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Therapeutic Application of Pineapple Protease (Bromelain): A Review

Authors:

Abstract

Bromelain (EC 3.4.22.32) is a crude extract from the pineapple ( Ananas comosus ) plant that contains, among other components various closely related proteinases (stem bromelain, fruit bromelain, comosain and ananain) demonstrating both in vitro and in vivo several therapeutic properties including malignant cell growth, thrombus formation, inflammation, control of diarrhoea, dermatological and skin debridement among others. Bromelain also contains peroxidase, acid phosphatase, several protease inhibitors and organically bound calcium and remains stable over a wide range of pH 2 to 9. Available evidence indicates bromelain is well absorbed orally with its therapeutic effects being enhanced in a dose dependent manner. It has been demonstrated to be safe and an effective food supplement. However, all the mechanisms of its action remain unresolved.
Pakistan Journal of Nutrition 7 (4): 513-520, 2008
ISSN 1680-5194
© Asian Network for Scientific Information, 2008
513
Therapeutic Application of Pineapple Protease (Bromelain): A Review
Bitange Nipa Tochi , Zhang Wang , Shi - Ying Xu and Wenbin Zhang
1, 2 1 1 1
Department of Food Science and Engineering, School of Food Science and Technology,
1
Jiangnan University, Wuxi 214122, PR China
Pwani University College - Formerly Kilifi Institute of Agriculture, P.O. Box: 195, Kilifi, Kenya, East Africa
2
Abstract: Bromelain (EC 3.4.22.32) is a crude extract from the pineapple (Ananas comosus) plant that
contains, among other components various closely related proteinases (stem bromelain, fruit bromelain,
comosain and ananain) demonstrating both in vitro and in vivo several therapeutic properties including
malignant cell growth, thrombus formation, inflammation, control of diarrhoea, dermatological and skin
debridement among others. Bromelain also contains peroxidase, acid phosphatase, several protease
inhibitors and organically bound calcium and remains stable over a wide range of pH 2 to 9. Available
evidence indicates bromelain is well absorbed orally with its therapeutic effects being enhanced in a dose
dependent manner. It has been demonstrated to be safe and an effective food supplement. However, all the
mechanisms of its action remain unresolved.
Key words: Bromelain, pineapple, proteinases, inflammation
Introduction
Pineapple (Ananas comosus) native to Central and
South America, is grown in several tropical and sub-
tropical countries including Hawaii, India, China, Kenya,
South Africa, Malaysia, the Philippines and Thailand.
It has been used as a medicinal plant in several native
cultures and bromelain has been chemically known
since 1876 (Peckoldt et al., In: Taussig, 1988).
Bromelain obtained from the stems of the pineapple
plant contains all the soluble components of the
pineapple stem in their original properties, which may
involve malignant cell growth, thrombus formation,
inflammation, control of diarrhoea, dermatological and
skin debridement (Cohen, 1964; Taussig and Batkin,
1988; Kelly, 1996; Maurer, 2001).
Heinecke and Gortner (1957) found that bromelain
concentrations is high in pineapple stems necessitating
its extraction and use as a phytomedical compound
because unlike the pineapple fruit which is normally
used as food, the stems are a waste by-product and
thus inexpensive.
The main proteolytic constituents contained in
pharmacological preparations or food supplements of
bromelain (stem bromelain, fruit bromelain and
ananain) are also present in the pineapple fruit (Hale et
al., 2005). Bromelain’s primary component is a
Sulfhydryl proteolytic fraction. Bromelain also contains a
Peroxidase, acid Phosphatase, several protease
inhibitors and organically bound calcium (Kelly, 1996).
Bromelain activity is stable over a wide pH range
(Cohen, 1964; Taussig and Batkin, 1988; Kelly, 1996;
Maurer, 2001; Heinecke and Gortner, 1957; Hale et al.,
2005; Mynott et al., 1999; Cooreman et al., 1976).
Therefore it may not be necessary to enteric-protect the
protease from acid conditions in the stomach. However,
it may be necessary to protect the enzyme from digestion
by acid proteases in the gut. It may be administered with
a buffering agent, for example bicarbonate or in water or
in a solution containing nutrients to assist with
absorption of fluid and nutrients (Mynott et al., 1999).
Several studies have been carried out and results
generated indicate bromelain has useful phytomedical
applications. However, these results are yet to be
amalgamated and critically compared so as to chat the
way forward as to whether bromelain will gain wide
acceptance as a phytomedical supplement. The
purpose of the present paper is to highlight some
relevant contributions regarding bromelain’s
phytomedical applications that have been reported in
recent times.
Anti - inflammatory agent: Botanicals such as Ananas
comosus (Pineapple) and their extracts (bromelain) have
been used clinically as anti-inflammatory agents in
rheumatoid arthritis, soft tissue injuries, colonic
inflammation, chronic pain and asthma (Taussig and
Batkin, 1988; Kelly, 1996; Maurer, 2001; Cooreman et al.,
1976; Izaka et al., 1972; Hale et al., 2005; Jaber, 2002)
and are currently in use as anti-inflammatory agents
(Ammon, 2002; Lemay et al., 2004; Darshan and
Doreswamy, 2004).
The major mechanism of action of bromelain appears to
be proteolytic in nature, although evidence also
suggests an immunomodulatory and hormone like
activity acting via intracellular signalling pathways. In
vitro studies have shown that bromelain can inhibit pre-
incubated with medium alone (PMA) - induced T cell
production of the Th cytokine IL - 4 and to a lesser
2
degree the Th cytokines IL-2 and induced interferon-
1
gamma (IFN-() via modulation of the extracellular
Tochi et al.: Bromelain’s Pharmacology
514
regulated kinase-2 (ERK-2) intracellular signallingprotection techniques. These results could explain
pathway (Mynott et al., 1999). Bromelain has also beenearlier reports that bromelain decreased intestinal
shown to reduce cell surface receptors such asinflammation in human with UC (Kane and Goldberg,
hyaluronan receptor CD44, which is associated with2000).
leukocyte migration and induction of proinflammatoryWalker et al. (2002), in their pilot study while
mediators (Engwerda et al., 2001; Eckert et al., 1999;investigating the effect of bromelain on acute knee pain,
Hale et al., 2002). Manhart et al. (2002) have shownreported significant improvement after a month’s
bromelain to significantly reduce CD4 T lymphocytes,intervention. These results were consistent with earlier
+
which are primary effectors in animal models ofreports of bromelain supplementation (Uhlig, 1981;
inflammation. Vogler, 1988; Lotti et al., 1993) even though they could
Beneficial effects of bromelain have been suggested ornot be compared directly. Meanwhile Akhtar et al. (2004)
proven in a variety of inflammatory disease and animalin their study where they assessed the efficacy of an oral
models of inflammation. These include immunologicallyenzyme combination (ERC: Enzyme-rutin combination
mediated arteriosclerosis in rat aortic allograftswhich contains rutin and enzymes bromelain and
(Gaciong et al., 1996), the experimental allergictrypsin) versus diclofenac (a non-steroidal anti-
encephalomyelitis (EAE) model for the humaninflammatory drug-NSAID) among patients with knee
autoimmune disease multiple sclerosis (Targoni et al.,osteoarthritis (OA) in a double blind randomized version,
1999; Hale et al., 2005), IgE- mediated perennial allergic found ERC to be as equally efficacious to diclofenac.
rhinitis (Thornhill and Kelly, 2000) and collagen-inducedThese results are consistent with those reported earlier
arthritis in the rat (Rovenska et al., 2001). In their studyby (Vogler, 1988; Klein and Kullich, 2000; Tilwe et al.,
on bromelain’s anti-inflammatory effects in an2001). More so, unlike diclofenac, which exhibits
ovalbumin - induced murine model of allergic airwayinherent toxicities, ERC has a well known superior safety
disease (AAD), Secor et al. (2005) observed thatand tolerable profile (Akhtar et al., 2004).
bromelain demonstrated both anti-inflammatory and
immunomodulatory effects. In this particular study, theyBromelain as an anti-tumour agent: Pharmacological
found that bromelain treatment significantly reduced theagents with modulation of anti-inflammatory, proteolytic,
primary outcomes of murine AAD: Total bronchoalveolar platelet aggregation inhibition and prostaglandin
lavage (BAL) leukocytes (eosinophilis and lymphocytes), synthesis have been considered to be beneficial in
IL-13, CD4 T cells, CD8 T cells and CD4 CD25 T regulating tumour growth and its metastasis (Batkin et
+ + + +
cells, while also altering the CD4 /CD8 ratio. Theseal., 1985; Honn, 1983; Sato et al., 1983). Bromelain, with
+ +
findings indicate that systemic bromelain treatmentsimilar regulating actions, has shown protective
reduces an allergen induced localized airwayproperties on tumour cell growth retardation and lung
inflammatory process. metastasis (Batkin et al., 1985; Batkin et al., 1988a;
Kane and Goldberg (2000) gave a description of twoBatkin et al., 1988b; Taussig and Batkin, 1988).
patients suffering from ulcerative colitis (UC) that wasBatkin et al. (1988b) while studying the antimetastatic
refractory to conventional treatment, who rapidly entered effect of bromelain with or without its proteolytic and
and remained in clinical and endoscopic remission afteranticoagulant activities in the animal model of Lewis
self treatment with oral bromelain obtained from alung carcinoma, reported significant reduction in total
healthy food store. Studies by Hale (2004) show thatnumber of metastasis in both active and inactive
daily treatment with 5mg of oral bromelain significantlybromelain as compared to control groups. This
decreased spontaneous colon inflammation in IL-10 phenomenon had been reported earlier by Batkin et al.
-1-
mice. They further did show that anti-inflammatory activity (1985) whose study of three cell lines was done in vitro.
of bromelain is dependent on its proteolytic activity. In both studies, they conclude that bromelain could be
Wen et al. (2006) while studying the effect of bromelainhaving other pharmacological entities besides its
on postoperative defecation in rats, supports Hale’srecognized proteolytic anticoagulant functions.
(2004) findings that proteolytic activity of bromelain in the Recently, study results reported by researchers at the
colonic micro-environment is not only responsible for itsQueensland Institute of Medical Research-QIMR (QIMR,
anti-inflammatory activity but may be involved in the2005), give a window of hope for this phenomenon.
improvement of post operative ileus. That orallyWhile studying bromelain, researchers at QIMR reported
administered bromelain retains its proteolytic activity,the discovery of two proteins they named CCS and CCZ
was previously documented only in the small intestine and found that they could block growth of a broad range
of pigs (Mynott et al., 1996; Chandler and Mynott, 1998). of tumour cells including breast, lung, colon, ovarian and
The bromelain used in this study was enterically melanoma. However, the study is on going and these
protected. In his studies however, Hale (2004)results are not reliable at the moment. Batkin et al. (1985
showed that oral bromelain retains its proteolytic activityand 1988a) noted that in vitro Lewis lung cancer cell
throughout the entire gastrointestinal tract of mice in thegrowth retardation was a necessary correlate to
absence of encapsulation or other classic entericantimetastatic activity. In this regard therefore,
Tochi et al.: Bromelain’s Pharmacology
515
peroxidase and proteolytic anticoagulant activities maycapable of inhibiting both platelet aggregation in vitro
not be relevant features of bromelain’s antimetastaticand in vivo, as well as platelet-stimulated invasiveness
potential. of tumour cells. Thus what was described and used as
Maurer et al. (1988) found that bromelain may inducefolk medicine by the natives of the tropics over a Century
differentiation of leukemic cells in vitro and proposedago as over time been confirmed to have
this phenomenon as a possible mechanism of action.pharmaceutical applications. However, more research
In their studies, Grabowska et al. (1997) found thatis required to determine the structure and characteristics
B16F10 mouse melanoma cells, pre-incubated in vitroof the two compounds (CCS and CCZ) that were
with bromelain, significantly reduced lung metastaticreported by researchers at the QIMR (QIMR, 2005).
tumour weight to about three times. However, no survival
benefit was seen. Furthermore bromelain diminishedBromelain promotes debridement of burns: Burns are
the capacity of these cells to migrate through ancharacterized by formation of an eschar, which is made
extracellular matrix layer in an in vitro invasion assay and up of burned and traumatized tissue. The eschar not
inhibited the growth of tumour cells in a concentrationonly hinders accurate diagnosis of the burn’s depth but
dependent manner, whereas the anti-proliferation effectalso serves as a medium for bacterial growth and
did not correlate with the proteolytic activity. Earliertherefore a source of infection, contamination and
studies by Goldstein et al. (1975) and Taussig andsepsis of the injury and to the neighbouring originally
Goldstein (1976) reported that bromelain feedingundamaged tissues (Rosenberg et al., 2004). Rapid
enhanced the resistance of mice to the harmful effect ofdebridement considerably reduces morbidity and
UV (Ultra Violet) irradiation. It took twice as long for themortality of severely burned patients. It permits early skin
bromelain fed group to develop pre-cancerous lesionsgrafting and lessens the problems of infection,
as compared to the control group. Finally, humancontamination and sepsis thus abbreviating the
platelets pre-treated in vitro with bromelain lost theirconvalescence period (Maurer, 2001; Sheridan et al.,
capacity to stimulate the invasiveness of several1994; Sheridan et al., 1998; Prasanna et al., 1994;
metastatic tumour cells in the in vitro invasion assay.Monafo, 1974; Nada et al., 1998).
Meanwhile it has been shown that metastasized cells,While surgical debridement is non-selective, chemical
while migrating through the vessels, carry CD44debridement removes only the burned denatured skin
adhesion molecules on their surface by which they(Maurer, 2001; Sheridan et al., 1994; Janzekovic, 1970;
adhere to endothelial cells via the ligand hyaluron.Salisbury, 1990; Miller et al., 1992). Furthermore,
Bromelain preferentially cleaves off CD44 molecules bysurgical excision is painful and exposes patients to the
virtue of its proteolytic activity, thus inhibiting the firstrisks of repeated anaesthesia and significant bleeding.
steps of the metastatic process (Eckert et al., 1999; Hale Enzymatic debridement has been suggested with
et al., 2002; Hale and Haynes, 1992). experimental runs giving positive results. Topical
Maurer (2001) noted that metastasized tumour cellsbromelain (35% in a lipid base) was reported to achieve
carry the receptor (uPAR) for urokinase plasminogencomplete debridement on experimental burns in rats in
activator (uPA), which generates plasmin fromabout 2 days, as compared with collagenase, which
plasminogen. Plasmin degrades the extracellular matrixrequired about 10 days, with no side effects or damage
(ECM), composed of collagen type IV, laminin andto adjacent burned tissue (Klaue et al., 1979). When
fibronectin. Tumour cells also secrete matrixtopical bromelain was used for frostbite eschar removal,
metalloproteinases (MMPs), enabling the malignantno debridement other than of superficial eschar layers
cells to invade through the ECM. Bromelain diminisheswas noted; after two topical applications of bromelain,
uPAR expression and uPA activity, thus inhibiting thefrostbite injuries remained unaffected (Ahle and Hamlet,
invasion step of metastasis. Maurer further notes that1987).
interactions between tumour cells and platelets takeRosenberg et al. (2004), reported complete debridement
place on different levels i.e. intravasal distribution,of the eschar after only one to two brief applications with
adhesion on endothelial cells, invasion andminimal side effects and no blood loss. In the same
extravasation. Platelets he notes, directly bind to tumour study, no specific debridase (a bromelain derived
cells, a process promoted by the release of factors such debriding agent) related morbidity or mortality was
as platelet factor 4, thrombospondin, thrombin andnoted. However, due to incomplete data in a large
gelatinase A from platelets, which facilitate thrombusnumber of subjects, inaccuracies may have been
formation. Apart from this, transforming growth factor- $possible thus calling for more controlled studies to
(TGF-$), produced by both platelets and tumour cells,assess the safety and efficacy of a proteolytic enzyme for
plays an important role: it induces the synthesis of ECMenzymatic skin debridement.
proteins and stimulates the activity of uPA, MMPs and
angiogenesis. Thus, disturbance of the bloodEffects of bromelain on diarrhoea: Diarrhoea is a major
coagulation system may lead to the formation of thrombi cause of illness and death in children and young
by aggregating platelets and tumour cells. Bromelain isanimals (Cravioto et al., 1988; Smith and Lingood, 1982;
Tochi et al.: Bromelain’s Pharmacology
516
Roselli et al., 2007). Vibro cholerae and enterotoxigenicBromelain improves decrease in defecation in ileus
Escherichia coli (ETEC) are two important
microorganisms that cause diarrhoea Levine et al.
(1983). ETEC produces one or both of a heat-labile
(LT) and/or heat stable enterotoxin (either STa or STb)
and V.cholerae liberate cholera toxin (CT) (Mynott et al.,
1997). To contain this problem, drugs such as
chlorpromazine, nicotinic acid, loperamide and
berberine sulfate have been used in animal models to
inhibit secretion by CT and LT (Guandalini et al., 1984;
Holmgren et al., 1978; Turjman et al., 1978). Berberine,
chlorpromazine and indomethacin also reduce secretion
induced by STa (Greenberg et al., 1980; Abbey and
Knoop, 1979; Guandalini et al., 1987). Despite the
efficacy of these antisecretory compounds in animals,
none are routinely available for use in children and
adults because of adverse side effects or the large
doses required for efficacy (Chandler and Mynott, 1998).
Over time, oral rehydration therapy which has a
significant impact on morbidity and mortality of patients
with acute infectious diarrhoea has been used.
However, oral rehydration therapy does not interfere with
the secretory process nor diminish diarrhoea (Field,
1981). Bromelain has been demonstrated to have anti-
diarrhoea activity (Chandler and Mynott, 1998; Thomson
et al., 2001).
Studies by Mynott et al. (1997) have reported stem
bromelain to show antisecretory properties. Using a
rabbit ileum mounted in using chambers, they showed
that bromelain could prevent net changes in short-circuit
current (Isc) and therefore, fluid secretion mediated by
secretagogues that act through cAMP (cyclic-3, 5-
adenosine monophosphate), cGMP (cyclic-3, 5-
guanosine monophosphate) and calcium-dependent
signalling pathways. Because most toxins that cause
diarrhoea activate one of these pathways, bromelain
would be expected to be an effective anti diarrhoea
nutraceutical drug.
The efficacy of bromelain in this study was 62% in
preventing LT induced secretion, 51% effective against
CT and 35% effective against STa. Bromelain alsogene expression is involved in the improvement by
prevented secretory changes caused by prostaglandin
E, theophylline, calcium-ionophore A23187, 8-Br-cAMP
2
(8-bromocyclic-3, 5-adenosine monophosphate) and 8-
Br-cGMP (8- bromocyclic-3, 5-guanosine mono-
phosphate), well known intracellular mediators of ion
secretion. The efficacy of bromelain was reported not
caused by reduced tissue viability resulting from its
proteolytic effects on enterocytes, indicated by
experiments measuring uptake of nutrients into
intestinal cells and experiments measuring short circuit
responses to glucose. Meanwhile studies by Roselli et
al. (2007) on the effect of different plant extracts and
natural substances (PENS) against membrane damage
induced by ETEC in pig intestinal cells showed
bromelain to be among those with protective effect.
condition: Postoperative gastrointestinal dysmotility
(ileus) is a common consequence of abdominal surgery
causing significant patient discomfort (nausea, vomiting,
abdominal distension and inability to eat or defecate),
and often leads to more serious problems (acute gastric
dilatation, aspiration, respiratory compromise, cardiac
arrhythmia and perforation). Due to limited therapy
specific for this procedure, ileus remains an important
clinical problem (Wen et al., 2006).
In the US, bromelain is sold in health food stores as a
nutritional supplement to promote digestive health and
as an anti-inflammatory medication for horses (Hale,
2004). It has been used successfully as a digestive
enzyme following pancreatectomy in cases of exocrine
pancreas insufficiency and in other intestinal disorders
(Knill-Jones et al., 1970). Recently, it was reported that
stool discharge improved in some Japanese patients
concomitantly suffering from haemorrhoids and
constipation after using bromelain {private
communication in (Wen et al., 2006). This in essence
suggests that bromelain may improve intestinal
propulsive motility.
In another study, the combination of ox bile, pancreatin
and bromelain was shown to be effective in lowering
stool fat excretion in patients with pancreatic
steatorrhoea. In addition, this combination resulted in a
gain in weight in most cases as well as enhanced
subjective feeling of well being. Symptomatic
improvement was also noted in relation to pain,
flatulence and stool frequency (Balakrishnan et al.,
1981). In a recent study, Wen et al. (2006) did show that
treatment with 500 mg/kg bromelain significantly
increased wet weight and water content of faecal pellets
to near normal levels in postoperative rats. The results
suggest that bromelain may play an important role in
treatment of ileus. In the same study, bromelain
treatment was shown to significantly suppress
overexpression of colonic iNOS mRNA, accompanied by
improvement of decrease in defecation in postoperative
rats. It is therefore suggested that modulation of iNOS
bromelain of the decreased defecation in postoperative
rats, at least in part, by inhibiting colonic iNOS gene
expression probably through NF- B pathway.
k
Bromelain inhibits thrombus formation: Studies have
indicated that bromelain prevents aggregation of human
blood platelets in vivo and in vitro, prevents or minimizes
the severity of angina pectoris and transient ischemic
attacks (TIA), is useful in the prevention and treatment of
thrombosis and thrombophlebitis, may break down
cholesterol plaques and exerts a potent fibrinolytic
activity (Taussig and Nieper, 1979; Kelly, 1996).
Furthermore, it has been suggested that bromelain
increases vessels wall permeability to oxygen and
nutrients while increasingly thinning blood both of which
aid in these conditions (Kelly, 1996).
Tochi et al.: Bromelain’s Pharmacology
517
Heinicke et al. (1972) were the first to report thatonset of these diseases (Wiest-Ladenburger et al.,
bromelain prevents aggregation of blood platelets. In1997; Emancipator et al., 1997; White et al., 1991). Later,
their study carried among human volunteers with aHale (2004) unexpectedly found bromelain to exhibit
history of heart attack or stroke or with people havingstrong immunogenicity following oral dosing. In further
high aggregation values, as well as with health subjects, studies following this phenomenon, Hale et al. (2006)
oral administration of bromelain (160-1000 mg per day)reported that repeated exposure was necessary for
decreased aggregation of blood platelets in all thedevelopment of anti-bromelain antibodies, with
subjects. Later studies by Nieper (1978), whoexposure period ranging from 3 to 6 weeks on a dose
administered 400-1000 mg per day of bromelain to 14dependent manner.
patients with angina pectoris resulted in the
disappearance of symptoms in all patients within 4 to 90
days but reappeared after bromelain administration was
discontinued.
Metzig et al. (1999) showed that pre-incubation of human
platelets with 10ug/ml bromelain completely prevents
thrombin induced platelet aggregation in vitro and also
reduced the adhesion of thrombin stimulated,
fluorescently labelled platelets to bovine aorta
endothelial cells. Similarly, they reported that oral (60
mg/kg) and intravenous (30 mg/kg) bromelain inhibited
in vivo thrombus formation in a model of laser-induced
thrombosis in rats. The ability of bromelain to
influence these conditions could be due to its ability to
breakdown fibrinous plaques. Bromelain has been
shown to dissolve arteriosclerotic plaque in rabbit aorta
in vivo and in vitro (Taussig and Nieper, 1979). Later,
Hale et al. (2002) showed that in vitro bromelain
treatment of leukocytes in whole blood proteolytically
altered 14 of 59 leukocyte makers studied. It is important
to note that bromelain induced loss of CD41 and
CD42a via proteolysis would be expected to decrease
platelet function and thus inhibit thrombus formation.
Bromelain gives strong immunogenicity: Bromelain
has been shown to remove T-cell CD44 molecules from
lymphocytes among other bromelain sensitive
molecules (Hale et al., 2002; Eckert et al., 1999; Hale
and Haynes, 1992; Roep et al., 2002; Desser et al.,
1993). Munzig et al. (1994) did show that highly purified
bromelain protease F9 reduced the expression of CD44
to about 10 times more than the crude bromelain,
achieving about 97% inhibition of CD44 expression.
Roep et al. (Roep et al., 2002) reported that protease
treatment reduced expression of cell surface receptors
on T-cells and antigen-presenting cells. Previously,
reduction of CD44 expression on lymphocytes of
patients with multiple sclerosis during protease therapy
had been reported (Munzig et al., 1994; Stauder et al.,
1997; Hale and Haynes, 1992).
Roep et al. (2002) suggested that the generation of
soluble forms of adhesion molecules by proteolytic
cleavage could act as an additional benefit for
immonomudulatory function of protease treatment.
However, they noted that the quality of immune activation
plays an important role during chronic autoimmunity.
Earlier, animal models for rheumatoid arthritis and Type
1 diabetes protease treatment prevented or delayed the
Bromelain application in dermatological disorders:
Bromelain among other fruit extracts from apricots,
apples, peaches, pears, papayas, pomegranates,
cherries, kiwis, tangerines and oranges have been
described to play an important role in treating
dermatological disorders (Murad, 2003). Ozlen (1995)
has disclosed a cosmetic composition containing at
least one alpha-hydroxy acid, salicylic acid and at least
one digestive enzyme derived from fruit. Preferably the
digestive enzyme is a mixture of bromelain and papain.
Bromelain is disclosed as being typically obtained from
pineapple and papain is disclosed as being typically
obtained from dry papaya latex. The compositions are
allegedly useful for treating various cosmetic conditions
or dermatological disorders, such as lack of adequate
skin firmness, wrinkles and dry skin.
Conclusion: Bromelain being a plant extract, contains
various components such as proteinases, peroxidises,
phosphatises, protease inhibitors and organically bound
calcium whose ratio to each other might vary according
to soil composition, climate conditions during plant
growth, geographical location where the pineapple was
grown, pineapple variety and the process of extraction.
These factors might contribute to the variations of
bromelain’s pharmacological activities.
Proteolytic activity of bromelain has been shown to play
only a part in its pharmacological activity while other
factors such as immunomodulatory, hormone like
properties, fibrinolytic activity and uncharacterised
components such as CCS and CCZ complement
towards its pharmacological activity. However, there is
need for further investigation on the uncharacterised
components.
Bromelain’s activity remains stable over a wide pH
range which explains why its activity has been found to
be effective over the entire gastrointestinal tract. Since it
is safe and non toxic, there is need to investigate how it
can be incorporated in foods. On our view, if successfully
incorporated in foods, it could become more acceptable
as a nutraceutical product than it now is.
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... It was established in various studies that bromelain has anti-inflammatory properties as they inhibit prostaglandins that assist in inflammation and have anti-inflammatory, anti-oedematous, analgesic, anti-thrombotic activities by influencing the arachidonic acid and kallikrein-kinin pathways leading to cerebrovascular and cardiovascular effects [17]- [20]. Anti-cancer applications were also seen as bromelain suspends cell proliferation through activation of apoptosis [21]- [23]. In a study conducted by Saptarini et al., bromelain was found to have immunomodulatory activity due to anti-oxidant abilities and protease activity. ...
... In a study conducted by Saptarini et al., bromelain was found to have immunomodulatory activity due to anti-oxidant abilities and protease activity. Subsequently, it activates NK cells, heightens tumour necrosis factor-a (TNF-ab), IL-b IL-1, IL-2, IL-6, IL-8, Interferon γ and granulocyte-macrophage stimulating factor and suppresses CD4+ T cells and CD25 expression [23]- [25]. It also is a non-invasive therapy for metabolic disorders like osteoarthritis [26]. ...
... Bromelain's abilities as a phytotherapeutic drug are unmatched as it has a plethora of applications in sinusitis, IJSER bronchitis, surgical trauma, thrombophlebitis and high absorption of drugs [24], [29], [30]. Keeping in mind the patient's comfort, the increased economic nature and comfort given by oral administration of drugs are singularly the most effective administration and bromelain available through natural sources like pineapple increases its therapeutic potential [23], [30]- [32]. Acceleration of wound healing through proliferation and clearing up skin debris results in its applications in the cosmetic field [23], [33]. ...
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According To World Health Organization (WHO), the COVID-19 pandemic caused by the novel coronavirus has been a huge challenge to the medical personnel, healthcare systems and governments, infecting about 213 million people worldwide, causing 4.4 million deaths (WHO). There is also a dearth of drugs, vaccines and oxygen support. The present-day plethora of drugs tends to be exorbitant and excruciating for the patients affected with COVID-19. Amidst the distressing symptoms of COVID-19, these drugs also carry a multitude of side effects, making the patient's life an abyss of despair. Bromelain, a particularly novel and interesting concoction of enzymes, has lately been proved to have extensive therapeutic applications for COVID-19. This study gives an overview of the effects of COVID-19, the therapeutic targets for COVID drugs, the role of ACE2 receptor in COVID-19 infection, how blocking of ACE2 receptor can potentially inhibit COVID-19, the common medications presently used and finally, the potential of bromelain to be a cure for the existing pandemic. The unique properties of bromelain make it a potential drug capable of taking on the high virulence of Coronaviruses through cleavage of the S domain or binding to the ACE2 receptor. The smooth administration and negligible side effects allow us to view this as a game-changer in COVID-19 therapeutics.
... Several in vitro and in vivo studies indicate that bromelain at appropriate doses may reduce or minimize symptoms associated with several cardiovascular diseases [44,45]. Due to its anticoagulant and fibrinolytic properties, bromelain is used for the prevention and treatment of thrombophlebitis. ...
... Bromelain is considered an attractive candidate in therapy against chronic rhinosinusitis [175,176]. It is believed that bromelain may reduce the secretion of pro-inflammatory agents during rhinitis and mucus secretion and aids its drainage [45,174]. Matschke et al. [177] emphasize the therapeutic use and benefits of postoperative use of bromelain in otorhinolaryngology. ...
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Bromelain is a major sulfhydryl proteolytic enzyme found in pineapple plants, having multiple activities in many areas of medicine. Due to its low toxicity, high efficiency, high availability, and relative simplicity of acquisition, it is the object of inexhaustible interest of scientists. This review summarizes scientific reports concerning the possible application of bromelain in treating cardiovascular diseases, blood coagulation and fibrinolysis disorders, infectious diseases, inflammation-associated diseases, and many types of cancer. However, for the proper application of such multi-action activities of bromelain, further exploration of the mechanism of its action is needed. It is supposed that the anti-viral, anti-inflammatory, cardioprotective and anti-coagulatory activity of bromelain may become a complementary therapy for COVID-19 and post-COVID-19 patients. During the irrepressible spread of novel variants of the SARS-CoV-2 virus, such beneficial properties of this biomolecule might help prevent escalation and the progression of the COVID-19 disease.
... The extent of its effectiveness and the methods by which it operates need to be better understood. However, due to its potential, Bromelain attracts the attention of the medical community and will be the subject of future research [5,[13][14][15]. ...
... The main finding in the present study was that the pineapple has some sort of analgesic effects. In addition, it showed a significant effect in minimizing post-operative swelling and ecchymosis in the surgical site of operation during the early postoperative period, which is agreed with some other researches that support the pre-operative beneficial effects of Bromelain contained pineapple [6,[14][15][16][17]; however, some randomized controlled trials have also shown no significant difference [1,4,16]. In addition, pineapple is a natural product and essentially nontoxic and showed a significant analgesic effect during the first post-operative week compared with control group [4,18]. ...
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Background: Facial plastic surgeries are usually associated with various post-surgical unde- sirable symptoms, particularly pain, Swelling, and ecchymosis. Depending on the nature of the procedures, these symptoms could last for days, sometimes over a week or more. Considering the optimal efficacy of Bromelain, this study is used to justify the benefits of pre-operative use of Bro- melain found in pineapple using fresh pineapple juice to reduce such complications. Materials and Methods: A randomized clinical study was performed among 100 patients undergoing various facial surgical operations; the patients were randomly divided into two groups; fifty patients received the pre-operative fresh pineapple juice (350ml glass) twice every day, a week before and continued for seven days after surgery. The pain level was determined using a visual an- alog scale, Swelling, and ecchymosis judged by visual inspection. Average scores for all symptoms were added to obtain the clinical sum score for each visit. Results: Pre-operative use of fresh pineapple juice was significantly reduced post-surgical pain, swelling, and ecchymosis with statistically significant results (p<0.005) in each pineapple groups. Conclusion: Bromelain found in pineapple fruit can be used as a successful therapy before var- ious facial surgical procedures to minimize and provide faster recovery from undesirable post-op- erative symptoms.
... Bromelain is an enzyme extract with protease activity, which is found mainly in the pineapple plant (Ananas comosus) of the genus Bromeliaceae [6]. This extract can be obtained from both the stem and the fruit of the pineapple plant and contains as the main component a mixture of glycosylated proteolytic sulfhydryl enzymes [7][8][9][10][11]. ...
... This extract can be obtained from both the stem and the fruit of the pineapple plant and contains as the main component a mixture of glycosylated proteolytic sulfhydryl enzymes [7][8][9][10][11]. The bromelain strain possesses different biochemical properties and compositions compared to fruit bromelain [12], the latter containing several thiol endopeptidases and also compounds such as peroxidases, acid phosphatase, glycoproteins, carbohydrates and organic complexed Ca 2+ [6,13]. To date, eight active proteolytic components have been isolated from bromelain [14]. ...
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The growing interest in the appearance and color of teeth has led to the emergence of a wide range of teeth whitening methods, both in dental offices and in patients’ homes. Concerns about the possible side effects or toxic effects of peroxide-based whitening gels leads to the identification of alternative whitening methods, based on natural compounds with mild action on tooth enamel and remineralizing effect. In this context, this study describes the preparation and in vitro analysis of whitening gels based on natural active agents—bromelain, quince and whey—using organic (polyacrylate, polyethylene glycol) and/or inorganic (silicate) excipients. Five natural products gels were prepared, containing bromelain extract, quince extract and whey, in various proportions. Two supplementary gels, one containing Lubrizol and another containing SiO2, were prepared. All gels were submitted for multiple in vitro analysis such as: SDS-PAGE analysis, UV-vis and FTIR spectroscopy, SEM microscopy, antibacterial activity on Streptococcus mutans ATCC 25175, Porphyromonas gingivalis ATCC 33277, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923. The quince extract sample was the only one which completely discolored the blue dye on SDS-PAGE analysis. On the UV-vis spectra, the 303 nm band is assigned to an in situ modified form of bromelain. SEM images of gels containing SiO2 particles show evident marks of these particles, while the rest of the gels containing Lubrizol or whey are more uniform. Regarding antibacterial tests, the SiO2 gel samples did not show inhibition in any strains, but the other tested samples varied in the size of the inhibition diameter depending on the amicrobial strain tested; the protease activity of bromelain modulates the composition of the added whey proteins. Bromelain added as a nanoencapsulated assembly better preserves its integrity. The prepared gels showed antibacterial properties.
... Core of pineapple represents 15% of the total pineapple processing waste (PPW) and is a rich source of bromelain enzyme [31]. Meanwhile, bromelain shows therapeutic effect for human body [32]. ...
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Pineapple processing industry generates large amounts of by-products (peel, core and crown) with a negative environmental impact. The elimination of these implies high costs for food industries, being their main destination animal feed or composting, thus wasting their great potential value attributed to the rich content of bioactive compounds. In this review, we have focused on the description of the bioactive compounds present in pineapple by-products and on the environment-friendly extraction methodologies used to obtain them (ultrasound-assisted extraction, microwave-assisted extraction, submerged and solid-state fermentation), as well as applications of these compounds in different areas. The use of these by-products is a great alternative to mitigate current environmental problems; in addition, green extraction technologies have the advantage of using few solvents, have shorter extraction times and good yields, so they are suitable for obtaining bioactive compounds (gallic acid, catechin, epicatechin, ferulic acid, among others) present in these by-products, which have a high antioxidant, anti-inflammatory, antifungal, anticancer activity and have very relevant applications. This review article demonstrates the great potential of the bioactive compounds present in the pineapple waste that might be used on drugs or foods for treatment of diseases or improvement of the people health. Graphical abstract
... Bromelain, a protease enzyme, is abundant in the pineapple fruit pulp and its byproducts (Ketnawa et al., 2012;Mala et al., 2021a). In the food industry, it is used for meat tenderization, grain protein solubilization during the baking process, beer clarification, and as a supplement (Tochi et al., 2008). Bromelain has also been found effective as a therapeutic agent, including as a suppressor of tumor growth and as an antibacterial, anti-inflammatory, anticoagulant, antiemetic, and antidiarrheal agent (Siow and Lee, 2012;Secor et al., 2013). ...
Article
Full-text available
Hybrid pectin and resistant starch–based hydrogel beads loaded with bromelain using the extrusion gelation method were prepared and evaluated to enhance the activity of bromelain during gastrointestinal passage and thermal processing. The solutions of pectin–resistant starch with bromelain were dropped into the gelation bath containing calcium chloride (0.2 M) solution to develop various types of hydrogel beads. The physicochemical characteristics of the synthesized hydrogel beads were evaluated. The ratio (4.5:1.5 w/w) of pectin and resistant starch concentration significantly (p < 0.05) enhanced the encapsulation efficiency (80.53%). The presence of resistant starch resulted in increased entrapment of bromelain, improved swelling properties with sustained release behavior, and improved gastric stability than pectin hydrogels alone. The swelling of hydrogel beads was higher at pH 7.4 than pH 1.2. Optimized batch of hybrid pectin/resistant starch exhibited a spherical shape. Optical and scanning electron microscopy showed a more packed and spherical shape from the pectin/resistant starch hydrogel bead network. Fourier transformation infrared spectroscopy was also used to confirm the presence of bromelain in the hydrogel beads. The encapsulated bromelain in the pectin/hi-maize starch beads produced at a pectin/hi-maize ratio of 4.5:1.5 (percent w/w; formulation P4) obtained the highest relative bromelain activity in all heat treatments including at 95°C, whereas the highest activity of free bromelain was found only at 30°C. Bromelain encapsulated in hydrogels released at a faster rate at simulated intestinal fluid (SIF, pH 7.4) than at simulated gastrointestinal fluid (SGF, pH 1.2).
... In order to avoid or minimize post-surgical complications, like pain, swelling, and trismus, surgeons have either modified surgical techniques, like using lasers and cryotherapy, or advised the patients to use proteolytic enzymes, like trypsin, chymotrypsin, papain, serratiopeptidase, and bromelain (pineapple enzyme), alongside routine antibiotics, analgesics, and corticosteroids [4]. The advantages of administering enzymes after surgical procedures demonstrated both in vitro and in vivo are anti-inflammatory, antithrombotic, and fibrinolytic, thereby minimizing postoperative complications [5]. ...
... Bromelain is also an industrially important enzyme that can be obtained from pineapple stem. Bromelain is known for its anti-inflammatory activity and is used for treating the swelling especially of nose post-surgery (Tochi et al. 2008). This enzyme has also been used as a meat tenderizer, bread batter improver, tooth brightener, animal feed, and in the material industry (Choonut et al. 2014;Kodagoda and Marapana 2017). ...
Article
Full-text available
Bromelain is a crude extract from the fruit or stem of pineapple (Ananas cosmosus Linn.) plant that contains proteinases, which are good anti-inflammatory, anti-thrombotic and fibrinolytic properties. Among other components various closely related proteinases exhibiting actions such as inhibition of platelet aggregation, anti-cancer, mucolytic, skin debridement, digestive assistance, enhanced wound healing, cardiovascular and circulatory improvement, enhanced absorption of other drugs etc. Further, Bromelain also contains peroxidase, acid phosphatase, several protease inhibitors. It has earned universal acceptability as a phytotherapeutic drug because of its history of safe use and minimal side effects. This communication for review deals with the applications of bromelain in the treatment of various pathological conditions.
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Infectious diseases along with various cancer types are among the most significant public health problems and the leading cause of death worldwide. The situation has become even more complex with the rapid development of multidrug-resistant microorganisms. New drugs are urgently needed to curb the increasing spread of diseases in humans and livestock. Promising candidates are natural antimicrobial peptides produced by bacteria, and therapeutic enzymes, extracted from medicinal plants. This review highlights the structure and properties of plant origin bromelain and antimicrobial peptide nisin, along with their mechanism of action, the immobilization strategies, and recent applications in the field of biomedicine. Future perspectives towards the commercialization of new biomedical products, including these important bioactive compounds, have been highlighted.
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Oral hydrolytic enzymes in combination with rutosid have been applied in MS patients for more than 20 years. We investigated whether immunological alterations in MS patients are influenced by enzyme treatment. We determined the phenotypes of specific lymphocytic antigens in 12 patients with relapsing-remitting MS, who were known to be under long-term treatment with oral hydrolytic enzymes (Phlogenzym®). Matched untreated (i.e., only treated for symptoms) MS patients (n = 18) and healthy volunteers (n = 10) served as controls. For phenotyping, the following lymphocytic antigens were measured: CD4, CD8, CD3, CD2, CD19, CD56, CD14, CD45, CD45RA, CD45RO, CD25, CD54 and HLA-DR. Tests were carried out with a panel of different fluorescence-conjugated murine monoclonal antibodies and subsequent two color flow-cytometry. Data is expressed as percentage gated cells. Symptomatically treated patients had increased CD4, CD19, CD2 and CD45RO, CD54 and CD56. These changes were influenced by hydrolytic enzymes in the following manner: CD8 was markedly decreased; CD4, CD2, CD25, CD-45-RO, CD-45RA, CD56 slightly decreased. Furthermore, a statistically significant decrease was found for CD45 and CD54. From these results the conclusion can be drawn that positive clinical findings in MS patients under oral hydrolytic enzymes are causatively linked to a decrease in inflammatory activity.
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It has recently been demonstrated that proteolytic enzyme treatment modulates certain immune-mediated diseases. We have, therefore, studied the effect of administration of a protease mixture in the NOD mouse, an elegant animal model for autoimmune insulin-dependent diabetes mellitus (IDDM). Female NOD mice were fed proteolytic enzymes from age 6 weeks to 10 weeks, within the subclinical phase of IDDM. Once a week animals received intragastrically 1 mg Phlogenzym® (n = 10 mice) or 0.5 mg Phlogenzym® (n = 10) in 0.5 ml saline or saline only (n = 10). Mice were followed for development of IDDM up to week 23. At week 21, all control animals were diabetic, whereas 25% of the treated mice were still normoglycemic at the end of the observation period. No significant appearance of autoantibodies against either isoform of the important islet cell antigen glutamic acid decarboxylase (GAD), GAD65 and GAD67, was observed in the mouse sera as determined by a highly sensitive radioimmunoassay. The histopathological examination of pancreatic islets showed signs of insulitis in all mice with a tendancy of milder insulitis in the protease-treated groups.
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Three groups of randomly selected mice were immunized and boosted with Type II collagen; age-matched nonimmunized controls were maintained. Beginning on day 28, groups were given 120 mg/kg oral Phlogenzym® twice daily, 40 mg/kg oral ibuprofen twice daily, or no therapy. Swelling of the footpads, measured with a tensioning caliper generally appeared on day 21, and was identical in the three immunized groups until day 31; subsequently, mice given Phlogenzym® or ibuprofen had significantly less swelling than the untreated mice, with no difference between the two therapies. At sacrifice, there was severe joint degeneration in the untreated groups at 42 and 49 days, with ankylosis in 3 of 8 untreated mice examined at 49 days. Joint degeneration was moderate at day 42 and moderate to severe at day 49 in the ibuprofen-treated mice, but mild at day 42 and generally mild at day 49 in Phlogenzym®-treated mice (chi-squared = 5.8, p < 0.05). Computer morphometry revealed an average cartilage thickness of 720 μm in normals, 630 μm in Phlogenzym®-treated diseased mice, 380 μm in ibuprofen-treated diseased mice, and 290 μm in untreated diseased mice (F = 9.8, p < 0.01). Radiographic scores correlated with the pathologic scores. We conclude that Phlogenzym® protects articular cartilage significantly better than ibuprofen in this murine model of rheumatoid arthritis, despite equal antiinflammatory potency.
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latory effects. In this study, we show for the first time that extracellular proteases may also block signal transduction. We show that bromelain, a mixture of cysteine proteases from pineapple stems, blocks activation of ERK-2 in Th0 cells stimulated via the TCR with anti-CD3e mAb, or stimulated with combined PMA and calcium ionophore. The inhibitory activity of bromelain was dependent on its proteolytic activity, as ERK-2 inhibition was abrogated by E-64, a selective cysteine protease inhibitor. However, inhibitory effects were not caused by nonspecific proteolysis, as the protease trypsin had no effect on ERK activation. Bromelain also inhibited PMA-induced IL-2, IFN-g, and IL-4 mRNA accumulation, but had no effect on TCR-induced cytokine mRNA production. This data suggests a critical requirement for ERK-2 in PMA-induced cytokine production, but not TCR-induced cytokine production. Bromelain did not act on ERK-2 directly, as it also inhibited p21ras activation, an effector molecule upstream from ERK-2 in the Raf-1/MEK/ERK-2 kinase signaling cascade. The results indicate that bromelain is a novel inhibitor of T cell signal transduction and suggests a novel role for extracellular proteases as inhibitors of intracellular signal transduction pathways. The Journal of Immunology, 1999, 163: 2568 -2575.
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First introduced as a therapeutic compound in 1957, bromelain's actions include: (1) inhibition of platelet aggregation; (2) fibrinolytic activity; (3) anti-inflammatory action; (4) anti-tumor action; (5) modulation of cytokines and immunity; (6) skin debridement properties; (7) enhanced absorption of other drugs; (8) mucolytic properties; (9) digestive assistance; (10) enhanced wound healing; and (11) cardiovascular and circulatory improvement. Bromelain is well absorbed orally and available evidence indicates that it's therapeutic effects are enhanced with higher doses. Although all of its mechanisms of action are still not completely resolved, it has been demonstrated to be a safe and effective supplement. (Alt Med Rev 1996;1(4):243-257)
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Objective: To compare the short-term efficacy and tolerability of an oral enzyme therapy with the NSAID diclofenac in patients with symptomatic osteoarthritis of the knee (gonarthritis). Methods: In a double-blind clinical trial, 73 patients with painful gonarthritis were randomised to receive 3 weeks of treatment with an oral enzyme preparation (Phlogenzym®) containing bromelain, trypsin and rutin (n = 36), or the NSAID diclofenac (n = 37). Efficacy was primarily evaluated using the Lequesne index (measuring pain and function of the affected knee). Other investigations included assessment of pain symptoms using a visual analogue scale (VAS), global assessment of efficacy and tolerability (by both patients and one physician), and various laboratory parameters. Patients were evaluated at baseline, at weekly intervals throughout the 3-week treatment period, and at 7 weeks (i.e. 4 weeks after discontinuing therapy). Results: The Lequesne index improved continuously in both groups: from 13.56 at baseline to 3.10 after 3 weeks (end of therapy) to 2.05 at 7 weeks (follow-up) in the enzyme group, and from 14.04 to 3.50 to 2.24, respectively, in the diclofenac group. Statistical evaluation showed the treatment groups to be equivalent; the lower bound of the 95% confidence interval of the Mann-Whitney estimator was above 0.44 (the limit for equivalence) at all time points. Global assessment of efficacy and tolerability of the drugs was ‘very good’ or ‘good’ for the majority patients. Conclusions: Short-term evaluation indicates that oral enzymes may be considered an effective and safe alternative to NSAIDs such as diclofenac in the treatment of painful gonarthritis.