Bromelain a Potential Bioactive Compound: A Comprehensive Overview from a Pharmacological Perspective

Heinicke, 1957, Stem bromelain—A new protease preparation from pineapple plants, Econ. Bot., 11, 225, 10.1007/BF02860437

Hatano, 1996, Solution structure of bromelain inhibitor VI from pineapple stem: Structural similarity with Bowman—Birk trypsin/chymotrypsin inhibitor from soybean, Biochemistry, 35, 5379, 10.1021/bi952754+

Tayab, M.A., Chowdhury, K.A.A., Jabed, M., Mohammed Tareq, S., Kamal, A.T.M.M., Islam, M.N., Uddin, A.M.K., Hossain, M.A., Emran, T.B., and Simal-Gandara, J. (2021). Antioxidant-Rich Woodfordia fruticosa Leaf Extract Alleviates Depressive-Like Behaviors and Impede Hyperglycemia. Plants, 10.

Mamo, 2019, Antibacterial and Anticancer Property of Bromelain: A Plant Protease Enzyme from Pineapples (Ananas comosus), Curr. Trends Biomed. Eng. Biosci., 19, 60

Manzoor, Z., Nawaz, A., Mukhtar, H., and Haq, I. (2016). Bromelain: Methods of Extraction, Purification and Therapeutic Applications. Braz. Arch. Biol. Technol., 59.

Bhui, 2009, 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., 282, 167, 10.1016/j.canlet.2009.03.003

Mynott, 1999, Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells, J. Immunol., 163, 2568, 10.4049/jimmunol.163.5.2568

Bhattacharyya, 2008, Bromelain: An overview, Indian J. Nat. Prod. Resour., 7, 359

Chobotova, 2010, Bromelain’s activity and potential as an anti-cancer agent: Current evidence and perspectives, Cancer Lett., 290, 148, 10.1016/j.canlet.2009.08.001

Tochi, 2008, Therapeutic application of pineapple protease (Bromelain): A review, Pak. J. Nutr., 7, 513, 10.3923/pjn.2008.513.520

Ataide, 2018, Bromelain-loaded nanoparticles: A comprehensive review of the state of the art, Adv. Colloid Interface Sci., 254, 48, 10.1016/j.cis.2018.03.006

Dighe, 2010, Bromelain A Wonder Supplement: A Review, Pharmacologyonline, 1, 11

Munzig, 1994, Bromelain protease F9 reduces the CD44 mediated adhesion of human peripheral blood lymphocytes to human umbilical vein endothelial cells, FEBS Lett., 351, 215, 10.1016/0014-5793(94)00860-4

Jyoti, M.A., Barua, N., Hossain, M.S., Hoque, M., Bristy, T.A., Mahmud, S., Adnan, M., Chy, M.N.U., and Paul, A. (2020). Unravelling the biological activities of the Byttneria pilosa leaves using experimental and computational approaches. Molecules, 25.

Houck, 1983, Isolation of an effective debriding agent from the stems of pineapple plants, Int. J. Tissue React., 5, 125

Larocca, 2010, Analysis of pineapple [Ananas comosus (L.) Merr.] fruit proteinases by 2-D zymography and direct identification of the major zymographic spots by mass spectrometry, Food Chem., 123, 1334, 10.1016/j.foodchem.2010.06.016

Pavan, 2012, Properties and Therapeutic Application of Bromelain: A Review, Biotechnol. Res. Int., 2012, 976203, 10.1155/2012/976203

Corzo, 2012, Pineapple fruit bromelain affinity to different protein substrates, Food Chem., 133, 631, 10.1016/j.foodchem.2011.05.119

Harrach, 1998, Isolation and characterization of two forms of an acidic bromelain stem proteinase, J. Protein Chem., 17, 351, 10.1023/A:1022507316434

Illanes, A. (2008). Enzyme Biocatalysis: Principles and Applications, Springer.

Abreu, 2019, Bromelain separation and purification processes from pineapple extract, Braz. J. Chem. Eng., 36, 1029, 10.1590/0104-6632.20190362s20180417

Benucci, 2011, Bromelain from pineapple stem in alcoholic-acidic buffers for wine application, Food Chem., 124, 1349, 10.1016/j.foodchem.2010.07.087

Manderson, 2006, Production of an active recombinant Aspin antigen in Escherichia coli for identifying animals resistant to nematode infection, Enzyme Microb. Technol., 38, 591, 10.1016/j.enzmictec.2005.03.029

Muntari, 2012, Recombinant bromelain production in Escherichia coli: Process optimization in shake flask culture by response surface methodology, AMB Express, 2, 12, 10.1186/2191-0855-2-12

Dutta, 2020, Pharmacological evidence for the use of Cissus assamica as a medicinal plant in the management of pain and pyrexia, Biochem. Biophys. Rep., 21, 100715

Maurer, 2001, Bromelain: Biochemistry pharmacology and medical use, Cell. Mol. Life Sci., 58, 1234, 10.1007/PL00000936

Harrach, 1995, Isolation and partial characterization of basic proteinases from stem bromelain, J. Protein Chem., 14, 41, 10.1007/BF01902843

Hidayat, 2019, Green peas protein hydrolyzed by bromelain in simple procedure to improve kidney function in cisplatin-induced rats, J. Rep. Pharm. Sci., 8, 68, 10.4103/jrptps.jrptps_15_17

Steinkraus, 1976, The use of bromelain in the hydrolysis of mackerel and the investigation of fermented fish aroma, Int. J. Food Sci. Technol., 11, 379, 10.1111/j.1365-2621.1976.tb00736.x

Babu, 2008, Liquid-liquid extraction of bromelain and polyphenol oxidase using aqueous two-phase system, Chem. Eng. Process. Process. Intensif., 47, 83, 10.1016/j.cep.2007.08.006

Ketnawa, 2011, Aqueous two-phase extraction of bromelain from pineapple peels (‘Phu Lae’ cultv.) and its biochemical properties, Food Sci. Biotechnol., 20, 1219, 10.1007/s10068-011-0168-5

Krishna, 2002, Reverse micellar extraction for downstream processing of proteins/enzymes, Adv. Biochem. Eng. Biotechnol., 75, 119

Ahmed, 2019, In vivo and in vitro pharmacological activities of Tacca integrifolia rhizome and investigation of possible lead compounds against breast cancer through in silico approaches, Clin. Phytosci., 5, 36, 10.1186/s40816-019-0127-x

Mezzanotte, 2003, Study on anaerobic and aerobic degradation of different non-ionic surfactants, Bioresour. Technol., 87, 87, 10.1016/S0960-8524(02)00211-0

Sumana, 2008, Use of reverse micellar systems for the extraction and purification of bromelain from pineapple wastes, Bioresour. Technol., 99, 4896, 10.1016/j.biortech.2007.09.038

Hebbar, 2012, Separation and Purification of Bromelain by Reverse Micellar Extraction Coupled Ultrafiltration and Comparative Studies with Other Methods, Food Bioprocess Technol., 5, 1010, 10.1007/s11947-010-0395-4

Hung, 2002, Purification and characterization of hydrolase with chitinase and chitosanase activity from commercial stem bromelain, J. Agric. Food Chem., 50, 4666, 10.1021/jf0114886

Arumugam, 2013, Pineapple fruit bromelain recovery using recyclable functionalized ordered mesoporous silica synthesized from sugarcane leaf ash, Braz. J. Chem. Eng., 30, 477, 10.1590/S0104-66322013000300006

Swaroop, 2013, Isolation and Characterization of Bromelain (BML) Proteases from Ananas cosmosus an asset to Cancer Chemotherapy, Int. J. Pharmacol. Toxicol., 1, 82

Biswas, 2014, An in vitro antibacterial and antifungal effects of cadmium(II) complexes of hexamethyltetraazacyclotetradecadiene and isomers of its saturated analogue, Asian Pac. J. Trop. Med., 7, S534, 10.1016/S1995-7645(14)60286-8

Costa, 2009, Proteolytic Activity in Stems of ‘Vitória’, ‘Smooth Cayenne’ and ‘Pérola’ Pineapple Plants, Acta Hortic., 822, 239, 10.17660/ActaHortic.2009.822.29

Devakate, 2009, Purification and drying of bromelain, Sep. Purif. Technol., 64, 259, 10.1016/j.seppur.2008.09.012

Yin, 2011, Preparative purification of bromelain (EC 3.4.22.33) from pineapple fruit by high-speed counter-current chromatography using a reverse-micelle solvent system, Food Chem., 129, 925, 10.1016/j.foodchem.2011.05.048

Taussig, 1980, The mechanism of the physiological action of bromelain, Med. Hypotheses, 6, 99, 10.1016/0306-9877(80)90038-9

Rathnavelu, 2016, Potential role of bromelain in clinical and therapeutic applications (Review), Biomed. Rep., 5, 283, 10.3892/br.2016.720

Lopes, 2007, In vivo antitumoral activity of stem pineapple (Ananas comosus) bromelain, Planta Med., 73, 1377, 10.1055/s-2007-990221

Qais, 2017, Phytochemical investigations and antioxidant potential of leaf of Leea macrophylla (Roxb.), BMC Res. Notes, 10, 245, 10.1186/s13104-017-2503-2

Juhasz, 2008, Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium, Am. J. Physiol. Heart Circ. Physiol., 294, H1365, 10.1152/ajpheart.01005.2007

Lima, 2012, Bromelain enzyme from pineapple: In vitro activity study under different micropropagation conditions, Appl. Biochem. Biotechnol., 168, 234, 10.1007/s12010-012-9753-1

Bhui, 2010, Pineapple bromelain induces autophagy, facilitating apoptotic response in mammary carcinoma cells, BioFactors, 36, 474, 10.1002/biof.121

Dhandayuthapani, 2012, Bromelain-induced apoptosis in GI-101A breast cancer cells, J. Med. Food, 15, 344, 10.1089/jmf.2011.0145

Bhui, 2012, Bromelain inhibits nuclear factor kappa-B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G 2/M arrest to apoptosis, Mol. Carcinog., 51, 231, 10.1002/mc.20769

Harrach, 1994, Bromelain proteinases modulate the cd44 expression on human molt-4/8 leukemia and sk-mel-28 melanoma-cells in-vitro, Int. J. Oncol., 5, 485

Paschke, S., Jafarov, S., Staib, L., Kreuser, E.D., Maulbecker-Armstrong, C., Roitman, M., Holm, T., Harris, C.C., Link, K.H., and Kornmann, M. (2018). Are colon and rectal cancer two different tumor entities? A proposal to abandon the term colorectal cancer. Int. J. Mol. Sci., 19.

Chang, T.C., Wei, P.L., Makondi, P.T., Chen, W.T., Huang, C.Y., and Chang, Y.J. (2019). Bromelain inhibits the ability of colorectal cancer cells to proliferate via activation of ROS production and autophagy. PLoS ONE, 14.

Higashi, 2020, Efficient Anticancer Drug Delivery for Pancreatic Cancer Treatment Utilizing Supramolecular Polyethylene-Glycosylated Bromelain, ACS Appl. Bio Mater., 3, 3005, 10.1021/acsabm.0c00070

Pillai, 2020, Enhancing the potency of chemotherapeutic agents by combination with bromelain and N-acetylcysteine—An in vitro study with pancreatic and hepatic cancer cells, Am. J. Transl. Res., 12, 7404

Rahaman, M.M., Rakib, A., Mitra, S., Tareq, A.M., Emran, T.B., Shahid-Ud-daula, A.F.M., Amin, M.N., and Simal-Gandara, J. (2021). The genus curcuma and inflammation: Overview of the pharmacological perspectives. Plants, 10.

Huang, 2008, Bromelain inhibits lipopolysaccharide-induced cytokine production in human THP-1 monocytes via the removal of CD14, Immunol. Investig., 37, 263, 10.1080/08820130802083622

Gaspani, 2002, In vivo and in vitro effects of bromelain on PGE2 and SP concentrations in the inflammatory exudate in rats, Pharmacology, 65, 83, 10.1159/000056191

Emran, T.B., Rahman, M.A., Uddin, M.M.N., Rahman, M.M., Uddin, M.Z., Dash, R., and Layzu, C. (2015). Effects of organic extracts and their different fractions of five Bangladeshi plants on in vitro thrombolysis. BMC Complement. Altern. Med., 15.

Engwerda, 2001, Bromelain activates murine macrophages and natural killer cells in vitro, Cell. Immunol., 210, 5, 10.1006/cimm.2001.1793

Engwerda, 2001, Bromelain modulates T cell and B cell immune responses in vitro and in vivo, Cell. Immunol., 210, 66, 10.1006/cimm.2001.1807

Barth, 2005, In vitro study on the immunological effect of bromelain and trypsin on mononuclear cells from humans, Eur. J. Med. Res., 10, 325

Kane, 2000, Use of bromelain for mild ulcerative colitis, Ann. Intern. Med., 132, 680, 10.7326/0003-4819-132-8-200004180-00026

Hale, 2005, Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease, Clin. Immunol., 116, 135, 10.1016/j.clim.2005.04.011

Onken, 2008, Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro, Clin. Immunol., 126, 345, 10.1016/j.clim.2007.11.002

Stopper, 2003, Genotoxicity of advanced glycation end products in mammalian cells, Cancer Lett., 190, 151, 10.1016/S0304-3835(02)00626-2

Rahman, 2013, Antioxidative, antimicrobial and cytotoxic effects of the phenolics of Leea indica leaf extract, Saudi J. Biol. Sci., 20, 213, 10.1016/j.sjbs.2012.11.007

Subramaniam, 2007, Soluble CD44 secretion contributes to the acquisition of aggressive tumor phenotype in human colon cancer cells, Exp. Mol. Pathol., 83, 341, 10.1016/j.yexmp.2007.08.007

Bierie, 2006, Tumour microenvironment—TGFΒ: The molecular Jekyll and Hyde of cancer, Nat. Rev. Cancer, 6, 506, 10.1038/nrc1926

Leipner, 2001, Therapy with proteolytic enzymes in rheumatic disorders, BioDrugs, 15, 779, 10.2165/00063030-200115120-00001

Moss, 1963, Bromelains. the Pharmacology of the Enzymes, Arch. Int. Pharmacodyn. Thérapie, 145, 166

Giacca, 1964, Clinical Experiences on the Action of Bromelin in Peripheral Venous Diseases and in Chronic Bronchitic States, Minerva Med., 55, 3925

Bakare, 2020, Antinociceptive and neuroprotective effects of bromelain in chronic constriction injury-induced neuropathic pain in Wistar rats, Korean J. Pain, 33, 13, 10.3344/kjp.2020.33.1.13

Pirotta, 1978, Bromelain interaction with some protease inhibitors and rabbit specific antiserum, Drugs Exp. Clin., 4, 21

Jahan, I., Tona, M.R., Sharmin, S., Sayeed, M.A., Tania, F.Z., Paul, A., Chy, M., Uddin, N., Rakib, A., and Emran, T.B. (2020). GC-MS phytochemical profiling, pharmacological properties, and in silico studies of Chukrasia velutina leaves: A novel source for bioactive agents. Molecules, 25.

Brakebusch, 2001, Bromelain is an accelerator of phagocytosis, respiratory burst and Killing of Candida albicans by human granulocytes and monocytes, Eur. J. Med. Res., 6, 193

Sartini, S., Permana, A.D., Mitra, S., Tareq, A.M., Salim, E., Ahmad, I., Harapan, H., Emran, T.B., and Nainu, F. (2021). Current State and Promising Opportunities on Pharmaceutical Approaches in the Treatment of Polymicrobial Diseases. Pathogens, 10.

Massimiliano, 2007, Role of bromelain in the treatment of patients with pityriasis lichenoides chronica, J. Dermatolog. Treat., 18, 219, 10.1080/09546630701299147

Uddin, M.Z., Paul, A., Rakib, A., Sami, S.A., Mahmud, S., Rana, M.S., Hossain, S., Tareq, A.M., Dutta, M., and Emran, T.B. (2021). Chemical Profiles and Pharmacological Properties with In Silico Studies on Elatostema papillosum Wedd. Molecules, 26.

Taussig, 1988, Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update, J. Ethnopharmacol., 22, 191, 10.1016/0378-8741(88)90127-4

Rakib, 2020, Pharmacological studies on the antinociceptive, anxiolytic and antidepressant activity of Tinospora crispa, Phytother. Res., 34, 2978, 10.1002/ptr.6725

Errasti, 2016, Effects on fibrinogen, fibrin, and blood coagulation of proteolytic extracts from fruits of Pseudananas macrodontes, Bromelia balansae, and B. hieronymi (Bromeliaceae) in comparison with bromelain, Blood Coagul. Fibrinolysis, 27, 441, 10.1097/MBC.0000000000000531

Kelly, 1996, Bromelain: A literature review and discussion of its therapeutic applications, Altern. Med. Rev., 1, 243

Ratnaningsih, 2018, The Effectiveness of Waste Crude Bromelain Pineapple and Papaya Fruit Mixture as Anti-Plaque Toothpaste, J. Med. Sci. Clin. Res., 6, 1

Harmely, 2015, Efektifitas Bromelain Kasar dari Batang Nenas (Ananas comosus L. Merr) sebagai Antiplak dalam Pasta Gigi, Sci. J. Farm. Dan Kesehat., 1, 14

Howat, 1972, The Effect of Bromelain Therapy on Episiotomy Wounds—A Double Blind Controlled Clinical Trial, BJOG Int. J. Obstet. Gynaecol., 79, 951, 10.1111/j.1471-0528.1972.tb12194.x

Singer, 2010, Rapid and selective enzymatic debridement of porcine comb burns with bromelain-derived Debrase®: Acute-phase preservation of noninjured tissue and zone of stasis, J. Burn Care Res., 31, 304, 10.1097/BCR.0b013e3181d0f4d4

Krieger, 2005, Escharotomy using an enzymatic debridement agent for treating experimental burn-induced compartment syndrome in an animal model, J. Trauma Inj. Infect. Crit. Care, 58, 1259, 10.1097/01.TA.0000169867.08607.F1

Rosenberg, 2004, Safety and efficacy of a proteolytic enzyme for enzymatic burn debridement: A preliminary report, Burns, 30, 843, 10.1016/j.burns.2004.04.010

Banu, N., Alam, N., Islam, M.N., Islam, S., Sakib, S.A., Hanif, N.B., Chowdhury, M.R., Tareq, A.M., Chowdhury, K.H., and Jahan, S. (2020). Insightful Valorization of the Biological Activities of Pani Heloch Leaves through Experimental and Computer-Aided Mechanisms. Molecules, 25.

Lawrence, 1998, Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States, Arthritis Rheum., 41, 778, 10.1002/1529-0131(199805)41:5<778::AID-ART4>3.0.CO;2-V

Bodi, 1966, The Effects of Oral Bromelains on Tissue Permeability to Antibiotics and Pain Response to Bradykinin: Double Blind Studies on Human Subjects, Clin. Med., 73, 61

Kumakura, 1988, Effect of bromelain on kaolin-induced inflammation in rats, Eur. J. Pharmacol., 150, 295, 10.1016/0014-2999(88)90010-6

Brien, 2004, Bromelain as a Treatment for Osteoarthritis: A Review of Clinical Studies, Evid. Based Complement. Altern. Med., 1, 251, 10.1093/ecam/neh035

Akhtar, 2004, Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—A double-blind prospective randomized study, Clin. Rheumatol., 23, 410, 10.1007/s10067-004-0902-y

Renzini, 1972, Absorption of tetracycline in presence of bromelain after oral administration, Arzneim.-Forsch./Drug Res., 22, 410

Bradbrook, 1978, The effect of bromelain on the absorption of orally administered tetracycline, Br. J. Clin. Pharmacol., 6, 552, 10.1111/j.1365-2125.1978.tb00888.x

Tinozzi, 1978, Effect of bromelain on serum and tissue levels of amoxycillin, Drugs Exp. Clin. Res., 4, 39

Tumilaar, 2021, Potential of leaf extract of Pangium edule Reinw as HIV-1 protease inhibitor: A computational biology approach, J. Appl. Pharm. Sci., 11, 101

Batkin, 1988, Antimetastatic effect of bromelain with or without its proteolytic and anticoagulant activity, J. Cancer Res. Clin. Oncol., 114, 507, 10.1007/BF00391501

Bristy, T.A., Barua, N., Tareq, A.M., Sakib, S.A., Etu, S.T., Chowdhury, K.H., Jyoti, M.A., Aziz, M., Ibn, A., and Reza, A. (2020). Deciphering the pharmacological properties of methanol extract of Psychotria calocarpa leaves by in vivo, in vitro and in silico approaches. Pharmaceuticals, 13.

Shukuru, 2020, Toxicity, anthelmintic efficacy and proteolytic activity of chitosan-encapsulated bromelain within the gastrointestinal tract of small east african goats, World’s Vet. J., 10, 190

Rakesh, 2016, In vitro evaluation of anthelmintic efficacy of bromelain against goat gastrointestinal nematodes, J. Vet. Parasitol., 30, 68

Saptarini, 2020, Immunomodulatory Activity of Crude Bromelain of Pineapple (Ananas comosus (L.) Merr.) Crown from Subang District, Indonesia, Res. J. Pharm. Technol., 13, 5177

Golezar, S. (2016). Ananas comosus effect on perineal pain and wound healing after episiotomy: A randomized double-blind placebo-controlled clinical trial. Iran. Red Crescent Med. J., 18.

Majid, 2014, Perioperative bromelain reduces pain and swelling and improves quality of life measures after mandibular third molar surgery: A randomized, double-blind, placebo-controlled clinical trial, J. Oral Maxillofac. Surg., 72, 1043, 10.1016/j.joms.2013.12.035

Walker, 2002, Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults, Phytomedicine, 9, 681, 10.1078/094471102321621269

Bakare, 2020, Bromelain reversed electrolyte imbalance in the chronically constricted sciatic nerve of Wistar rats, Naunyn. Schmiedebergs. Arch. Pharmacol., 393, 457, 10.1007/s00210-019-01744-w

Mallik, 2019, Evaluation of Ananas comosus Fruit for Antiulcer Potentials on Experimental Animals, J. Harmon. Res. Appl. Sci., 7, 89, 10.30876/JOHR.7.2.2019.89-97

Rahman, J., Tareq, A.M., Hossain, M.M., Sakib, S.A., Islam, M.N., Uddin, A.B.M.N., Hoque, M., Nasrin, M.S., Ali, M.H., and Caiazzo, E. (2020). Biological evaluation, DFT calculations and molecular docking studies on the antidepressant and cytotoxicity activities of Cycas pectinata Buch.-Ham. Compounds. Pharmaceuticals, 13.

Tassman, 1965, A Double-Blind Crossover Study of a Plant Proteolytic Enzyme in Oral Surgery, J. Dent. Med., 20, 51

Rakib, 2020, Antipyretic and hepatoprotective potential of Tinospora crispa and investigation of possible lead compounds through in silico approaches, Food Sci. Nutr., 8, 547, 10.1002/fsn3.1339

Secor, 2012, Bromelain Limits Airway Inflammation in an Ovalbumin-induced Murine Model of Established Asthma, Altern. Ther. Health Med., 18, 9

Secor, 2005, Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease, Cell. Immunol., 237, 68, 10.1016/j.cellimm.2005.10.002

Jaber, 2002, Respiratory and allergic diseases: From upper respiratory tract infections to asthma, Prim. Care Clin. Off. Pract., 29, 231, 10.1016/S0095-4543(01)00008-2

Secor, 2013, Bromelain inhibits allergic sensitization and murine asthma via modulation of dendritic cells, Evid. Based Complement. Altern. Med., 2013, 702196, 10.1155/2013/702196

Uddin, 2019, In vivo neuroprotective, antinociceptive, anti-inflammatory potential in Swiss albino mice and in vitro antioxidant and clot lysis activities of fractionated Holigarna longifolia Roxb. bark extract, J. Complement. Integr. Med., 17, 1

Someshwar, 2012, Pityriasislichenoides, Indian Pediatr., 49, 936, 10.1007/s13312-012-0212-4

Shifah, 2020, Antidiarrheal, cytotoxic and thrombolytic activities of methanolic extract of Hedychium coccineum leaves, J. Adv. Biotechnol. Exp. Ther., 3, 77, 10.5455/jabet.2020.d110

Gabrielli, 2009, Scleroderma, N. Engl. J. Med., 360, 1989, 10.1056/NEJMra0806188

Gaby, 2006, Natural remedies for scleroderma, Altern. Med. Rev., 11, 188

Emran, 2015, Molecular docking and inhibition studies on the interactions of Bacopa monnieri’s potent phytochemicals against Staphylococcus aureus, DARU J. Pharma. Sci., 23, 26, 10.1186/s40199-015-0106-9

Hale, 2002, Bromelain treatment alters leukocyte expression of cell surface molecules involved in cellular adhesion and activation, Clin. Immunol., 104, 183, 10.1006/clim.2002.5254

Hale, 2005, Proteinase activity and stability of natural bromelain preparations, Int. Immunopharmacol., 5, 783, 10.1016/j.intimp.2004.12.007

Fahad, F.I., Barua, N., Islam, M.S., Sayem, S.A.J., Barua, K., Uddin, M.J., Chy, M.N.U., Adnan, M., Islam, M.N., and Sayeed, M.A. (2021). Investigation of the Pharmacological Properties of Lepidagathis hyaline Nees through Experimental Approaches. Life, 11.

Praveen, 2014, In vitro Evaluation of Antibacterial Efficacy of Pineapple Extract (Bromelain) on Periodontal Pathogens, J. Int. Oral Health JIOH, 6, 96

Giller, 1962, The effect of bromelain on levels of penicillin in the cerebrospinal fluid of rabbits, Am. J. Pharm. Sci. Support. Public Health, 134, 238

1990, On the pharmacology of bromelain: An update with special regard to animal studies on dose-dependent effects, Planta Med., 56, 249, 10.1055/s-2006-960949

Bahde, 2007, Bromelain Ameliorates Hepatic Microcirculation After Warm Ischemia, J. Surg. Res., 139, 88, 10.1016/j.jss.2006.10.004

Guha, 2021, Unveiling pharmacological studies provide new insights on Mangifera longipes and Quercus gomeziana, Saudi J. Biol. Sci., 28, 183, 10.1016/j.sjbs.2020.09.037

Tona, 2020, Phytochemical screening and in vitro pharmacological activities of methanolic leaves extract of Caryota mitis, J. Adv. Biotechnol. Exp. Ther., 3, 109, 10.5455/jabet.2020.d114

Tareq, 2020, Possible neuropharmacological effects of Apis cerana indica beehive in the Swiss Albino mice, J. Adv. Biotechnol. Exp. Ther., 3, 128, 10.5455/jabet.2020.d117

Kargutkar, 2016, Anti-rheumatic activity of Ananas comosus fruit peel extract in a complete Freund’s adjuvant rat model, Pharm. Biol., 54, 2616, 10.3109/13880209.2016.1173066

Hu, 2011, Facile synthesis of 3D cubic mesoporous silica microspheres with a controllable pore size and their application for improved delivery of a water-insoluble drug, J. Colloid Interface Sci., 363, 410, 10.1016/j.jcis.2011.07.022

Parodi, 2014, Bromelain surface modification increases the diffusion of silica nanoparticles in the tumor extracellular matrix, ACS Nano, 8, 9874, 10.1021/nn502807n

Couto, 2017, Gold nanoparticles and bioconjugation: A pathway for proteomic applications, Crit. Rev. Biotechnol., 37, 238, 10.3109/07388551.2016.1141392

Khan, 2015, A novel process for size controlled biosynthesis of gold nanoparticles using bromelain, Mater. Lett., 159, 373, 10.1016/j.matlet.2015.06.118

Cattoz, 2015, Nanoparticles decorated with proteolytic enzymes, a promising strategy to overcome the mucus barrier, Eur. J. Pharm. Biopharm., 97, 257, 10.1016/j.ejpb.2015.01.008

Bodnar, 2009, Preparation and characterization of poly(acrylic acid)-based nanoparticles, Colloid Polym. Sci., 287, 739, 10.1007/s00396-009-2061-9

Nagpal, 2010, Chitosan nanoparticles: A promising system in novel drug delivery, Chem. Pharm. Bull., 58, 1423, 10.1248/cpb.58.1423

Ataide, J.A., Gérios, E.F., Cefali, L.C., Fernandes, A.R., Teixeira, M.d.C., Ferreira, N.R., Tambourgi, E.B., Jozala, A.F., Chaud, M.V., and Oliveira-Nascimento, L. (2019). Effect of polysaccharide sources on the physicochemical properties of Bromelain-Chitosan nanoparticlesw. Polymers, 11.

Pauzi, 2016, Combination of cisplatin and bromelain exerts synergistic cytotoxic effects against breast cancer cell line MDA-MB-231 in vitro, Chin. Med., 11, 46, 10.1186/s13020-016-0118-5

Kritis, 2020, The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19, Metab. Open, 8, 100066, 10.1016/j.metop.2020.100066

Akhter, J., Queromes, G., Pillai, K., Kepenekian, V., Badar, S., Mekkawy, A., Frobert, E., Valle, S., and Morris, D.L. (2021). The combination of Bromelain and Acetylcysteine (BromAc) synergistically inactivates SARS-CoV-2. Viruses, 13.

Pekas, 2021, Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: A double-blind placebo-controlled randomised crossover clinical trial, Br. J. Nutr., 125, 161, 10.1017/S0007114520002548

Rahman, 2013, Effects of organic extracts of six Bangladeshi plants on in vitro thrombolysis and cytotoxicity, BMC Complement. Altern. Med., 13, 25, 10.1186/1472-6882-13-25

Orsini, 2006, Bromelain, Plast. Reconstr. Surg., 118, 1640, 10.1097/01.prs.0000242503.50548.ee

Taussig, 1975, Bromelain: A proteolytic enzyme and its clinical application. A review, Hiroshima J. Med. Sci., 24, 185

Seligman, 1962, Bromelain: An anti-inflammatory agent, Angiology, 13, 508, 10.1177/000331976201301103

Cohen, 1964, Bromelains Therapy in Rheumatoid Arthritis, Pa. Med. J., 67, 27

Klein, 2000, Short-term treatment of painful osteoarthritis of the knee with oral enzymes. A randomised, double-blind study versus diclofenac, Clin. Drug Investig., 19, 15, 10.2165/00044011-200019010-00003

Tilwe, 2001, Efficacy and Tolerability of Oral Enzyme Therapy as Compared to Diclofenac in Active Osteoarthrosis of Knee Joint: An Open Randomized Controlled Clinical Trial, J. Assoc. Physicians India, 49, 617

Emran, 2016, Evaluation of analgesic, anti-inflammatory, thrombolytic and hepatoprotective activities of roots of Premna esculenta (Roxb), J. Basic Clin. Physiol. Pharmacol., 27, 63, 10.1515/jbcpp-2015-0056

Ordesi, 2014, Therapeutic efficacy of bromelain in impacted third molar surgery: A randomized controlled clinical study, Quintessence Int., 45, 679

Baur, 1979, Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure, Clin. Exp. Allergy, 9, 443, 10.1111/j.1365-2222.1979.tb02507.x

Masson, 1995, Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice, Fortschr. Med., 113, 303

Cirelli, 1963, Effects of bromelain anti-edema therapy on coagulation, bleeding, and prothrombin times, J. New Drugs, 3, 37, 10.1002/j.1552-4604.1963.tb00060.x

Rosenberg, 2015, Minimally invasive burn care: A review of seven clinical studies of rapid and selective debridement using a bromelain-based debriding enzyme (Nexobrid®), Ann. Burns Fire Disasters, 28, 264