What is pineapple good for

The pineapple (Ananas comosus) is a tropical plant with an edible multiple fruit consisting of coalesced berries, also called pineapples and the most economically significant plant in the Bromeliaceae family ¹. Pineapple crop is cultivated in all tropical and subtropical regions and ranks third in production among noncitrus tropical fruits, following banana (including plantain) and mango. The annual worldwide production reached 21.9 million metric tons in 2012 and the top seven producers (Brazil, Philippines, Thailand, Costa Rica, Indonesia, India, and China) jointly accounted for 90% of the global production (FAO, 2014) ². The pineapple plant is indigenous to South America ³. The putative center of origin is located in the Paraná–Paraguay River drainages between southern Brazil and Paraguay, based on the diversity distribution of related species and botanical varieties of pineapple in this region ⁴.

The flesh and juice of the pineapple are used in cuisines around the world. In many tropical countries, pineapple is prepared and sold on roadsides as a snack. It is sold whole or in halves with a stick inserted. Whole, cored slices with a cherry in the middle are a common garnish on hams in the West. Chunks of pineapple are used in desserts such as fruit salad, as well as in some savory dishes, including pizza toppings, or as a grilled ring on a hamburger. Crushed pineapple is used in yogurt, jam, sweets, and ice cream. The juice of the pineapple is served as a beverage, and it is also the main ingredient in cocktails such as the piña colada and in the drink tepache.

Pineapples can be consumed fresh, cooked, juiced, or preserved. They are found in a wide array of cuisines. In addition to consumption, the pineapple leaves are used to produce the textile fiber piña in the Philippines, commonly used as the material for the men’s barong and women’s baro’t saya formal wear in the country ⁵. The fiber is also used as a component for wallpaper and other furnishings.

Figure 1. Pineapples

Pineapple nutrition facts

In a 100-gram reference amount, raw pineapple is a rich source of manganese (44% Daily Value, DV) and vitamin C (58% DV), but otherwise contains no essential nutrients in significant quantities. Also in 100 gram of pineapple has 13.12 gram of carbs and only 50 calories. Sugar/acid ratio and ascorbic acid content vary considerably with the cultivar. The sugar content may change from 4% to 15% during the final 2 weeks before full ripening.

Table 1. Pineapple, raw, all varieties nutrition facts

Nutrient	Unit	Value per 100 g
Approximates
Water	g	86
Energy	kcal	50
Energy	kJ	209
Protein	g	0.54
Total lipid (fat)	g	0.12
Ash	g	0.22
Carbohydrate, by difference	g	13.12
Fiber, total dietary	g	1.4
Sugars, total	g	9.85
Sucrose	g	5.99
Glucose (dextrose)	g	1.73
Fructose	g	2.12
Lactose	g	0
Maltose	g	0
Galactose	g	0
Starch	g	0
Minerals
Calcium, Ca	mg	13
Iron, Fe	mg	0.29
Magnesium, Mg	mg	12
Phosphorus, P	mg	8
Potassium, K	mg	109
Sodium, Na	mg	1
Zinc, Zn	mg	0.12
Copper, Cu	mg	0.11
Manganese, Mn	mg	0.927
Selenium, Se	µg	0.1
Vitamins
Vitamin C, total ascorbic acid	mg	47.8
Thiamin	mg	0.079
Riboflavin	mg	0.032
Niacin	mg	0.5
Pantothenic acid	mg	0.213
Vitamin B-6	mg	0.112
Folate, total	µg	18
Folic acid	µg	0
Folate, food	µg	18
Folate, DFE	µg	18
Choline, total	mg	5.5
Betaine	mg	0.1
Vitamin B-12	µg	0
Vitamin B-12, added	µg	0
Vitamin A, RAE	µg	3
Retinol	µg	0
Carotene, beta	µg	35
Carotene, alpha	µg	0
Cryptoxanthin, beta	µg	0
Vitamin A, IU	IU	58
Lycopene	µg	0
Lutein + zeaxanthin	µg	0
Vitamin E (alpha-tocopherol)	mg	0.02
Vitamin E, added	mg	0
Tocopherol, beta	mg	0
Tocopherol, gamma	mg	0
Tocopherol, delta	mg	0
Vitamin D (D2 + D3)	µg	0
Vitamin D	IU	0
Vitamin K (phylloquinone)	µg	0.7
Lipids
Fatty acids, total saturated	g	0.009
04:00:00	g	0
06:00:00	g	0
08:00:00	g	0
10:00:00	g	0
12:00:00	g	0
14:00:00	g	0
16:00:00	g	0.005
18:00:00	g	0.003
Fatty acids, total monounsaturated	g	0.013
16:1 undifferentiated	g	0.001
18:1 undifferentiated	g	0.012
20:01:00	g	0
22:1 undifferentiated	g	0
Fatty acids, total polyunsaturated	g	0.04
18:2 undifferentiated	g	0.023
18:3 undifferentiated	g	0.017
18:04:00	g	0
20:4 undifferentiated	g	0
20:5 n-3 (EPA)	g	0
22:5 n-3 (DPA)	g	0
22:6 n-3 (DHA)	g	0
Fatty acids, total trans	g	0
Cholesterol	mg	0
Phytosterols	mg	6
Amino Acids
Tryptophan	g	0.005
Threonine	g	0.019
Isoleucine	g	0.019
Leucine	g	0.024
Lysine	g	0.026
Methionine	g	0.012
Cystine	g	0.014
Phenylalanine	g	0.021
Tyrosine	g	0.019
Valine	g	0.024
Arginine	g	0.019
Histidine	g	0.01
Alanine	g	0.033
Aspartic acid	g	0.121
Glutamic acid	g	0.079
Glycine	g	0.024
Proline	g	0.017
Serine	g	0.035
Other
Alcohol, ethyl	g	0
Caffeine	mg	0
Theobromine	mg	0
Anthocyanidins
Cyanidin	mg	0
Petunidin	mg	0
Delphinidin	mg	0
Malvidin	mg	0
Pelargonidin	mg	0
Peonidin	mg	0
Flavan-3-ols
(+)-Catechin	mg	0
(-)-Epigallocatechin	mg	0
(-)-Epicatechin	mg	0
(-)-Epicatechin 3-gallate	mg	0
(-)-Epigallocatechin 3-gallate	mg	0
(+)-Gallocatechin	mg	0
Flavanones
Hesperetin	mg	0
Naringenin	mg	0
Flavones
Apigenin	mg	0
Luteolin	mg	0
Flavonols
Kaempferol	mg	0
Myricetin	mg	0
Quercetin	mg	0.1
Isoflavones
Daidzein	mg	0
Genistein	mg	0
Total isoflavones	mg	0
Proanthocyanidin
Proanthocyanidin dimers	mg	0
Proanthocyanidin trimers	mg	0
Proanthocyanidin 4-6mers	mg	0
Proanthocyanidin 7-10mers	mg	0
Proanthocyanidin polymers (>10mers)	mg	0

[Source ⁶]

Table 2. Pineapple juice canned or bottled, unsweetened, without added ascorbic acid nutrition facts

Nutrient	Unit	Value per 100 g
Approximates
Water	g	86.37
Energy	kcal	53
Protein	g	0.36
Total lipid (fat)	g	0.12
Carbohydrate, by difference	g	12.87
Fiber, total dietary	g	0.2
Sugars, total	g	9.98
Minerals
Calcium, Ca	mg	13
Iron, Fe	mg	0.31
Magnesium, Mg	mg	12
Phosphorus, P	mg	8
Potassium, K	mg	130
Sodium, Na	mg	2
Zinc, Zn	mg	0.11
Vitamins
Vitamin C, total ascorbic acid	mg	10
Thiamin	mg	0.058
Riboflavin	mg	0.021
Niacin	mg	0.199
Vitamin B-6	mg	0.1
Folate, DFE	µg	18
Vitamin B-12	µg	0
Vitamin A, RAE	µg	0
Vitamin A, IU	IU	5
Vitamin E (alpha-tocopherol)	mg	0.02
Vitamin D (D2 + D3)	µg	0
Vitamin D	IU	0
Vitamin K (phylloquinone)	µg	0.3
Lipids
Fatty acids, total saturated	g	0.008
Fatty acids, total monounsaturated	g	0.014
Fatty acids, total polyunsaturated	g	0.042
Fatty acids, total trans	g	0
Cholesterol	mg	0
Other
Caffeine	mg	0

[Source ⁶]

Pineapple health benefits

Present in all parts of the pineapple plant, bromelain is a mixture of proteolytic enzymes ⁷.

Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple ⁸. 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 ⁹ 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 ¹⁰.

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.

Pineapple Side Effects and Toxicity

When unripe, the pineapple is not only inedible but poisonous, irritating the throat and acting as a strong laxative ¹¹.

The bromelain content of raw pineapple is responsible for the sore mouth feeling often experienced when eating it, due to the enzymes breaking down the proteins of sensitive tissues in the mouth. Also, raphides, needle-shaped crystals of calcium oxalate that occur in pineapple fruits and leaves, likely cause microabrasions, contributing to mouth discomfort ¹².

Excessive consumption of pineapple cores has caused the formation of fiber balls (bezoars) in the digestive tract ¹¹.

Bromelain enzyme

Bromelainis a mixture of different thiol endopeptidases and other components like phosphatases, glucosidase, peroxidases, cellulases, glycoproteins, carbohydrates, and several protease inhibitors ¹³. Stem bromelain is different from fruit bromelain ¹⁴. Proteinases are considered to be the most active fraction, which comprise ~2% of the total proteins ¹⁵. Bromelain enzymatic activities comprise a wide spectrum with pH range of 4.5 to 9.5 ¹⁶. Nowadays, bromelain is prepared from cooled pineapple juice by centrifugation, ultrafiltration, and lyophilization ¹⁷. 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 ¹⁸.

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 ¹⁹. 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 ¹⁸. 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 ²⁰. The highest concentration of bromelain was identified in the blood one hour after administration ²¹. Bromelain increases bioavailability and reduces the side effects that are associated with various antibiotics ²². Furthermore, bromelain acts as an immunomodulator, is anti-metastatic, anti-edematous, anti-thrombotic and anti-inflammatory ²³. 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 ¹⁹. 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 ²⁴. In a study carried out by Castell et al. ¹⁹ 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 ²⁵.

Bromelain benefits

A wide range of therapeutic benefits have been claimed for bromelain, such as reversible inhibition of platelet aggregation, sinusitis, surgical traumas ²⁶, 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] ²⁷, and enhanced absorption of drugs, particularly of antibiotics ¹⁸. 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 ²⁸. Bromelain acts on fibrinogen giving products that are similar, at least in effect, to those formed by plasmin ²⁹. Experiment in mice showed that antacids such as sodium bicarbonate preserve the proteolytic activity of bromelain in the gastrointestinal tract ³⁰. 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 ³¹. Existing evidence indicates that bromelain can be a promising candidate for the development of future oral enzyme therapies for cancer patients ³². Bromelain can be absorbed in human intestines without degradation and without losing its biological activity ³².

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 ³³ 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 ³⁴ 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 ³⁵. 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 ³⁶. COX-2 converts arachidonic acid into PGE-2 and promotes tumor angiogenesis and cancer progression ³⁷. It has been shown that bromelain downregulates COX-2 and PGE-2 expression levels in murine microglial cells and human monocytic leukemia cell lines ³⁸. 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 ³⁹. 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 ⁴⁰. Studies have shown that bromelain reduced the expression of INF-γ and TNF-α in inflammatory bowel disease ⁴¹. 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 ⁴¹ and controlled the inflammation ⁴¹. 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 ⁴². 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 ⁴³. 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 ⁴⁴. There are various studies that report the immunomodulatory effect of bromelain ⁴⁵. 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 ⁴⁶. Thus, bromelain decreases the majority of inflammatory mediators and has demonstrated a significant role as an anti-inflammatory agent in various conditions ⁴⁷.

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

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 ⁶². A combination of bromelain with enzymes derived from Aspergillus niger improved protein utilization in elderly nursing home patients ⁶⁶. Another study demonstrated that bromelain, in combination with sodium alginate, sodium bicarbonate and essential oils, significantly improved dyspeptic symptoms ⁶⁷. In addition, bromelain has been administered successfully as a digestive enzyme to treat intestinal disorders, pancreatectomy and exocrine pancreas insufficiency ⁶⁸. 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 ⁶⁹.

Bromelain on Cardiovascular and Circulation System

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 ⁷⁰. 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 ⁷¹. 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 ⁷². King et al. ⁷³ 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 ⁷⁴. 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 ⁷⁵.

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 ⁷⁶. 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 ⁷⁷. Bromelain is a food supplement that may provide an alternative treatment to nonsteroidal anti-inflammatory drug (NSAIDs) ⁷⁸. It plays an important role in the pathogenesis of arthritis ⁷⁹. Bromelain has analgesic properties which are thought to be the result of its direct influence on pain mediators such as bradykinin ⁸⁰. The earliest reported studies investigating bromelain were a series of case reports on 28 patients, with moderate or severe rheumatoid or osteoarthritis ⁸¹.

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 ⁸². 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 ⁸³. 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 ⁸⁴. 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 ⁸⁵. Both iNOS and COX2 are pro-inflammatory mediators which play crucial roles in inflammatory responses ⁸⁵. 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 ⁸⁶. Myosin light chain kinase-induced phosphorylation of perijunctional actomyosin mediates tight junction loss, which triggers the initiation and development of inflammatory bowel disease (IBD) ⁸⁷. 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 ⁸⁸. Oral administration of bromelain relieved IBD symptoms ⁸⁹; 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 ⁹⁰. Treatment of cells with bromelain decreases the activation of CD4 (+) T cells and reduce the expression of CD25 ⁹¹. 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 ⁹².

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 ⁹³. 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 ⁹⁴. 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 ⁹⁵.

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 ⁹⁶. 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 ⁹⁷.

Bromelain in Surgery

Administration of bromelain before a surgery can reduce the average number of days for complete disappearance of pain and postsurgery inflammation ⁹⁸. Trials indicate that bromelain might be effective in reducing swelling, bruising, and pain in women having episiotomy ⁹⁹. Nowadays, bromelain is used for treating acute inflammation and sports injuries ⁷⁸.

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 ¹⁰⁰. 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 ¹⁰¹, ¹⁰². 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 ¹⁰³. 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 ¹⁰⁴, ¹⁰⁵.

Bromelain side effects

Studies that have used a higher daily dose of bromelain to treat osteoarthritis [945 mg/day ¹⁰⁶; 1890 mg/day ¹⁰⁷] 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) ¹⁰⁸.

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. ¹⁰⁹ 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 ¹¹⁰. Eckert et al. ¹¹¹ 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.

References

1. Pineapple. https://hort.purdue.edu/newcrop/morton/pineapple.html
2. Food and Agriculture Organization of the United Nations. Statistical databases. United Nations: FAO, 2014. http://www.fao.org
3. Pearsall DM. The origins of plant cultivation in South America. In: Cowan CW, Watson PJ, editors. The Origins of Agriculture: An International Perspective. Washington, DC: Smithsonian Institution Press; 1992, pp 173–205.
4. Bartholomew DP, Paull RE, Rohrbach KG. The Pineapple: Botany, Production and Uses. Wallingford: CABI Publishing; 2003
5. Morton JF. Fruits warm clim. Miami, Florida: Creative Resource Systems, Inc; 1987. Pineapple; pp. 18–28.
6. United States Department of Agriculture Agricultural Research Service. National Nutrient Database for Standard Reference Release 28. https://ndb.nal.usda.gov/ndb/search/list
7. Arshad ZI, Amid A, Yusof F, Jaswir I, Ahmad K, Loke SP (2014). “Bromelain: an overview of industrial application and purification strategies”. Appl Microbiol Biotechnol. 98 (17): 7283–97. doi:10.1007/s00253-014-5889-y https://www.ncbi.nlm.nih.gov/pubmed/24965557
8. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529416/
9. 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.
10. Heinicke RM, Gortner WA. Stem bromelain: a new protease preparation from pineapple plants. Economic Botany. 1957;11(3):225–234.
11. https://hort.purdue.edu/newcrop/morton/pineapple.html
12. Konno K, Inoue TA, Nakamura M. Synergistic Defensive Function of Raphides and Protease through the Needle Effect. Yu F-H, ed. PLoS ONE. 2014;9(3):e91341. doi:10.1371/journal.pone.0091341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951349/
13. Bhattacharyya BK. Bromelain: an overview. Natural Product Radiance. 2008;7(4):359–363.
14. Pineapple cysteine endopeptidases. Rowan AD, Buttle DJ. Methods Enzymol. 1994; 244():555-68. https://www.ncbi.nlm.nih.gov/pubmed/7845232/
15. PURIFICATION AND PHYSICAL CHARACTERIZATION OF STEM BROMELAIN. MURACHI T, YASUI M, YASUDA Y. Biochemistry. 1964 Jan; 3():48-55. https://www.ncbi.nlm.nih.gov/pubmed/14114503/
16. Proteinase activity and stability of natural bromelain preparations. Hale LP, Greer PK, Trinh CT, James CL. Int Immunopharmacol. 2005 Apr; 5(4):783-93. https://www.ncbi.nlm.nih.gov/pubmed/15710346/
17. 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.
18. Bromelain: biochemistry, pharmacology and medical use. Maurer HR. Cell Mol Life Sci. 2001 Aug; 58(9):1234-45. https://www.ncbi.nlm.nih.gov/pubmed/11577981/
19. 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. https://www.ncbi.nlm.nih.gov/pubmed/9252520/
20. [Effect of phlogenzym in long-term treatment of patients with multiple sclerosis]. Mialovyts’ka OA. Lik Sprava. 2003 Apr-Jun; (3-4):109-13. https://www.ncbi.nlm.nih.gov/pubmed/12889375/
21. 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. https://www.ncbi.nlm.nih.gov/pubmed/3207859/
22. 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. https://www.ncbi.nlm.nih.gov/pubmed/3287010/
23. Cell signaling pathways altered by natural chemopreventive agents. Sarkar FH, Li Y. Mutat Res. 2004 Nov 2; 555(1-2):53-64. https://www.ncbi.nlm.nih.gov/pubmed/15476851/
24. [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. https://www.ncbi.nlm.nih.gov/pubmed/105480/
25. 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
26. 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.
27. A plant protease for potentiation of and possible replacement of antibiotics. NEUBAUER RA. Exp Med Surg. 1961; 19():143-60. https://www.ncbi.nlm.nih.gov/pubmed/14479142/
28. 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.
29. The mechanism of the physiological action of bromelain. Taussig SJ. Med Hypotheses. 1980 Jan; 6(1):99-104. https://www.ncbi.nlm.nih.gov/pubmed/7382892/
30. Proteolytic activity and immunogenicity of oral bromelain within the gastrointestinal tract of mice. Hale LP. Int Immunopharmacol. 2004 Feb; 4(2):255-64. https://www.ncbi.nlm.nih.gov/pubmed/14996417/
31. 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. https://www.ncbi.nlm.nih.gov/pubmed/21749819/
32. 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. https://www.ncbi.nlm.nih.gov/pubmed/19700238/
33. Herbal Medicines for the Treatment of Rhinosinusitis: A Systematic Review. Otolaryngology—Head and Neck Surgery. 2006;135(4):496-506. http://journals.sagepub.com/doi/pdf/10.1016/j.otohns.2006.06.1254
34. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642126/
35. 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. https://www.ncbi.nlm.nih.gov/pubmed/18569070
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. Massagué J. TGFbeta in Cancer. Cell. 2008;134:215–230. doi: 10.1016/j.cell.2008.07.001.
44. Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic disorders. BioDrugs. 2001;15:779–789. doi: 10.2165/00063030-200115120-00001.
45. 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.
46. Moss JN, Frazier CV, Martin GJ. Bromelains. The pharmacology of the enzymes. Arch Int Pharmacodyn Ther. 1963;145:166–189.
47. De-Giuli M, Pirotta F. Bromelain, interaction with some protease inhibitor and rabbit specific antiserum. Drugs Exp Clin Res. 1978;4:21–23.
48. 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. https://www.ncbi.nlm.nih.gov/pubmed/19700238
49. 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. https://www.ncbi.nlm.nih.gov/pubmed/17893836
50. 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. https://www.ncbi.nlm.nih.gov/pubmed/4095199
51. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1506565/
52. 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.
53. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444.
54. Wang MT, Honn KV, Nie D. Cyclooxygenases, prostanoids, and tumor progression. Cancer and Metastasis Reviews. 2007;26(3-4):525–534.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. Neubauer RA. A plant protease for potentiation of and possible replacement of antibiotics. Exp Med Surg. 1961;19:143–160.
64. 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.
65. 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.
66. 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.
67. 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.
68. 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.
69. 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.
70. 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.
71. World Health Organization. Cardiovascular diseases. http://www.who.int/cardiovascular_diseases/en/
72. Heinicke RM, van der Wal L, Yokoyama M. Effect of bromelain (Ananase) on human platelet aggregation. Experientia. 1972;28(10):844–845.
73. 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.
74. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2576519/
75. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581828/
76. 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.
77. 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. https://www.ncbi.nlm.nih.gov/pubmed/15278753
78. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC538506/
79. 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.
80. 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.
81. Cohen A, Goldman J. Bromelain therapy in rheumatoid arthritis. Pennsylvania Medical Journal. 1964;67:27–30.
82. 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.
83. 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.
84. 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. https://www.ncbi.nlm.nih.gov/pubmed/24206084/
85. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726555/
86. 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.
87. 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.
88. 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.
89. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998156/
90. 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.
91. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662479/
92. Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic disorders. BioDrugs. 2002;15(12):779–789.
93. 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.
94. 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.
95. 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.
96. 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.
97. 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.
98. 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. https://www.ncbi.nlm.nih.gov/pubmed/14282458
99. 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. https://www.ncbi.nlm.nih.gov/pubmed/4563795
100. 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. https://www.ncbi.nlm.nih.gov/pubmed/6352539
101. Rosenberg L, Krieher Y, Silverstain E, et al. Selectivity of a Bromelain Based Enzymatic Debridement Agent: A Porcine Study. Elsevier; 2012. https://www.ncbi.nlm.nih.gov/pubmed/22385643
102. 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. https://www.ncbi.nlm.nih.gov/pubmed/20182376
103. 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. https://www.ncbi.nlm.nih.gov/pubmed/22341346
104. 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. https://www.ncbi.nlm.nih.gov/pubmed/21399550
105. 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. https://www.ncbi.nlm.nih.gov/pubmed/10146651
106. [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. https://www.ncbi.nlm.nih.gov/pubmed/8867274/
107. 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. https://www.ncbi.nlm.nih.gov/pubmed/11584936/
108. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC538506/
109. 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. https://www.ncbi.nlm.nih.gov/pubmed/780325
110. Moss IN, Frazier CV, Martin GJ. Bromelain -the pharmacology of the enzyme. Archives of International Pharmacody. 1963;145:166–189. https://www.ncbi.nlm.nih.gov/pubmed/14077679
111. 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. https://www.ncbi.nlm.nih.gov/pubmed/10523679