Advertisement

Plant Proteolytic Enzymes: Their Role as Natural Pharmacophores

  • Carlos E. Salas
  • Dalton Dittz
  • Maria-Jose Torres
Chapter

Abstract

Proteases or proteinases are enzymes that catalyze cleavage of proteins at peptide bonds generating smaller peptides. Some of them are very specific in their choice of target site while others act rather nonspecifically and hydrolyze the protein substrate if conditions allow into short peptides. They must have appeared early in evolution along with proteins, to keep a balance between synthesis and protein degradation. Their early emergence is confirmed by their ubiquitous presence in most living forms including viruses, plants, and animals.

Keywords

Inflammation Immunomodulation Wound healing Antitumoral Dalton Bioactive peptides Protease inhibitors 

References

  1. Abdul Khalek A, Elkateb MA, Abdel Aziz WE, El Tantawi M (2017) Effect of papacarie and alternative restorative treatment on pain reaction during caries removal among children: a randomized controlled clinical trial. J Clin Pediatr Dent 41:219–224.  https://doi.org/10.17796/1053-4628-41.3.219CrossRefGoogle Scholar
  2. Agoro R, Piotet-Morin J, Palomo J, Michaudel C, Vigne S, Maillet I, Chenuet P, Guillou N, Le Bérichel J, Kisielow M, Flodby P, Borok Z, Crandall ED, Le Bert M, Quesniaux V, Muller M, Di Padova F, Ryffel B, Gabay C, Couturier-Maillard A (2016) IL-1R1-MyD88 axis elicits papain-induced lung inflammation. Eur J Immunol 46:2531–2541.  https://doi.org/10.1002/eji.201646366CrossRefGoogle Scholar
  3. Agostinis C, Zorzet S, De Leo R, Zauli G, De Seta F, Bulla R (2015) The combination of N-acetyl cysteine, alpha-lipoic acid, and bromelain shows high anti-inflammatory properties in novel in vivo and in vitro models of endometriosis. Mediat Inflamm 2015:918089.  https://doi.org/10.1155/2015/918089CrossRefGoogle Scholar
  4. Aichele K, Bubel M, Deubel G, Pohlemann T, Oberringer M (2013) Bromelain down-regulates myofibroblast differentiation in an in vitro wound healing assay. Naunyn Schmiedeberg’s Arch Pharmacol 386(10):853–863CrossRefGoogle Scholar
  5. Aiyegbusi AI, Duru FI, Awelimobor D, Noronha CC, Okanlawon AO (2010) The role of aqueous extract of pineapple fruit parts on the healing of acute crush tendon injury. Nig Q J Hosp Med 20:223–227CrossRefGoogle Scholar
  6. Amini A, Ehteda A, Masoumi S, Moghaddam AJ, Pillai K, Morris DL (2013) Cytotoxic effects of bromelain in human gastrointestinal carcinoma cell lines (MKN45, KATO-III, HT29-5F12, and HT29-5M21). Onco Targets Ther 6:403–409.  https://doi.org/10.2147/OTT.S43072CrossRefGoogle Scholar
  7. Araujo e Silva AC, de Oliveira Lemos F, Gomes MTR, Salas CE, Lopes MTP (2015) Role of gastric acid inhibition, prostaglandins and endogenous-free thiol groups on the gastroprotective effect of a proteolytic fraction from Vasconcellea cundinamarcensis latex. J Pharm Pharmacol 67:133–141.  https://doi.org/10.1111/jphp.12318CrossRefGoogle Scholar
  8. Arruda MS, Silva FO, Egito AS, Silva TMS, Lima-Filho JL, Porto ALF, Moreira KA (2012) New peptides obtained by hydrolysis of caseins from bovine milk by protease extracted from the latex Jacaratia corumbensis. LWT - Food Sci Technol 49:73–79.  https://doi.org/10.1016/J.LWT.2012.04.001CrossRefGoogle Scholar
  9. Atacan K, Özacar M, Özacar M (2018) Investigation of antibacterial properties of novel papain immobilized on tannic acid modified Ag/CuFe2O4magnetic nanoparticles. Int J Biol Macromol 109:720–731.  https://doi.org/10.1016/j.ijbiomac.2017.12.066CrossRefGoogle Scholar
  10. Auwal S, Zarei M, Tan C, Basri M, Saari N (2017) Improved in vivo efficacy of anti-hypertensive biopeptides encapsulated in chitosan nanoparticles fabricated by ionotropic gelation on spontaneously hypertensive rats. Nanomaterials 7:421.  https://doi.org/10.3390/nano7120421CrossRefGoogle Scholar
  11. Bagga P, Ansari TM, Siddiqui HH, Syed A, Bahkali AH, Rahman MA, Khan MS (2016) Bromelain capped gold nanoparticles as the novel drug delivery carriers to aggrandize effect of the antibiotic levofloxacin. EXCLI J 15:772–780.  https://doi.org/10.17179/excli2016-710CrossRefGoogle Scholar
  12. Balakireva AV, Kuznetsova NV, Petushkova AI, Savvateeva L, Zamyatnin AA (2017) Trends and prospects of plant proteases in therapeutics. Curr Med Chem.  https://doi.org/10.2174/0929867325666171123204403
  13. Barrett AJ, Fred Woessner J (2013) Handbook of proteolytic enzymes. Academic, London, pp li–livCrossRefGoogle Scholar
  14. Baur X, Fruhmann G (1979) Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure. Clin Allergy 9:443–450CrossRefGoogle Scholar
  15. Bernela M, Ahuja M, Thakur R (2016) Enhancement of anti-inflammatory activity of bromelain by its encapsulation in katira gum nanoparticles. Carbohydr Polym 143:18–24.  https://doi.org/10.1016/j.carbpol.2016.01.055CrossRefGoogle Scholar
  16. Beuth J (2008) Proteolytic enzyme therapy in evidence-based complementary oncology: fact or fiction? Integr Cancer Ther 7:311–316.  https://doi.org/10.1177/1534735408327251CrossRefGoogle Scholar
  17. Bhatnagar P, Patnaik S, Srivastava AK, Mudiam MKR, Shukla Y, Panda AK, Pant AB, Kumar P, Gupta KC (2014) Anti-cancer activity of bromelain nanoparticles by oral administration. J Biomed Nanotechnol 10:3558–3575CrossRefGoogle Scholar
  18. Bhatnagar P, Pant AB, Shukla Y, Chaudhari B, Kumar P, Gupta KC (2015) Bromelain nanoparticles protect against 7,12-dimethylbenz[a]anthracene induced skin carcinogenesis in mouse model. Eur J Pharm Biopharm 91:35–46.  https://doi.org/10.1016/j.ejpb.2015.01.015CrossRefGoogle Scholar
  19. Bhatnagar P, Pant AB, Shukla Y, Panda A, Gupta KC (2016) Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of bromelain in Ehrlich’s ascites carcinoma. Eur J Pharm Biopharm 105:176–192.  https://doi.org/10.1016/j.ejpb.2016.06.002CrossRefGoogle Scholar
  20. Bhui K, Tyagi S, Prakash B, Shukla Y (2010) Pineapple bromelain induces autophagy, facilitating apoptotic response in mammary carcinoma cells. Biofactors 36:474–482.  https://doi.org/10.1002/biof.121CrossRefGoogle Scholar
  21. Bilheiro RP, Braga AD, Filho ML, Carvalho-Tavares J, Agero U, Carvalho M Das G, Sanchez EF, Salas CE, Lopes MTP (2013) The thrombolytic action of a proteolytic fraction (P1G10) from Carica candamarcensis. Thromb Res 131:e175–e182.  https://doi.org/10.1016/j.thromres.2013.01.028CrossRefGoogle Scholar
  22. Brien S, Lewith G, Walker AF, Middleton R, Prescott P, Bundy R (2006) Bromelain as an adjunctive treatment for moderate-to-severe osteoarthritis of the knee: a randomized placebo-controlled pilot study. QJM 99:841–850.  https://doi.org/10.1093/qjmed/hcl118CrossRefGoogle Scholar
  23. Burney RO, Giudice LC (2012) Pathogenesis and pathophysiology of endometriosis. Fertil Steril 98:511–519.  https://doi.org/10.1016/j.fertnstert.2012.06.029CrossRefGoogle Scholar
  24. Bussadori SK, Castro LC, Galvão AC (2005) Papain gel: a new chemo-mechanical caries removal agent. J Clin Pediatr Dent 30:115–119CrossRefGoogle Scholar
  25. Büttner L, Achilles N, Böhm M, Shah-Hosseini K, Mösges R (2013) Efficacy and tolerability of bromelain in patients with chronic rhinosinusitis - a pilot study. B-ENT 9:217–225Google Scholar
  26. Carrilho DM, Duarte IC, Francisco R, Ricardo CPP, Duque-Magalhães MC (2009) Discovery of novel plant peptides as strong inhibitors of metalloproteinases. Protein Pept Lett 16:543–551CrossRefGoogle Scholar
  27. Chay SY, Tan WK, Saari N (2015) Preparation and characterisation of nanoliposomes containing winged bean seeds bioactive peptides. J Microencapsul 32:488–495.  https://doi.org/10.3109/02652048.2015.1057250CrossRefGoogle Scholar
  28. Chen Y-Y, Lu Y-H, Ma C-H, Tao W-W, Zhu J-J, Zhang X (2017) A novel elastic liposome for skin delivery of papain and its application on hypertrophic scar. Biomed Pharmacother 87:82–91.  https://doi.org/10.1016/j.biopha.2016.12.076CrossRefGoogle Scholar
  29. Choi J-H, Kim D-W, Park S-E, Choi B-S, Sapkota K, Kim S, Kim S-J (2014) Novel thrombolytic protease from edible and medicinal plant Aster yomena (Kitam.) Honda with anticoagulant activity: purification and partial characterization. J Biosci Bioeng 118:372–377.  https://doi.org/10.1016/j.jbiosc.2014.03.004CrossRefGoogle Scholar
  30. Cordts T, Horter J, Vogelpohl J, Kremer T, Kneser U, Hernekamp J-F (2016) Enzymatic debridement for the treatment of severely burned upper extremities – early single center experiences. BMC Dermatol 16:8.  https://doi.org/10.1186/s12895-016-0045-2CrossRefGoogle Scholar
  31. de Menezes Y, Félix-Silva J, da Silva-Júnior A, Rebecchi I, de Oliveira A, Uchoa A, Fernandes-Pedrosa M (2014) Protein-Rich Fraction of Cnidoscolus urens (L.) Arthur Leaves: Enzymatic Characterization and Procoagulant and Fibrinogenolytic Activities. Molecules 19:3552–3569.  https://doi.org/10.3390/molecules19033552CrossRefGoogle Scholar
  32. Dąbrowska A, Szołtysik M, Babij K, Pokora M, Zambrowicz A, Chrzanowska J (2013) Application of Asian pumpkin (Cucurbita ficifolia) serine proteinase for production of biologically active peptides from casein. Acta Biochim Pol 60:117–122Google Scholar
  33. DeClerck MP, Bailey Y, Craig D, Lin M, Auerbach LJ, Linney O, Morrison DE, Patry W, Auerbach PS (2016) Efficacy of topical treatments for Chrysaora Chinensis species: a human model in comparison with an in vitro model. Wilderness Environ Med 27:25–38.  https://doi.org/10.1016/j.wem.2015.10.008CrossRefGoogle Scholar
  34. Déry O, Corvera CU, Steinhoff M, Bunnett NW (1998) Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Phys 274:C1429–C1452CrossRefGoogle Scholar
  35. Dhandayuthapani S, Perez HD, Paroulek A, Chinnakkannu P, Kandalam U, Jaffe M, Rathinavelu A (2012) Bromelain-induced apoptosis in GI-101A breast cancer cells. J Med Food 15:344–349.  https://doi.org/10.1089/jmf.2011.0145CrossRefGoogle Scholar
  36. Dittz D, Figueiredo C, Lemos FO, Viana CTR, Andrade SP, Souza-Fagundes EM, Fujiwara RT, Salas CE, Lopes MTP (2015) Antiangiogenesis, loss of cell adhesion and apoptosis are involved in the antitumoral activity of proteases from v. Cundinamarcensis (C. candamarcensis) in murine melanoma B16F1. Int J Mol Sci 16:7027–7044.  https://doi.org/10.3390/ijms16047027CrossRefGoogle Scholar
  37. Divya G, Prasad MG, Vasa AAK, Vasanthi D, Ramanarayana B, Mynampati P (2015) Evaluation of the efficacy of caries removal using polymer bur, stainless steel bur, carisolv, papacarie - an in vitro comparative study. J Clin Diagn Res 9:ZC42–ZC46.  https://doi.org/10.7860/JCDR/2015/12705.6202CrossRefGoogle Scholar
  38. Domsalla A, Melzig MF (2008) Occurrence and properties of proteases in plant latices. Planta Med 74:699–711.  https://doi.org/10.1055/s-2008-1074530CrossRefGoogle Scholar
  39. Dutta S, Bhattacharyya D (2013) Enzymatic, antimicrobial and toxicity studies of the aqueous extract of Ananas comosus (pineapple) crown leaf. J Ethnopharmacol 150:451–457.  https://doi.org/10.1016/j.jep.2013.08.024CrossRefGoogle Scholar
  40. Errasti M, Caffini N, Pelzer L, Rotelli A (2013) Anti-inflammatory activity of bromelia hieronymi: comparison with bromelain. Planta Med 79:207–213.  https://doi.org/10.1055/s-0032-1328201CrossRefGoogle Scholar
  41. Errasti ME, Prospitti A, Viana CA, Gonzalez MM, Ramos MV, Rotelli AE, Caffini NO (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 27:441–449.  https://doi.org/10.1097/MBC.0000000000000531CrossRefGoogle Scholar
  42. Eskenazi B, Warner ML (1997) Epidemiology of endometriosis. Obstet Gynecol Clin N Am 24:235–258CrossRefGoogle Scholar
  43. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP (2008) Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol 128:66–74.  https://doi.org/10.1016/j.clim.2008.02.015CrossRefGoogle Scholar
  44. Fortelny N, Cox JH, Kappelhoff R, Starr AE, Lange PF, Pavlidis P, Overall CM (2014) Network analyses reveal pervasive functional regulation between proteases in the human protease web. PLoS Biol 12:e1001869.  https://doi.org/10.1371/journal.pbio.1001869CrossRefGoogle Scholar
  45. Freitas KM, Barcelos LS, Caliari MV, Salas CE, Lopes MTP (2017) Healing activity of proteolytic fraction (P1G10) from Vasconcellea cundinamarcensis in a cutaneous wound excision model. Biomed Pharmacother 96:269–278.  https://doi.org/10.1016/j.biopha.2017.09.109CrossRefGoogle Scholar
  46. Gajanan PG, Elavarasan K, Shamasundar BA (2016) Bioactive and functional properties of protein hydrolysates from fish frame processing waste using plant proteases. Environ Sci Pollut Res Int 23:24901–24911.  https://doi.org/10.1007/s11356-016-7618-9CrossRefGoogle Scholar
  47. 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:e21019.  https://doi.org/10.5812/ircmj.21019CrossRefGoogle Scholar
  48. Gomes MTRTR, Mello VJ, Rodrigues KC, Bemquerer MP, Lopes MTP, Faça VM, Salas CE (2005) Isolation of two plant proteinases in latex from Carica candamarcensis acting as mitogens for mammalian cells. Planta Med 71:244–248.  https://doi.org/10.1055/s-2005-837824CrossRefGoogle Scholar
  49. Gomes MTR, Turchetti AP, Lopes MTP, Salas CE (2009) Stimulation of fibroblast proliferation by the plant cysteine protease CMS2MS2 is independent of its proteolytic activity and requires ERK activation. Biol Chem 390:1285–1291.  https://doi.org/10.1515/BC.2009.137CrossRefGoogle Scholar
  50. Gomes FSL, Spínola CDV, Ribeiro HA, Lopes MTP, Cassali GD, Salas CE (2010) Wound-healing activity of a proteolytic fraction from Carica candamarcensis on experimentally induced burn. Burns 36:277–283.  https://doi.org/10.1016/j.burns.2009.04.007CrossRefGoogle Scholar
  51. Guimarães-Ferreira C, Rodrigues E, Mortara R, Cabral H, Serrano F, Ribeiro-dos-Santos R, Travassos L (2007) Antitumor effects in vitro and in vivo and mechanisms of protection against melanoma B16F10-Nex2 cells by fastuosain, a cysteine proteinase from Bromelia fastuosa. Neoplasia 9:723–733.  https://doi.org/10.1593/neo.07427CrossRefGoogle Scholar
  52. Hafez MA, Elkateb M, El Shabrawy S, Mahmoud A, El Meligy O (2017) Microleakage evaluation of composite restorations following papain-based chemo-mechanical caries removal in primary teeth. J Clin Pediatr Dent 41:53–61.  https://doi.org/10.17796/1053-4628-41.1.53CrossRefGoogle Scholar
  53. Hale LP, Greer PK, Trinh CT, Gottfried MR (2005) Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease. Clin Immunol 116:135–142.  https://doi.org/10.1016/j.clim.2005.04.011CrossRefGoogle Scholar
  54. Hale LP, Chichlowski M, Trinh CT, Greer PK (2010) Dietary supplementation with fresh pineapple juice decreases inflammation and colonic neoplasia in IL-10-deficient mice with colitis. Inflamm Bowel Dis 16:2012–2021.  https://doi.org/10.1002/ibd.21320CrossRefGoogle Scholar
  55. Harada T, Yoshioka H, Yoshida S, Iwabe T, Onohara Y, Tanikawa M, Terakawa N (1997) Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. Am J Obstet Gynecol 176:593–597.  https://doi.org/10.1016/S0002-9378(97)70553-2CrossRefGoogle Scholar
  56. Heinicke RM, Gortner WA (1957) Stem bromelain---a new protease preparation from pineapple plants. Econ Bot 11:225–234.  https://doi.org/10.1007/BF02860437CrossRefGoogle Scholar
  57. Ho D, Jagdeo J, Waldorf HA (2016) Is there a Role for Arnica and Bromelain in prevention of post-procedure ecchymosis or Edema? A systematic review of the literature. Dermatol Surg 42(4):445–463CrossRefGoogle Scholar
  58. Huffaker RC (1990) Proteolytic activity during senescence of plants. New Phytol 116:199–231.  https://doi.org/10.1111/j.1469-8137.1990.tb04710.xCrossRefGoogle Scholar
  59. Iida H, Takai T, Hirasawa Y, Kamijo S, Shimura S, Ochi H, Nishioka I, Maruyama N, Ogawa H, Okumura K, Ikeda S (2014) Epicutaneous administration of papain induces IgE and IgG responses in a cysteine protease activity-dependent manner. Allergol Int 63:219–226.  https://doi.org/10.2332/allergolint.13-OA-0621CrossRefGoogle Scholar
  60. Iram S, Zahera M, Khan S, Khan I, Syed A, Ansary AA, Ameen F, Shair OHM, Khan MS (2017) Gold nanoconjugates reinforce the potency of conjugated cisplatin and doxorubicin. Colloids Surf B Biointerfaces 160:254–264.  https://doi.org/10.1016/j.colsurfb.2017.09.017CrossRefGoogle Scholar
  61. Kim D-W, Choi J-H, Park S-E, Kim SS-J, Sapkota K, Kim SS-J (2015) Purification and characterization of a fibrinolytic enzyme from Petasites japonicus. Int J Biol Macromol 72:1159–1167.  https://doi.org/10.1016/j.ijbiomac.2014.09.046CrossRefGoogle Scholar
  62. Kong X, Guo M, Hua Y, Cao D, Zhang C (2008) Enzymatic preparation of immunomodulating hydrolysates from soy proteins. Bioresour Technol 99:8873–8879CrossRefGoogle Scholar
  63. Kush A, Thakur R, Patil SDS, Paul ST, Kakanur M (2015) Evaluation of antimicrobial action of Carie CareTM and Papacarie DuoTM on Aggregatibacter actinomycetemcomitans a major periodontal pathogen using polymerase chain reaction. Contemp Clin Dent 6:534–538.  https://doi.org/10.4103/0976-237X.169860CrossRefGoogle Scholar
  64. Lacroix IME, Li-Chan ECY (2012) Dipeptidyl peptidase-IV inhibitory activity of dairy protein hydrolysates. Int Dairy J 25:97–102.  https://doi.org/10.1016/J.IDAIRYJ.2012.01.003CrossRefGoogle Scholar
  65. Lemos FO, Ferreira LAM, Cardoso VN, Cassali GD, Salas CE, Lopes MTP (2011) Skin-healing activity and toxicological evaluation of a proteinase fraction from Carica candamarcensis. Eur J Dermatol 21:722–730.  https://doi.org/10.1684/ejd.2011.1466CrossRefGoogle Scholar
  66. Levecke B, Buttle DJ, Behnke JM, Duce IR, Vercruysse J (2014) Cysteine proteinases from papaya (Carica papaya) in the treatment of experimental Trichuris suis infection in pigs: two randomized controlled trials. Parasit Vectors 7:255.  https://doi.org/10.1186/1756-3305-7-255CrossRefGoogle Scholar
  67. Lewinsohn TM (1991) The geographical distribution of plant latex. Chemoecology 2:64–68.  https://doi.org/10.1007/BF01240668CrossRefGoogle Scholar
  68. Li-Chan ECY, Hunag S-L, Jao C-L, Ho K-P, Hsu K-C (2012) Peptides derived from Atlantic salmon skin gelatin as dipeptidyl-peptidase IV inhibitors. J Agric Food Chem 60:973–978.  https://doi.org/10.1021/jf204720qCrossRefGoogle Scholar
  69. Luoga W, Mansur F, Lowe A, Duce IR, Buttle DJ, Behnke JM (2015) Factors affecting the anthelmintic efficacy of papaya latex in vivo: host sex and intensity of infection. Parasitol Res 114:2535–2541.  https://doi.org/10.1007/s00436-015-4456-5CrossRefGoogle Scholar
  70. Majid OW, Al-Mashhadani BA (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(6):1043–1048CrossRefGoogle Scholar
  71. Manosroi A, Chankhampan C, Manosroi W, Manosroi J (2012) Toxicity reduction and MMP-2 stimulation of papain and Bromelain loaded in elastic Niosomes. J Biomed Nanotechnol 8(5):720–729CrossRefGoogle Scholar
  72. Mansur F, Luoga W, Buttle DJ, Duce IR, Lowe A, Behnke JM (2014) The anthelmintic efficacy of natural plant cysteine proteinases against two rodent cestodes Hymenolepis diminuta and Hymenolepis microstoma in vitro. Vet Parasitol 201:48–58.  https://doi.org/10.1016/j.vetpar.2013.12.018CrossRefGoogle Scholar
  73. Mazorra-Manzano MA, Ramírez-Suarez JC, Yada RY (2017) Plant proteases for bioactive peptides release: a review. Crit Rev Food Sci Nutr 10:1–17.  https://doi.org/10.1080/10408398.2017.1308312CrossRefGoogle Scholar
  74. Medeiros AF, Costa IS, Carvalho FMC, Kiyota S, Souza BBP, Sifuentes DN, Serquiz RP, Maciel BLL, Uchôa AF, Santos EA, Morais AHA (2018) Biochemical characterisation of a Kunitz-type inhibitor from Tamarindus indica L. seeds and its efficacy in reducing plasma leptin in an experimental model of obesity. J Enzyme Inhib Med Chem 33:334–348.  https://doi.org/10.1080/14756366.2017.1419220CrossRefGoogle Scholar
  75. Mello VJ, Gomes MTR, Lemos FO, Delfino JL, Andrade SP, Lopes MTP, Salas CE (2008) The gastric ulcer protective and healing role of cysteine proteinases from Carica candamarcensis. Phytomedicine 15:237–244.  https://doi.org/10.1016/j.phymed.2007.06.004CrossRefGoogle Scholar
  76. Mendonça RJ, Maurício VB, Teixeira LB, Lachat JJ, Coutinho-Netto J (2010) Increased vascular permeability, angiogenesis and wound healing induced by the serum of natural latex of the rubber tree Hevea brasiliensis. Phytother Res 24:764–768.  https://doi.org/10.1002/ptr.3043CrossRefGoogle Scholar
  77. Menzel C, Bernkop-Schnürch A (2018) Enzyme decorated drug carriers: targeted swords to cleave and overcome the mucus barrier. Adv Drug Deliv Rev 124:164–174.  https://doi.org/10.1016/j.addr.2017.10.004CrossRefGoogle Scholar
  78. Miranda ÍKSPB, Miranda AFS, Souza FVD, Vannier-Santos MA, Pirovani CP, Pepe IM, Rodowanski IJ, Ferreira KTSE, Vaz LMS, de Assis SA (2017) The biochemical characterization, stabilization studies and the antiproliferative effect of bromelain against B16F10 murine melanoma cells. Int J Food Sci Nutr 68:442–454.  https://doi.org/10.1080/09637486.2016.1254599CrossRefGoogle Scholar
  79. Morimatsu F, Ito M, Budijanto S, Watanabe I, Furukawa Y, Kimura S (1996) Plasma cholesterol-suppressing effect of papain-hydrolyzed pork meat in rats fed hypercholesterolemic diet. J Nutr Sci Vitaminol 42:145–153CrossRefGoogle Scholar
  80. Motta LJ, Bussadori SK, Campanelli AP, Silva AL, Alfaya TA, Godoy CHL, Navarro MFL (2014) Randomized controlled clinical trial of long-term chemo-mechanical caries removal using PapacarieTM gel. J Appl Oral Sci 22:307–313.  https://doi.org/10.1590/1678-775720130488CrossRefGoogle Scholar
  81. Mugita N, Nambu T, Takahashi K, Wang P-L, Komasa Y (2017) Proteases, actinidin, papain and trypsin reduce oral biofilm on the tongue in elderly subjects and in vitro. Arch Oral Biol 82:233–240.  https://doi.org/10.1016/j.archoralbio.2017.04.035CrossRefGoogle Scholar
  82. Muhammad ZA, Ahmad T (2017) Therapeutic uses of pineapple-extracted bromelain in surgical care - a review. J Pak Med Assoc 67:121–125Google Scholar
  83. Müller A, Barat S, Chen X, Bui KC, Bozko P, Malek NP, Plentz RR (2016) Comparative study of antitumor effects of bromelain and papain in human cholangiocarcinoma cell lines. Int J Oncol 48:2025–2034.  https://doi.org/10.3892/ijo.2016.3411CrossRefGoogle Scholar
  84. Nongonierma AB, FitzGerald RJ (2014) Susceptibility of milk protein-derived peptides to dipeptidyl peptidase IV (DPP-IV) hydrolysis. Food Chem 145:845–852.  https://doi.org/10.1016/j.foodchem.2013.08.097CrossRefGoogle Scholar
  85. Ochsner A, Storck A (1936) The prevention of peritoneal adhesions by papain: a clinical study. Ann Surg 104:736–747CrossRefGoogle Scholar
  86. Oliveira de Lima VC, de Araújo Machado RJ, Vieira Monteiro NK, de Lyra IL, da Silva Camillo C, Coelho Serquiz A, Silva de Oliveira A, da Silva Rufino FP, Leal Lima Maciel B, Ferreira Uchôa A, Antunes Dos Santos E, de Araújo Morais AH (2017) Gastroprotective and antielastase effects of protein inhibitors from Erythrina velutina seeds in an experimental ulcer model. Biochem Cell Biol 95:243–250.  https://doi.org/10.1139/bcb-2016-0034CrossRefGoogle Scholar
  87. Oliveira CP, Prado WA, Lavayen V, Büttenbender SL, Beckenkamp A, Martins BS, Lüdtke DS, Campo LF, Rodembusch FS, Buffon A, Pessoa A, Guterres SS, Pohlmann AR (2017) Bromelain-functionalized multiple-wall lipid-core nanocapsules: formulation, chemical structure and antiproliferative effect against human breast cancer cells (MCF-7). Pharm Res 34:438–452.  https://doi.org/10.1007/s11095-016-2074-2CrossRefGoogle Scholar
  88. Onken JE, Greer PK, Calingaert B, Hale LP (2008) Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol 126:345–352.  https://doi.org/10.1016/j.clim.2007.11.002CrossRefGoogle Scholar
  89. Ordesi P, Pisoni L, Nannei P, Macchi M, Borloni R, Siervo S (2014) Therapeutic efficacy of bromelain in impacted third molar surgery: a randomized controlled clinical study. Quintessence Int 45(8):679–684.  https://doi.org/10.3290/j.qi.a32237CrossRefGoogle Scholar
  90. Parodi A, Haddix SG, Taghipour N, Scaria S, Taraballi F, Cevenini A, Yazdi IK, Corbo C, Palomba R, Khaled SZ, Martinez JO, Brown BS, Isenhart L, Tasciotti E (2014) Bromelain surface modification increases the diffusion of silica nanoparticles in the tumor extracellular matrix. ACS Nano 8:9874–9883.  https://doi.org/10.1021/nn502807nCrossRefGoogle Scholar
  91. Patel DV, Sawant MG, Kaur G (2015) Evaluation of anti-osteoarthritic activity of Vigna mungo in papain induced osteoarthritis model. Indian J Pharm 47:59–64.  https://doi.org/10.4103/0253-7613.150340CrossRefGoogle Scholar
  92. Patil PA, Ankola AV, Hebbal MI, Patil AC (2015) Comparison of effectiveness of abrasive and enzymatic action of whitening toothpastes in removal of extrinsic stains - a clinical trial. Int J Dent Hyg 13(1):25–29CrossRefGoogle Scholar
  93. Pepe A, Frey ME, Muñoz F, Fernández MB, Pedraza A, Galbán G, García DN, Daleo GR, Guevara MG (2016) Fibrin(ogen)olytic and antiplatelet activities of a subtilisin-like protease from Solanum tuberosum (StSBTc-3). Biochimie 125:163–170.  https://doi.org/10.1016/j.biochi.2016.03.015CrossRefGoogle Scholar
  94. Phares K, Kubik J (1996) The growth factor from plerocercoids of Spirometra mansonoides is both a growth hormone agonist and a cysteine proteinase. J Parasitol 82:210–215CrossRefGoogle Scholar
  95. Pillai K, Akhter J, Chua TC, Morris DL (2013) Anticancer property of bromelain with therapeutic potential in malignant peritoneal mesothelioma. Cancer Investig 31:241–250CrossRefGoogle Scholar
  96. Pu C, Tang W (2017) The antibacterial and antibiofilm efficacies of a liposomal peptide originating from rice bran protein against Listeria monocytogenes. Food Funct 8:4159–4169.  https://doi.org/10.1039/C7FO00994ACrossRefGoogle Scholar
  97. Rakashanda S, Qazi AK, Majeed R, Andrabi SM, Hamid A, Sharma PR, Amin S (2015) Plant-derived protease inhibitors LC-pi (Lavatera cashmeriana) inhibit human lung cancer cell proliferation in vitro. Nutr Cancer 67:156–166.  https://doi.org/10.1080/01635581.2015.967876CrossRefGoogle Scholar
  98. Rakhimov MR (2001) Anti-inflammatory activity of domestic papain. Eksp Klin Farmakol 64:48–49Google Scholar
  99. Romano B, Fasolino I, Pagano E, Capasso R, Pace S, De Rosa G, Milic N, Orlando P, Izzo AA, Borrelli F (2014) The chemopreventive action of bromelain, from pineapple stem (Ananas comosus L.), on colon carcinogenesis is related to antiproliferative and proapoptotic effects. Mol Nutr Food Res 58:457–465.  https://doi.org/10.1002/mnfr.201300345CrossRefGoogle Scholar
  100. Rosenberg L, Krieger Y, Silberstein E, Arnon O, Sinelnikov IA, Bogdanov-Berezovsky A, Singer AJ (2012) Selectivity of a bromelain based enzymatic debridement agent: a porcine study. Burns 38:1035–1040.  https://doi.org/10.1016/j.burns.2012.02.011CrossRefGoogle Scholar
  101. Rosenberg L, Krieger Y, Bogdanov-Berezovski A, Silberstein E, Shoham Y, Singer AJ (2014) A novel rapid and selective enzymatic debridement agent for burn wound management: a multi-center RCT. Burns 40:466–474.  https://doi.org/10.1016/j.burns.2013.08.013CrossRefGoogle Scholar
  102. Sahana S, Vasa AAK, Geddam D, Reddy VK, Nalluri S, Velagapudi N (2016) Effectiveness of chemomechanical caries removal agents Papacarie(®) and Carie-CareTM in primary molars: an in vitro study. J Int Soc Prev Community Dent 6:S17–S22.  https://doi.org/10.4103/2231-0762.181162CrossRefGoogle Scholar
  103. Sahbaz A, Aynioglu O, Isik H, Ozmen U, Cengil O, Gun BD, Gungorduk K (2015) Bromelain: a natural proteolytic for intra-abdominal adhesion prevention. Int J Surg 14:7–11.  https://doi.org/10.1016/j.ijsu.2014.12.024CrossRefGoogle Scholar
  104. Sahu K, Kaurav M, Pandey RS (2017) Protease loaded permeation enhancer liposomes for treatment of skin fibrosis arisen from second degree burn. Biomed Pharmacother 94:747–757.  https://doi.org/10.1016/j.biopha.2017.07.141CrossRefGoogle Scholar
  105. Salampessy J, Phillips M, Seneweera S, Kailasapathy K (2010) Release of antimicrobial peptides through bromelain hydrolysis of leatherjacket (Meuchenia sp.) insoluble proteins. Food Chem 120:556–560.  https://doi.org/10.1016/J.FOODCHEM.2009.10.054CrossRefGoogle Scholar
  106. Salas CE, Gomes MTR, Hernandez M, Lopes MTP (2008) Plant cysteine proteinases: evaluation of the pharmacological activity. Phytochemistry 69:2263–2269.  https://doi.org/10.1016/j.phytochem.2008.05.016CrossRefGoogle Scholar
  107. Salu BR, Pando SC, Brito MV, Medina AF, Odei-Addo F, Frost C, Naude R, Sampaio MU, Emsley J, Maffei FHA, Oliva MLV (2018) Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors. Platelets 14:1–9.  https://doi.org/10.1080/09537104.2018.1428738CrossRefGoogle Scholar
  108. Schulz A, Shoham Y, Rosenberg L, Rothermund I, Perbix W, Christian Fuchs P, Lipensky A, Schiefer JL (2017) Enzymatic versus traditional surgical debridement of severely burned hands: a comparison of selectivity, efficacy, healing time, and three-month scar quality. J Burn Care Res 38:e745–e755.  https://doi.org/10.1097/BCR.0000000000000478CrossRefGoogle Scholar
  109. Seaf M, Ben-Zimra M, Mankuta D, Dayan N, Levi-Schaffer F (2016) Papain activates human mast cells to release proinflammatory mediators via its enzymatic activity. J Invest Dermatol 136:1523–1525.  https://doi.org/10.1016/j.jid.2016.03.030CrossRefGoogle Scholar
  110. Secor ER, Shah SJ, Guernsey LA, Schramm CM, Thrall RS (2012) Bromelain limits airway inflammation in an ovalbumin-induced murine model of established asthma. Altern Ther Health Med 18:9–17Google Scholar
  111. Shimizu M, Sawashita N, Morimatsu F, Ichikawa J, Taguchi Y, Ijiri Y, Yamamoto J (2009) Antithrombotic papain-hydrolyzed peptides isolated from pork meat. Thromb Res 123:753–757.  https://doi.org/10.1016/j.thromres.2008.07.005CrossRefGoogle Scholar
  112. Shing CM, Chong S, Driller MW, Fell JW (2015) Acute protease supplementation effects on muscle damage and recovery across consecutive days of cycle racing. European Journal of Sport Science 16(2):206–212CrossRefGoogle Scholar
  113. Shivalingu BR, Vivek HK, Priya BS, Soujanya KN, Swamy SN (2016) Purification and characterization of novel fibrin(ogen)olytic protease from Curcuma aromatica Salisb.: role in hemostasis. Phytomedicine 23:1691–1698.  https://doi.org/10.1016/j.phymed.2016.09.007CrossRefGoogle Scholar
  114. Shivaprasad HV, Rajesh R, Nanda BL, Dharmappa KK, Vishwanath BS (2009) Thrombin like activity of Asclepias curassavica L. latex: action of cysteine proteases. J Ethnopharmacol 123:106–109.  https://doi.org/10.1016/j.jep.2009.02.016CrossRefGoogle Scholar
  115. Shoba E, Lakra R, Syamala Kiran M, Korrapati PS (2017) Fabrication of core-shell nanofibers for controlled delivery of bromelain and salvianolic acid B for skin regeneration in wound therapeutics. Biomed Mater 12:35005.  https://doi.org/10.1088/1748-605X/aa6684CrossRefGoogle Scholar
  116. Singer AJ, Taira BR, Anderson R, McClain SA, Rosenberg L (2010) The Effects of rapid enzymatic debridement of deep partial-thickness burns with Debrase® on wound reepithelialization in swine. J Burn Care Res 31:795–802.  https://doi.org/10.1097/BCR.0b013e3181eed48eCrossRefGoogle Scholar
  117. Siritapetawee J, Sojikul P, Klaynongsruang S (2015) Biochemical characterization of a new glycosylated protease from Euphorbia cf. lactea latex. Plant Physiol Biochem 92:30–38.  https://doi.org/10.1016/j.plaphy.2015.04.012CrossRefGoogle Scholar
  118. Soplin SP, Millones EA, Campos JLA, Deza LG, Ríos EJ, Sánchez IB, Benítez MR, Pando LG, Panizo RS, Merino C del C, Rivera JC (1995) Perú: Informe nacional para la conferencia técnica internacional de la FAO sobre los recursos fitogenéticos (Leipzig, 1996). Peru, p 253Google Scholar
  119. Stevens LE (1968) A reassessment of papain in preventing peritoneal adhesions. Am J Surg 115:535–539CrossRefGoogle Scholar
  120. Tadikonda A, Pentapati K-C, Urala A-S, Acharya S (2017) Anti-plaque and anti-gingivitis effect of Papain, Bromelain, Miswak and Neem containing dentifrice: a randomized controlled trial. J Clin Exp Dent 9:e649–e653.  https://doi.org/10.4317/jced.53593CrossRefGoogle Scholar
  121. Tavares T, Contreras MDM, Amorim M, Pintado M, Recio I, Malcata FX (2011) Novel whey-derived peptides with inhibitory effect against angiotensin-converting enzyme: in vitro effect and stability to gastrointestinal enzymes. Peptides 32:1013–1019.  https://doi.org/10.1016/j.peptides.2011.02.005CrossRefGoogle Scholar
  122. Tharakan A, Dobzanski A, London NR, Khalil SM, Surya N, Lane AP, Ramanathan M (2018) Characterization of a novel, papain-inducible murine model of eosinophilic rhinosinusitis. Int Forum Allergy Rhinol 8(4):513–521.  https://doi.org/10.1002/alr.22072CrossRefGoogle Scholar
  123. Uday P, Maheshwari M, Sharanappa P, Nafeesa Z, Kameshwar VH, Priya BS, Nanjunda Swamy S (2017) Exploring hemostatic and thrombolytic potential of heynein - a cysteine protease from Ervatamia heyneana latex. J Ethnopharmacol 199:316–322.  https://doi.org/10.1016/j.jep.2016.12.047CrossRefGoogle Scholar
  124. van der Hoorn RAL (2008) Plant proteases: from phenotypes to molecular mechanisms. Annu Rev Plant Biol 59:191–223.  https://doi.org/10.1146/annurev.arplant.59.032607.092835CrossRefGoogle Scholar
  125. van Wijk KJ (2015) Protein maturation and proteolysis in plant plastids, mitochondria, and peroxisomes. Annu Rev Plant Biol 66:75–111.  https://doi.org/10.1146/annurev-arplant-043014-115547CrossRefGoogle Scholar
  126. Wang B, Li Z-R, Chi C-F, Zhang Q-H, Luo H-Y (2012) Preparation and evaluation of antioxidant peptides from ethanol-soluble proteins hydrolysate of Sphyrna lewini muscle. Peptides 36:240–250.  https://doi.org/10.1016/j.peptides.2012.05.013CrossRefGoogle Scholar
  127. Wei B, He L, Wang X, Yan GQ, Wang J, Tang R (2017) Bromelain-decorated hybrid nanoparticles based on lactobionic acid-conjugated chitosan for in vitro anti-tumor study. J Biomater Appl 32:206–218.  https://doi.org/10.1177/0885328217715537CrossRefGoogle Scholar
  128. Wu S-Y, Hu W, Zhang B, Liu S, Wang J-M, Wang A-M (2012) Bromelain ameliorates the wound microenvironment and improves the healing of firearm wounds. J Surg Res 176:503–509.  https://doi.org/10.1016/j.jss.2011.11.1027CrossRefGoogle Scholar
  129. Yariswamy M, Shivaprasad HV, Joshi V, Nanjaraj URSAN, Nataraju A, Vishwanath BS (2013) Topical application of serine proteases from Wrightia tinctoria R. Br. (Apocyanaceae) latex augments healing of experimentally induced excision wound in mice. J Ethnopharmacol 149:377–383.  https://doi.org/10.1016/j.jep.2013.06.056CrossRefGoogle Scholar
  130. Zetter BR, Chen LB, Buchanan JM (1976) Effects of protease treatment on growth, morphology, adhesion, and cell surface proteins of secondary chick embryo fibroblasts. Cell 7:407–412.  https://doi.org/10.1016/0092-8674(76)90170-7CrossRefGoogle Scholar
  131. Zhou Z, Wang L, Feng P, Yin L, Wang C, Zhi S, Dong J, Wang J, Lin Y, Chen D, Xiong Y, Peng J (2017) Inhibition of epithelial TNF-α receptors by purified fruit bromelain ameliorates intestinal inflammation and barrier dysfunction in colitis. Front Immunol 8:1468.  https://doi.org/10.3389/fimmu.2017.01468CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Carlos E. Salas
    • 1
  • Dalton Dittz
    • 1
  • Maria-Jose Torres
    • 2
  1. 1.Instituto de Ciências Biológicas, Departamento de Bioquímica e ImunologiaUniversidade Federal de Minas FeraisBelo HorizonteBrazil
  2. 2.Departamento de Ingeniería de AlimentosUniversidad de la SerenaLa SerenaChile

Personalised recommendations