical bromelain in incised wound tracks accelerated the recovery of blood perfusion, pO2 in wound tissue, controlled the expression of TNF-α, and raised the expression of TGT-β 94. Enzymatic debridement using bromelain is better than surgical debridement as surgical incision is painful, nonselective and exposes the patients to the risk of repeated anaesthesia and significant bleeding 95, 96.

Bromelain side effects

Studies that have used a higher daily dose of bromelain to treat osteoarthritis [945 mg/day 97; 1890 mg/day 98] appear to be conflicting. The authors employing the highest dose reported that the medication was well tolerated; the dose of 945 mg/day, however, showed a higher incidence of adverse drug reactions and drop-outs. Adverse events that have been reported are mainly gastrointestinal (i.e. diarrhoea, nausea and flatulence), but have also included headache, tiredness, dry mouth, skin rash and allergic reactions (not specified) 99.

There have been some reports of gastrointestinal problems, increased heart rate, and menstrual problems in people who have taken bromelain orally.

Allergic reactions may occur in individuals who are sensitive or allergic to pineapples or who may have other allergies.

According to Taussig et al. 100 bromelain has very low toxicity with an LD50 (lethal doses) greater than 10 g/kg in mice, rates, and rabbits. Toxicity tests on dogs, with increasing level of bromelain up to 750 mg/kg administered daily, showed no toxic effects after six months. Dosages of 1500 mg/kg per day when administered to rats showed no carcinogenic or teratogenic effects and did not provoke any alteration in food intake, histology of heart, growth, spleen, kidney, or hematological parameters 101. Eckert et al. 102 after giving bromelain (3000 FIP unit/day [FIP is an enzyme unit that produces a certain amount of enzymatic activity]) to human over a period of ten days found no significant changes in blood coagulation parameters.

  1. Pavan R, Jain S, Shraddha, Kumar A. Properties and Therapeutic Application of Bromelain: A Review. Biotechnology Research International. 2012;2012:976203. doi:10.1155/2012/976203.[]
  2. Mondal S, Bhattacharya S, Pandey JN, Biswas M. Evaluation of acute anti-inflametry effect of Ananas Comosus leaf extract in Rats. Pharmocologyonline. 2011;3:1312–1315.[]
  3. Heinicke RM, Gortner WA. Stem bromelain: a new protease preparation from pineapple plants. Economic Botany. 1957;11(3):225–234.[]
  4. Bhattacharyya BK. Bromelain: an overview. Natural Product Radiance. 2008;7(4):359–363.[]
  5. Pineapple cysteine endopeptidases. Rowan AD, Buttle DJ. Methods Enzymol. 1994; 244():555-68.[]
  7. Proteinase activity and stability of natural bromelain preparations. Hale LP, Greer PK, Trinh CT, James CL. Int Immunopharmacol. 2005 Apr; 5(4):783-93.[]
  8. Devakate RV, Patil VV, Waje SS, Thorat BN. Purification and drying of bromelain. Separ Purif Tech. 2009;64:259–264. doi: 10.1016/j.seppur.2008.09.012.[]
  9. Bromelain: biochemistry, pharmacology and medical use. Maurer HR. Cell Mol Life Sci. 2001 Aug; 58(9):1234-45.[][][]
  10. Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Castell JV, Friedrich G, Kuhn CS, Poppe GE. Am J Physiol. 1997 Jul; 273(1 Pt 1):G139-46.[][][]
  11. [Effect of phlogenzym in long-term treatment of patients with multiple sclerosis]. Mialovyts’ka OA. Lik Sprava. 2003 Apr-Jun; (3-4):109-13.[]
  12. Bioavailability of 125I bromelain after oral administration to rats. White RR, Crawley FE, Vellini M, Rovati LA. Biopharm Drug Dispos. 1988 Jul-Aug; 9(4):397-403.[]
  13. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update. Taussig SJ, Batkin S. J Ethnopharmacol. 1988 Feb-Mar; 22(2):191-203.[]
  14. Cell signaling pathways altered by natural chemopreventive agents. Sarkar FH, Li Y. Mutat Res. 2004 Nov 2; 555(1-2):53-64.[]
  15. [Absorption of a proteolytic enzyme originating from plants out of the gastro-intestinal tract into blood and lymph of rats (author’s transl)]. Seifert J, Ganser R, Brendel W. Z Gastroenterol. 1979 Jan; 17(1):1-8.[]
  16. Shiew PS, Fang YL, Majid FAA. In vitro study ofbromelain activity inartificial stomach juiceand blood. Proceedings of the 3rd International Conference on Biotechnology for the Wellness Industry; 2010; PWTC[]
  17. Livio M, Gaetano GDe, Donati MB. Effect of bromelain of fibrinogen level, protrombin complex and platelet aggregation in the rat-a preliminary report. Drugs under Experimental and Clinical Research. 1978;1:49–53.[]
  18. A plant protease for potentiation of and possible replacement of antibiotics. NEUBAUER RA. Exp Med Surg. 1961; 19():143-60.[]
  19. Tochi BN, Wang Z, Xu SY, Zhang W. Therapeutic application of pineapple protease (Bromelain): a review. Pakistan Journal of Nutrition. 2008;7(4):513–520.[]
  20. The mechanism of the physiological action of bromelain. Taussig SJ. Med Hypotheses. 1980 Jan; 6(1):99-104.[]
  21. Proteolytic activity and immunogenicity of oral bromelain within the gastrointestinal tract of mice. Hale LP. Int Immunopharmacol. 2004 Feb; 4(2):255-64.[]
  22. A review of the use of bromelain in cardiovascular diseases. Ley CM, Tsiami A, Ni Q, Robinson N. Zhong Xi Yi Jie He Xue Bao. 2011 Jul; 9(7):702-10.[]
  23. Bromelain’s activity and potential as an anti-cancer agent: Current evidence and perspectives. Chobotova K, Vernallis AB, Majid FA. Cancer Lett. 2010 Apr 28; 290(2):148-56.[][]
  24. Herbal Medicines for the Treatment of Rhinosinusitis: A Systematic Review. Otolaryngology—Head and Neck Surgery. 2006;135(4):496-506.[]
  25. Passali D, Bellussi LM, Sarafoleanu C, et al. Penetration of Bromelain in Serum and Rhinosinusal Mucosa in Patients Undergoing Endoscopic Sinus Surgery. Journal of Pharmacology & Pharmacotherapeutics. 2017;8(3):128-129. doi:10.4103/jpp.JPP_169_16.[]
  26. Huang JR, Wu CC, Hou RC, Jeng KC. Bromelain inhibits lipopolysaccharide-induced cytokine production in human THP-1 monocytes via the removal of CD14. Immunol Invest. 2008;37:263–277. doi: 10.1080/08820130802083622.[]
  27. Bhui K, Prasad S, George J, Shukla Y. Bromelain inhibits COX-2 expression by blocking the activation of MAPK regulated NF-kappa B against skin tumor-initiation triggering mitochondrial death pathway. Cancer Lett. 2009;282:167–176. doi: 10.1016/j.canlet.2009.03.003.[]
  28. Gaspani L, Limiroli E, Ferrario P, Bianchi M. In vivo and in vitro effects of bromelain on PGE(2) and SP concentrations in the inflammatory exudate in rats. Pharmacology. 2002;65:83–86. doi: 10.1159/000056191.[]
  29. Desser L, Rehberger A, Paukovits W. Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro. Cancer Biother. 1994;9:253–263. doi: 10.1089/cbr.1994.9.253.[]
  30. Engwerda CR, Andrew D, Murphy M, Mynott TL. Bromelain activates murine macrophages and natural killer cells in vitro. Cell Immunol. 2001;210:5–10. doi: 10.1006/cimm.2001.1793.[]
  31. Onken JE, Greer PK, Calingaert B, Hale LP. Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol. 2008;126:345–352. doi: 10.1016/j.clim.2007.11.002.[]
  32. Stopper H, Schinzel R, Sebekova K, Heidland A. Genotoxicity of advanced glycation end products in mammalian cells. Cancer Lett. 2003;190:151–156. doi: 10.1016/S0304-3835(02)00626-2.[][][]
  33. Subramaniam V, Gardner H, Jothy S. Soluble CD44 secretion contributes to the acquisition of aggressive tumor phenotype in human colon cancer cells. Exp Mol Pathol. 2007;83:341–346. doi: 10.1016/j.yexmp.2007.08.007.[]
  34. Massagué J. TGFbeta in Cancer. Cell. 2008;134:215–230. doi: 10.1016/j.cell.2008.07.001.[]
  35. Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic disorders. BioDrugs. 2001;15:779–789. doi: 10.2165/00063030-200115120-00001.[]
  36. Vellini M, Desideri D, Milanese A, Omini C, Daffonchio L, Hernandez A, Brunelli G. Possible involvement of eicosanoids in the pharmacological action of bromelain. Arzneimittelforschung. 1986;36:110–112.[]
  37. Moss JN, Frazier CV, Martin GJ. Bromelains. The pharmacology of the enzymes. Arch Int Pharmacodyn Ther. 1963;145:166–189. []
  38. De-Giuli M, Pirotta F. Bromelain, interaction with some protease inhibitor and rabbit specific antiserum. Drugs Exp Clin Res. 1978;4:21–23.[]
  39. Chobotova K, Vernallis AB, Majid FAA. Bromelain’s activity and potential as an anti-cancer agent: current evidence and perspectives. Cancer Letters. 2010;290(2):148–156.[]
  40. Béez R, Lopes MTP, Salas CE, Hernández M. In vivo antitumoral activity of stem pineapple (Ananas comosus) bromelain. Planta Medica. 2007;73(13):1377–1383.[]
  41. Taussig SJ, Szekerczes J, Batkin S. Inhibition of tumour growth in vitro by bromelain, an extract of the pineapple plant (Ananas comosus) Planta Medica. 1985;6:538–539.[]
  42. Tysnes BB, Maurer HR, Porwol T, Probst B, Bjerkvig R, Hoover F. Bromelain reversibly inhibits invasive properties of glioma cells. Neoplasia. 2001;3(6):469–479.[]
  43. Béez R, Lopes MTP, Salas CE, Hernández M. In vivo antitumoral activity of stem pineapple (Ananas comosus) bromelain. Planta Medica. 2007;73(13):1377–1383.[][][]
  44. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444.[]
  45. Wang MT, Honn KV, Nie D. Cyclooxygenases, prostanoids, and tumor progression. Cancer and Metastasis Reviews. 2007;26(3-4):525–534.[]
  46. Bhui K, Prasad S, George J, Shukla Y. Bromelain inhibits COX-2 expression by blocking the activation of MAPK regulated NF-kappa B against skin tumor-initiation triggering mitochondrial death pathway. Cancer Letters. 2009;282(2):167–176.[]
  47. Huang JR, Wu CC, Hou RCW, Jeng KC. Bromelain inhibits lipopolysaccharide-induced cytokine production in human THP-1 monocytes via the removal of CD14. Immunological Investigations. 2008;37(4):263–277.[]
  48. Mynott TL, Guandalini S, Raimondi F, Fasano A. Bromelain prevents secretion caused by Vibrio cholerae and Escherichia coli enterotoxins in rabbit ileum in vitro. Gastroenterology. 1997;113:175–184. doi: 10.1016/S0016-5085(97)70093-3.[]
  49. Chandler DS, Mynott TL. Bromelain protects piglets from diarrhoea caused by oral challenge with K88 positive enterotoxigenic Escherichia coli. Gut. 1998;43:196–202. doi: 10.1136/gut.43.2.196.[]
  50. Stepek G, Lowe AE, Buttle DJ, Duce IR, Behnke JM. In vitro and in vivo anthelmintic efficacy of plant cysteine proteinases against the rodent gastrointestinal nematode, Trichuris muris. Parasitology. 2006;132:681–689. doi: 10.1017/S003118200500973X.[]
  51. Brakebusch M, Wintergerst U, Petropoulou T, Notheis G, Husfeld L, Belohradsky BH, Adam D. Bromelain is an accelerator of phagocytosis, respiratory burst and Killing of Candida albicans by human granulocytes and monocytes. Eur J Med Res. 2001;6:193–200.[]
  52. Massimiliano R, Pietro R, Paolo S, Sara P, Michele F. Role of bromelain in the treatment of patients with pityriasis lichenoides chronica. J Dermatolog Treat. 2007;18:219–222. doi: 10.1080/09546630701299147.[]
  53. Shahid SK, Turakhia NH, Kundra M, Shanbag P, Daftary GV, Schiess W. Efficacy and safety of phlogenzym – a protease formulation, in sepsis in children. J Assoc Physicians India. 2002;50:527–531.[][]
  54. Neubauer RA. A plant protease for potentiation of and possible replacement of antibiotics. Exp Med Surg. 1961;19:143–160.[]
  55. Ryan RE. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache. 1967;7:13–17. doi: 10.1111/j.1526-4610.1967.hed0701013.x.[]
  56. Mori S, Ojima Y, Hirose T, Sasaki T, Hashimoto Y. The clinical effect of proteolytic enzyme containing bromelain and trypsin on urinary tract infection evaluated by double blind method. Acta Obstet Gynaecol Jpn. 1972;19:147–153.[]
  57. Glade MJ, Kendra D, Kaminski MV., Jr Improvement in protein utilization in nursing-home patients on tube feeding supplemented with an enzyme product derived from Aspergillus niger and bromelain. Nutrition. 2001;17:348–350. doi: 10.1016/S0899-9007(01)00528-7. []
  58. Knill-Jones RP, Pearce H, Batten J, Williams R. Comparative trial of Nutrizym in chronic pancreatic insufficiency. BMJ. 1970;4:21–24. doi: 10.1136/bmj.4.5726.21.[]
  59. Balakrishnan V, Hareendran A, Nair CS. Double-blind cross-over trial of an enzyme preparation in pancreatic steatorrhoea. J Assoc Physicians India. 1981;29:207–209.[]
  60. Pellicano R, Strona S, Simondi D, Reggiani S, Pallavicino F, Sguazzini C, Bonagura AG, Rizzetto M, Astegiano M. Benefit of dietary integrators for treating functional dyspepsia: a prospective pilot study. Minerva Gastroenterol Dietol. 2009;55:227–235.[]
  61. Neumayer C, Fügl A, Nanobashvili J, et al. Combined enzymatic and antioxidative treatment reduces ischemia-reperfusion injury in rabbit skeletal muscle. Journal of Surgical Research. 2006;133(2):150–158.[]
  62. World Health Organization. Cardiovascular diseases.[]
  63. Heinicke RM, van der Wal L, Yokoyama M. Effect of bromelain (Ananase) on human platelet aggregation. Experientia. 1972;28(10):844–845.[]
  64. King DE, Ellis TM, Everett CJ, Mainous AG. Medication use for diabetes, hypertension, and hypercholesterolemia from1988–1994 to 2001–2006. Southern Medical Journal. 2009;102(11):1127–1132.[]
  65. Secor ER, Jr., William FC, Michelle MC, et al. Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murin model of allergic disease. Cellular Immunology. 2005;237:68–75.[]
  66. Juhasz B, Thirunavukkarasu M, Pant R, et al. Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium. American Journal of Physiology. 2008;294(3):H1365–H1370.[]
  67. Lawrence RC, Helmich CG, Arnett F, et al. Estimates of prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis & Rheumatism. 1998;41:778–799.[]
  68. Akhtar NM, Naseer R, Farooqi AZ, Aziz W, Nazir M. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—a double-blind prospective randomized study. Clinical Rheumatology. 2004;23(5):410–415.[]
  69. Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a treatment for osteoarthritis: a review of clinical studies. Evidence-Based Complementary and Alternative Medicine. 2004;1(3):251–257.[][]
  70. Bellamy N, Buchanan W, Goldsmith C, Campbell J, Stitt L. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to anti-rheumatic drug therapy in patients with osteoarthritis of the hip or knee. Rheumatology. 1988;15:1833–1840.[]
  71. Bodi T. The effects of oral bromelains on tissue permeability to antibiotics and pain responseto bradykinin: double blind studies on human subjects. Clinical Medicine. 1966;73:61–65.[]
  72. Cohen A, Goldman J. Bromelain therapy in rheumatoid arthritis. Pennsylvania Medical Journal. 1964;67:27–30.[]
  73. Barth H, Guseo A, Klein R. In vitro study on the immunological effect of bromelain and trypsin on mononuclear cells from humans. European Journal of Medical Research. 2005;10(8):325–331.[]
  74. Hale LP, Haynes BF. Bromelain treatment of human T cells removes CD44, CD45RA, E2/MIC2, CD6, CD7, CD8, and Leu 8/LAM1 surface molecules and markedly enhances CD2-mediated T cell activation. Journal of Immunology. 1992;149(12):3809–3816.[]
  75. Targeting TNF-α for the treatment of inflammatory bowel disease. Billiet T, Rutgeerts P, Ferrante M, Van Assche G, Vermeire S. Expert Opin Biol Ther. 2014 Jan; 14(1):75-101.[]
  76. Protective effect of naringenin against experimental colitis via suppression of Toll-like receptor 4/NF-κB signalling. Dou W, Zhang J, Sun A, Zhang E, Ding L, Mukherjee S, Wei X, Chou G, Wang ZT, Mani S. Br J Nutr. 2013 Aug; 110(4):599-608.[][]
  77. Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Blair SA, Kane SV, Clayburgh DR, Turner JR. Lab Invest. 2006 Feb; 86(2):191-201.[]
  78. Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis. Suzuki M, Nagaishi T, Yamazaki M, Onizawa M, Watabe T, Sakamaki Y, Ichinose S, Totsuka M, Oshima S, Okamoto R, Shimonaka M, Yagita H, Nakamura T, Watanabe M. PLoS One. 2014; 9(2):e88369.[]
  79. Capsaicin alleviates abnormal intestinal motility through regulation of enteric motor neurons and MLCK activity: Relevance to intestinal motility disorders. Chen D, Xiong Y, Lin Y, Tang Z, Wang J, Wang L, Yao J. Mol Nutr Food Res. 2015 Aug; 59(8):1482-90.[]
  80. Potential role of bromelain in clinical and therapeutic applications. Rathnavelu V, Alitheen NB, Sohila S, Kanagesan S, Ramesh R. Biomed Rep. 2016 Sep; 5(3):283-288.[]
  81. Mynott TL, Ladhams A, Scarmato P, Engwerda CR. Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells. Journal of Immunology. 1999;163(5):2568–2575.[]
  82. Secor ER, Jr., Singh A, Guernsey LA, et al. Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro. International Immunopharmacology. 2009;9(3):340–346.[]
  83. Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic disorders. BioDrugs. 2002;15(12):779–789.[]
  84. Lotz-Winter H. On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects. Planta Medica. 1990;56(3):249–253.[]
  85. Livio M, De Gaetano G, Donati MB. Effect of bromelain on fibrinogen level, prothrombin complex factors and platelet aggregation in rat: a preliminary report. Drugs under Experimental and Clinical Research. 1978;4:21–23.[]
  86. De-Guili M, Pirotta F. Bromelain: interaction with some protease inhibitors and rabbit specific antiserum. Drugs under Experimental and Clinical Research. 1978;4:21–23.[]
  87. Mynott TL, Guandalini S, Raimondi F, Fasano A. Bromelain prevents secretion caused by Vibrio cholerae and Escherichia coli enterotoxins in rabbit ileum in vitro. Gastroenterology. 1997;113(1):175–184.[]
  88. Chandler DS, Mynott TL. Bromelain protects piglets from diarrhoea caused by oral challenge with K88 positive enterotoxigenic Escherichia coli. Gut. 1998;43(2):196–202.[]
  89. Tassman GC, Zafran JN, Zayon GM. A double-blind crossover study of a plant proteolytic enzyme in oral surgery. The Journal of Dental Medicine. 1965;20:51–54.[]
  90. Howat RCL, Lewis GD. The effect of bromelain therapy on episiotomy wounds—a double blind controlled clinical trial. Journal of Obstetrics and Gynaecology of the British Commonwealth. 1972;79(10):951–953. []
  91. Houck JC, Chang CM, Klein G. Isolation of an effective debriding agent from the stems of pineapple plants. International Journal of Tissue Reactions. 1983;5(2):125–134.[]
  92. Rosenberg L, Krieher Y, Silverstain E, et al. Selectivity of a Bromelain Based Enzymatic Debridement Agent: A Porcine Study. Elsevier; 2012.[]
  93. Singer AJ, McClain SA, Taira BR, Rooney J, Steinhauff N, Rosenberg L. Rapid and selective enzymatic debridement of porcine comb burns with bromelain-derived Debrase: acute-phase preservation of noninjured tissue and zone of stasis. Journal of Burn Care and Research. 2010;31(2):304–309.[]
  94. Wu SY, Hu W, Zhang B, Liu S, Wang JM, Wang AM. Bromelain ameliorates the wound microenvironment and improves the healing of firearm wounds. Journal of Surgical Research. 2012;176:503–509.[]
  95. Hu W, Wang AM, Wu SY, et al. Debriding effect of bromelain on firearm wounds in pigs. The Journal of Trauma. 2011;71(4):966–972.[]
  96. Sheridan RL, Tompkins RG, Burke JF. Management of burn wounds with prompt excision and immediate closure. Journal of Intensive Care Medicine. 1994;237:68–75.[]
  97. [Drug therapy of activated arthrosis. On the effectiveness of an enzyme mixture versus diclofenac]. inger F, Oberleitner H. Wien Med Wochenschr. 1996; 146(3):55-8.[]
  98. Efficacy and tolerability of oral enzyme therapy as compared to diclofenac in active osteoarthrosis of knee joint: an open randomized controlled clinical trial. Tilwe GH, Beria S, Turakhia NH, Daftary GV, Schiess W. J Assoc Physicians India. 2001 Jun; 49():617-21.[]
  99. Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evidence-based Complementary and Alternative Medicine. 2004;1(3):251-257. doi:10.1093/ecam/neh035.[]
  100. Taussig SJ, Yokoyama MM, Chinen A. Bromelain: a proteolytic enzyme and its clinical application: a review. Hiroshima Journal of Medical Sciences. 1975;24(2-3):185–193.[]
  101. Moss IN, Frazier CV, Martin GJ. Bromelain -the pharmacology of the enzyme. Archives of International Pharmacody. 1963;145:166–189. []
  102. Eckert K, Grabowska E, Stange R, Schneider U, Eschmann K, Maurer HR. Effects of oral bromelain administration on the impaired immunocytotoxicity of mononuclear cells from mammary tumor patients. Oncology Reports. 1999;6(6):1191–1199.[]
Health Jade