bromelain

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

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 11). 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 12). The highest concentration of bromelain was identified in the blood one hour after administration 13). Bromelain increases bioavailability and reduces the side effects that are associated with various antibiotics 14). Furthermore, bromelain acts as an immunomodulator, is anti-metastatic, anti-edematous, anti-thrombotic and anti-inflammatory 15). 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 16). 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 17). In a study carried out by Castell et al. 18) 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 19).

Bromelain benefits

A wide range of therapeutic benefits have been claimed for bromelain, such as reversible inhibition of platelet aggregation, sinusitis, surgical traumas 20), 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] 21), and enhanced absorption of drugs, particularly of antibiotics 22). 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 23). Bromelain acts on fibrinogen giving products that are similar, at least in effect, to those formed by plasmin 24). Experiment in mice showed that antacids such as sodium bicarbonate preserve the proteolytic activity of bromelain in the gastrointestinal tract 25). 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 26). Existing evidence indicates that bromelain can be a promising candidate for the development of future oral enzyme therapies for cancer patients 27). Bromelain can be absorbed in human intestines without degradation and without losing its biological activity 28).

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 29) 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 30) 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 31). 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 32). COX-2 converts arachidonic acid into PGE-2 and promotes tumor angiogenesis and cancer progression 33). It has been shown that bromelain downregulates COX-2 and PGE-2 expression levels in murine microglial cells and human monocytic leukemia cell lines 34). 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 35). 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 36). Studies have shown that bromelain reduced the expression of INF-γ and TNF-α in inflammatory bowel disease 37). 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 38) and controlled the inflammation 39). 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 40). 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 41). 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 42). There are various studies that report the immunomodulatory effect of bromelain 43). 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 44). Thus, bromelain decreases the majority of inflammatory mediators and has demonstrated a significant role as an anti-inflammatory agent in various conditions 45).

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 46). 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 47) 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 48) while in another study bromelain reduced the invasive capacity of glioblastoma cells and reduced de novo protein synthesis 49). Bromelain is found to increase the expression of p53 and Bax in mouse skin, the well-known activators of apoptosis 50). 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 51). Cox-2, a multiple target gene of NF-κB, facilitates the conversion of arachidonic acid into PGE2 and thus promotes tumour angiogenesis and progression 52). 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 53) and in models of skin tumourigenesis 54). 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 55). 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 56).

Antimicrobial activity

Bromelain supplementation protects animals against diarrhea caused by bacterial enterotoxins from Escherichia coli and Vibrio cholerae 57). Bromelain acts as anti-adhesion agent by modifying the receptor attachment sites and influences the intestinal secretory signaling pathways 58). 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 59). Conversely, bromelain acts as an anti-fungal agent by stimulating phagocytosis and respiratory burst killing of Candida albicans when incubated with trypsin in vitro 60). Pityriasis lichenoides chronica is an infectious skin disease and bromelain reportedly caused complete resolution of this condition 61). Bromelain has been documented to increase blood and urine levels of certain antibiotics in humans 62). 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 63), sinusitis 64) and urinary tract infections 65). A combination of bromelain, trypsin, and rutin has been administered as an adjuvant therapy in combination with antibiotics for children with sepsis 66). A combination of bromelain with enzymes derived from Aspergillus niger improved protein utilization in elderly nursing home patients 67). Another study demonstrated that bromelain, in combination with sodium alginate, sodium bicarbonate and essential oils, significantly improved dyspeptic symptoms 68). In addition, bromelain has been administered successfully as a digestive enzyme to treat intestinal disorders, pancreatectomy and exocrine pancreas insufficiency 69). 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 70).

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 71). 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 72). 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 73). King et al. 74) 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 75). 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 76).

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 77). 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 78). Bromelain is a food supplement that may provide an alternative treatment to nonsteroidal anti-inflammatory drug (NSAIDs) 79). It plays an important role in the pathogenesis of arthritis 80). Bromelain has analgesic properties which are thought to be the result of its direct influence on pain mediators such as bradykinin 81). The earliest reported studies investigating bromelain were a series of case reports on 28 patients, with moderate or severe rheumatoid or osteoarthritis 82).

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 83). 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 84). 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 85). 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 86). Both iNOS and COX2 are pro-inflammatory mediators which play crucial roles in inflammatory responses 87). 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 88). Myosin light chain kinase-induced phosphorylation of perijunctional actomyosin mediates tight junction loss, which triggers the initiation and development of inflammatory bowel disease (IBD) 89). 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 90). Oral administration of bromelain relieved IBD symptoms 91); 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 92). Treatment of cells with bromelain decreases the activation of CD4 (+) T cells and reduce the expression of CD25 93). 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 94).

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 95). 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 96). 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 97).

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 98). 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 99).

Bromelain in Surgery

Administration of bromelain before a surgery can reduce the average number of days for complete disappearance of pain and postsurgery inflammation 100). Trials indicate that bromelain might be effective in reducing swelling, bruising, and pain in women having episiotomy 101). Nowadays, bromelain is used for treating acute inflammation and sports injuries 102).

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 103). 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 104), 105). 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 106). 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 107), 108).

Bromelain side effects

Studies that have used a higher daily dose of bromelain to treat osteoarthritis [945 mg/day 109); 1890 mg/day 110)] 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) 111).

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. 112) 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 113). Eckert et al. 114) 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.

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