Lactoperoxidase

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Lactoperoxidase is a peroxidase enzyme secreted from mammary, salivary, and other mucosal glands[1] that functions as a natural antibacterial agent.[2] Lactoperoxidase is a member of the heme peroxidase family of enzymes. In humans, lactoperoxidase is encoded by the LPO gene.[3][4]

Lactoperoxidase catalyzes the oxidation of a number of inorganic and organic substrates by hydrogen peroxide.[5] These substrates include bromide and iodide and therefore lactoperoxidase can be categorised as a haloperoxidase. Another important substrate is thiocyanate. The oxidized products produced through the action of this enzyme have potent bactericidal activities. Lactoperoxidase together with its inorganic ion substrates, hydrogen peroxide, and oxidized products is known as the lactoperoxidase system.[6]

The lactoperoxidase system plays an important role in the innate immune system by killing bacteria in milk and mucosal (linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion) secretions hence augmentation of the lactoperoxidase system may have therapeutic applications. Furthermore, addition or augmentation of the lactoperoxidase system has potential applications in controlling bacteria in food and consumer health care products. The lactoperoxidase system does not attack DNA and is not mutagenic.[7] However, under certain conditions, the lactoperoxidase system may contribute to oxidative stress.[8] Furthermore, lactoperoxidase may contribute to the initiation of breast cancer, through its ability to oxidize estrogenic hormones producing free radical intermediates.[9]

Structure

The structure of lactoperoxidase consists mainly of alpha-helices plus two short antiparallel beta-strands.[10] Lactoperoxidase belongs to the heme peroxidase family of mammalian enzymes that also includes myeloperoxidase (MPO), eosinophil peroxidase (EPO), thyroid peroxidase (TPO), and prostaglandin H synthase (PGHS). A heme cofactor is bound near the center of the protein.[11]

Function

Lactoperoxidase catalyzes the hydrogen peroxide (H2O2) oxidation of several acceptor molecules:[12]

  • reduced acceptor + H2O2 → oxidized acceptor + H2O

Specific examples include:

Source of the hydrogen peroxide (H2O2) usually is the reaction of glucose with oxygen in the presence of the enzyme glucose oxidase (EC 1.1.3.4) that also takes place in saliva. Glucose, in turn, can be formed from starch in the presence of the saliva enzyme amyloglucosidase (EC 3.2.1.3).

These relatively short lived oxidized intermediates have potent bactericidal effects, hence lactoperoxidase is part of the antimicrobial defense system in tissues that express lactoperoxidase.[6] The lactoperoxidase system is effective in killing a range of aerobic[15] and certain anaerobic microorganisms.[16] Research (1984): "The effect of lactoperoxidase-thiocyanate-hydrogen peroxide mixtures on bacteria is dependent on experimental conditions. If the bacteria are cultured after the exposure to lactoperoxidase-thiocyanate-hydrogen peroxide on nutrient agar under aerobic conditions, they may not grow, whereas they grow readily on blood agar under anaerobic conditions."[17] In its antimicrobial capacity, lactoperoxidase appears to acts synergistically with lactoferrin[18] and lysozyme.[19]

Applications

Lactoperoxidase is an effective antimicrobial agent. Consequently, applications of lactoperoxidase are being found in preserving food, cosmetics, and ophthalmic solutions. Furthermore, lactoperoxidase have found application in dental and wound treatment. Finally lactoperoxidase may find application as anti-tumor and anti viral agents.[20]

Dairy products

Lactoperoxidase is an effective antimicrobial agent and is used as an antibacterial agent in reducing bacterial microflora in milk and milk products.[21] Activation of the lactoperoxidase system by addition of hydrogen peroxide and thiocyanate extends the shelf life of refrigerated raw milk.[12][22][23][24] It is fairly heat resistant and is used as an indicator of overpasteurization of milk.[25]

Oral care

A lactoperoxidase system is claimed to appropriate for the treatment of gingivitis and paradentosis.[26] Lactoperoxidase has been used in toothpaste or a mouthrinse to reduce oral bacteria and consequently the acid produced by those bacteria.[27]

Cosmetics

A combination of lactoperoxidase, glucose, glucose oxidase (GOD), iodide and thiocyanate is claimed to be effective in the preservations of cosmetics.[28]

Cancer and viral infections

Antibody conjugates of glucose oxidase and to lactoperoxidase have been found to effective in killing tumor cells in vitro.[29] In addition, macrophages exposed to lactoperoxidase are stimulated to kill cancer cells.[30]

Peroxidase-generated hypothiocyanite inhibits herpes simplex virus[31] and human immunodeficiency virus.[32]

Clinical significance

Innate immune system

The antibacterial activity of lactoperoxidase plays an important role in the immune defense system.[33][34][35]

Hypothiocyanite is one of the reactive intermediates produced by the activity of lactoperoxidase on thiocyanate and hydrogen peroxide produced by dual oxidase 2 proteins, also known as Duox2.[36][37] Thiocyanate secretion[38] in cystic fibrosis patients is decreased, resulting in a reduced production of the antimicrobial hypothiocyanite and consequently contributes to increased risk of airway infection.[39][40]

The lactoperoxidase system efficiently inhibits helicobacter pylori in buffer; however, in whole human saliva, it has a weaker antibacterial effect.[41] The lactoperoxidase system does not attack DNA and is not mutagenic.[7] However, under certain conditions, the lactoperoxidase system may contribute to oxidative stress.[8] It has been shown that lactoperoxidase in the presence of thiocyanate can trigger the bactericidal and cytotoxic effects of hydrogen peroxide under specific conditions, such as when hydrogen peroxide is present in the reaction mixtures in excess of thiocyanate.[17]

Breast cancer

The oxidation of estradiol by lactoperoxidase is a possible source of oxidative stress in breast cancer.[8][9] The ability of lactoperoxidase to propagate a chain reaction leading to oxygen consumption and intracellular hydrogen peroxide accumulation could explain the hydroxyl radical-induced DNA base lesions recently reported in female breast cancer tissue.[8] Lactoperoxidase may be involved in breast carcinogenesis, because of its ability to interact with estrogenic hormones and oxidise them through two one-electron reaction steps.[9] Lactoperoxidase reacts with the phenolic A-ring of estrogens to produce reactive free radicals.[42] In addition, lactoperoxidase may activate carcinogenic aromatic and heterocyclic amines and increase binding levels of activated products to DNA, which suggests a potential role of lactoperoxidase-catalyzed activation of carcinogens in the causation of breast cancer.[43]

Oral Care

During the last decades, several clinical studies describing the clinical efficacy of the lactoperoxidase system in a variety of oral care products (tooth pastes, mouth rinses) have been published. After showing indirectly, by means of measuring experimental gingivitis and caries parameters, that mouth rinses[44][45] containing amyloglucosidase (γ-amylase) and glucose oxidase activate the lactoperoxidase system, the protective mechanism of the enzymes in oral care products has been partially elucidated. Enzymes such as lysozyme, lactoperoxidase and glucose oxidase are transferred from the tooth pastes to the pellicle. Being components of the pellicle, these enzymes are catalytically highly active.[46][47] Also, as part of tooth pastes, the lactoperoxidase system has a beneficial influence to avoid early childhood caries[48] by reducing the number of colonies formed by the cariogenic microflora while increasing the thiocyanate concentration. With xerostomia patients, tooth pastes with the lactoperoxidase system are seemingly superior to fluoride-containing tooth pastes with respect to plaque formation and gingivitis.[49] More studies are required[50] to examine further the protective mechanisms.[51]

The application of lactoperoxidase is not restricted to caries, gingivitis, and periodontitis.[52] A combination of lysozyme and lactoperoxidase can be applied to support the treatment of the burning mouth syndrome (glossodynia). In combination with lactoferrin, lactoperoxidase combats halitosis;[53] in combination with lactoferrin and lysozyme, lactoperoxidase helps to improve symptoms of xerostomia.[54] Furthermore, gels with lactoperoxidase help to improve symptoms of oral cancer when saliva production is compromised due to irradiation. In this case, also the oral bacterial flora are influenced favorably.[55][56][57]

See also

References

  1. ↑ Tenovuo JO (1985). "The peroxidase system in human secretions". In Tenovuo JO, Pruitt KM. The Lactoperoxidase system: chemistry and biological significance. New York: Dekker. p. 272. ISBN 0-8247-7298-9.
  2. ↑ Pruitt KM, Reiter B (1985). "Biochemistry of peroxidase systems: antimicrobial effects". In Tenovuo JO, Pruitt KM. The Lactoperoxidase system: chemistry and biological significance. New York: Dekker. p. 272. ISBN 0-8247-7298-9.
  3. ↑ Dull TJ, Uyeda C, Strosberg AD, Nedwin G, Seilhamer JJ (September 1990). "Molecular cloning of cDNAs encoding bovine and human lactoperoxidase". DNA Cell Biol. 9 (7): 499–509. doi:10.1089/dna.1990.9.499. PMID 2222811.
  4. ↑ Kiser C, Caterina CK, Engler JA, Rahemtulla B, Rahemtulla F (September 1996). "Cloning and sequence analysis of the human salivary peroxidase-encoding cDNA". Gene. 173 (2): 261–4. doi:10.1016/0378-1119(96)00078-9. PMID 8964511.
  5. ↑ Kohler H, Jenzer H (1989). "Interaction of lactoperoxidase with hydrogen peroxide. Formation of enzyme intermediates and generation of free radicals". Free Radic. Biol. Med. 6 (3): 323–39. doi:10.1016/0891-5849(89)90059-2. PMID 2545551.
  6. ↑ 6.0 6.1 Tenovuo JO, Pruitt KM, eds. (1985). The Lactoperoxidase system: chemistry and biological significance. New York: Dekker. p. 272. ISBN 0-8247-7298-9.
  7. ↑ 7.0 7.1 White WE, Pruitt KM, Mansson-Rahemtulla B (February 1983). "Peroxidase-Thiocyanate-Peroxide Antibacterial System Does Not Damage DNA". Antimicrob. Agents Chemother. 23 (2): 267–72. doi:10.1128/aac.23.2.267. PMC 186035. PMID 6340603.
  8. ↑ 8.0 8.1 8.2 8.3 Sipe HJ, Jordan SJ, Hanna PM, Mason RP (November 1994). "The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer". Carcinogenesis. 15 (11): 2637–43. doi:10.1093/carcin/15.11.2637. PMID 7955118.
  9. ↑ 9.0 9.1 9.2 Ghibaudi EM, Laurenti E, Beltramo P, Ferrari RP (2000). "Can estrogenic radicals, generated by lactoperoxidase, be involved in the molecular mechanism of breast carcinogenesis?". Redox Rep. 5 (4): 229–35. doi:10.1179/135100000101535672. PMID 10994878.
  10. ↑ Singh AK, Smith ML, Yamini S, Ohlsson PI, Sinha M, Kaur P, Sharma S, Paul JA, Singh TP, Paul KG (October 2012). "Bovine carbonyl lactoperoxidase structure at 2.0Å resolution and infrared spectra as a function of pH". The Protein Journal. 31 (7): 598–608. doi:10.1007/s10930-012-9436-3. PMID 22886082.
  11. ↑ PDB: 2r5l​; Singh AK, Singh N, Sharma S, Singh SB, Kaur P, Bhushan A, Srinivasan A, Singh TP (February 2008). "Crystal structure of lactoperoxidase at 2.4 A resolution". Journal of Molecular Biology. 376 (4): 1060–75. doi:10.1016/j.jmb.2007.12.012. PMID 18191143.
  12. ↑ 12.0 12.1 de Wit JN, van Hooydonk AC (1996). "Structure, functions and applications of lactoperoxidase in natural antimicrobial systems". Netherlands Milk & Dairy Journal. 50: 227–244.
  13. ↑ Wever R, Kast WM, Kasinoedin JH, Boelens R (December 1982). "The peroxidation of thiocyanate catalysed by myeloperoxidase and lactoperoxidase". Biochim. Biophys. Acta. 709 (2): 212–9. doi:10.1016/0167-4838(82)90463-0. PMID 6295491.
  14. ↑ Pruitt KM, Tenovuo J, Andrews RW, McKane T (February 1982). "Lactoperoxidase-catalyzed oxidation of thiocyanate: polarographic study of the oxidation products". Biochemistry. 21 (3): 562–7. doi:10.1021/bi00532a023. PMID 7066307.
  15. ↑ Fweja LW, Lewis MJ, Grandison AS (July 2008). "Challenge testing the lactoperoxidase system against a range of bacteria using different activation agents". J. Dairy Sci. 91 (7): 2566–74. doi:10.3168/jds.2007-0322. PMID 18565914.
  16. ↑ Courtois P, Majerus P, Labbé M, Vanden Abbeele A, Yourassowsky E, Pourtois M (September 1992). "Susceptibility of anaerobic microorganisms to hypothiocyanite produced by lactoperoxidase". Acta Stomatol Belg. 89 (3): 155–62. PMID 1481764.
  17. ↑ 17.0 17.1 Carlsson J, Edlund MB, Hänström L (June 1984). "Bactericidal and cytotoxic effects of hypothiocyanite-hydrogen peroxide mixtures". Infect Immun. 44 (3): 581–6. PMC 263633. PMID 6724690.
  18. ↑ Reiter B (1983). "The biological significance of lactoferrin". Int J Tissue React. 5 (1): 87–96. PMID 6345430.
  19. ↑ Roger V, Tenovuo J, Lenander-Lumikari M, Söderling E, Vilja P (1994). "Lysozyme and lactoperoxidase inhibit the adherence of Streptococcus mutans NCTC 10449 (serotype c) to saliva-treated hydroxyapatite in vitro". Caries Res. 28 (6): 421–8. doi:10.1159/000262015. PMID 7850845.
  20. ↑ Harper, W. James (2000). Biological properties of whey components a review. Chicago, IL: American Dairy Products Institute. p. 54.
  21. ↑ Reiter B.; Härnulv BG. "The preservation of refrigerated and uncooled milk by its natural lactoperoxidase system". Dairy Ind. Int. 47 (5): 13–19.
  22. ↑ Zajac M, Glandys J, Skarzynska M, Härnulv G, Eilertsen K (1983). "Milk quality preservation by heat treatment or activation of the lactoperoxidase system in combination with refrigerated storage". Milchwissenschaft. 38 (11).
  23. ↑ Zajac M, Glandys J, Skarzynska M, Härnulv G, Björck L (1983). "Changes in bacteriological quality of raw milk stabilized by activation of its lactoperoxidase system and stored at different temperatures". J. Food Prot. 46 (12): 1065–1068. doi:10.4315/0362-028x-46.12.1065.
  24. ↑ Korhonen H (1980). "A new method for preserving raw milk: The lactoperoxidase antibacterial system". World Anim. Rev. 35: 23–29.
  25. ↑ Marks NE, Grandison AS, Lewis MJ (2008). "Use of hydrogen peroxide detection strips to determine the extent of pasteurization in whole milk". International Journal of Dairy Technology. 54 (1): 20–22. doi:10.1111/j.0134-727X.2001.00008.x.
  26. ↑ WO application WO1988002600, Poulson OM, "Enzyme-containing bactericidal composition, and dental and wound treatment preparations comprising this composition", published 1988-04-21 
  27. ↑ Hoogedoorn H (1985). "Activation of the salivary peroxidase system: clinical studies". In Tenovuo JO, Pruitt KM. The Lactoperoxidase system: chemistry and biological significance. New York: Dekker. pp. 217–228. ISBN 0-8247-7298-9.
  28. ↑ US 5607681, Galley E, Godfrey DC, Guthrie WG, Hodgkinson DM, Linnington HL, "Antimicrobial Compositions Containing Iodide, Thiocyanate, Glucose And Glucose Oxidase", published 1997-03-04, assigned to The Boots Company PLC 
  29. ↑ Stanislawski M, Rousseau V, Goavec M, Ito H (October 1989). "Immunotoxins containing glucose oxidase and lactoperoxidase with tumoricidal properties: in vitro killing effectiveness in a mouse plasmacytoma cell model". Cancer Res. 49 (20): 5497–504. PMID 2790777.
  30. ↑ Lefkowitz DL, Hsieh TC, Mills K, Castro A (1990). "Induction of tumor necrosis factor and cytotoxicity by macrophages exposed to lactoperoxidase and microperoxidase". Life Sci. 47 (8): 703–9. doi:10.1016/0024-3205(90)90625-2. PMID 2402192.
  31. ↑ Mikola H, Waris M, Tenovuo J (March 1995). "Inhibition of herpes simplex virus type 1, respiratory syncytial virus and echovirus type 11 by peroxidase-generated hypothiocyanite". Antiviral Res. 26 (2): 161–71. doi:10.1016/0166-3542(94)00073-H. PMID 7605114.
  32. ↑ Pourtois M, Binet C, Van Tieghem N, Courtois PR, Vandenabbeele A, Thirty L (May 1991). "Saliva can contribute in quick inhibition of HIV infectivity". AIDS. 5 (5): 598–600. doi:10.1097/00002030-199105000-00022. PMID 1650564.
  33. ↑ Wijkstrom-Frei C, El-Chemaly S, Ali-Rachedi R, Gerson C, Cobas MA, Forteza R, Salathe M, Conner GE (August 2003). "Lactoperoxidase and human airway host defense". Am. J. Respir. Cell Mol. Biol. 29 (2): 206–12. doi:10.1165/rcmb.2002-0152OC. PMID 12626341.
  34. ↑ Conner GE, Salathe M, Forteza R (December 2002). "Lactoperoxidase and hydrogen peroxide metabolism in the airway". Am. J. Respir. Crit. Care Med. 166 (12 Pt 2): S57–61. doi:10.1164/rccm.2206018. PMID 12471090.
  35. ↑ Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M (January 2007). "The Lactoperoxidase System Links Anion Transport To Host Defense in Cystic Fibrosis". FEBS Lett. 581 (2): 271–8. doi:10.1016/j.febslet.2006.12.025. PMC 1851694. PMID 17204267.
  36. ↑ Thomas EL, Bates KP, Jefferson MM (September 1980). "Hypothiocyanite ion: detection of the antimicrobial agent in human saliva". J. Dent. Res. 59 (9): 1466–72. doi:10.1177/00220345800590090201. PMID 6931123.
  37. ↑ Thomas EL, Aune TM (May 1978). "Lactoperoxidase, peroxide, thiocyanate antimicrobial system: correlation of sulfhydryl oxidation with antimicrobial action". Infect. Immun. 20 (2): 456–63. PMC 421877. PMID 352945.
  38. ↑ Xu Y, Szép S, Lu Z (December 2009). "The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases". Proc. Natl. Acad. Sci. U.S.A. 106 (48): 20515–9. doi:10.1073/pnas.0911412106. PMC 2777967. PMID 19918082.
  39. ↑ Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (January 2007). "A Novel Host Defense System of Airways Is Defective in Cystic Fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174–83. doi:10.1164/rccm.200607-1029OC. PMC 2720149. PMID 17082494.
  40. ↑ Minarowski Ł, Sands D, Minarowska A, Karwowska A, Sulewska A, Gacko M, Chyczewska E (2008). "Thiocyanate concentration in saliva of cystic fibrosis patients". Folia Histochem. Cytobiol. 46 (2): 245–6. doi:10.2478/v10042-008-0037-0. PMID 18519245.
  41. ↑ Haukioja A, Ihalin R, Loimaranta V, Lenander M, Tenovuo J (September 2004). "Sensitivity of Helicobacter pylori to an innate defence mechanism, the lactoperoxidase system, in buffer and in human whole saliva". Journal of Medical Microbiology. 53 (Pt 9): 855–60. doi:10.1099/jmm.0.45548-0. PMID 15314191.
  42. ↑ Løvstad RA (December 2006). "A kinetic study on the lactoperoxidase catalyzed oxidation of estrogens". Biometals. 19 (6): 587–92. doi:10.1007/s10534-006-0002-3. PMID 16944280.
  43. ↑ Gorlewska-Roberts KM, Teitel CH, Lay JO, Roberts DW, Kadlubar FF (December 2004). "Lactoperoxidase-catalyzed activation of carcinogenic aromatic and heterocyclic amines". Chem. Res. Toxicol. 17 (12): 1659–66. doi:10.1021/tx049787n. PMID 15606142.
  44. ↑ Hugoson A, Koch G, Thilander H, Hoogendorn H (1974). "Lactoperoxidase in the prevention of plaque accumulation, gingivitis and dental caries (III)". Odont revy. 25 (1): 69–80. PMID 4522423.
  45. ↑ Midda M, Cooksey MV (1986). "Clinical use of an enzyme-containing dentifrice". J Clin Periodontol. 13 (10): 950–6. doi:10.1111/j.1600-051x.1986.tb01433.x. PMID 3098804.
  46. ↑ Hannig C, Spitzmüller B, Lux HC, Altenburger M, Al-Ahmad A, Hannig M (2010). "Efficacy of enzymatic toothpastes for immobilisation of protective enzymes in the in situ pellicle". Arch Oral Biol. 55 (7): 463–469. doi:10.1016/j.archoralbio.2010.03.020. PMID 20417500.
  47. ↑ Hannig C, Hannig M, Attin T (2005). "Enzymes in the acquired enamel pellicle". Eur J Oral Sci. 113 (1): 2–13. doi:10.1111/j.1600-0722.2004.00180.x. PMID 15693823.
  48. ↑ Jyoti S, Shasikiran ND, Reddy VV (2009). "Effect of lactoperoxidase system containing toothpaste on cariogenic bacteria in children with early childhood caries". J Clin Pediatr Dent. 33 (4): 299–303. PMID 19725235.
  49. ↑ van Steenberghe D, Van den Eynde E, Jacobs R, Quirynen M (1994). "Effect of a lactoperoxidase containing toothpaste in radiation-induced xerostomia". Int Dent J. 44 (2): 133–138. PMID 8063434.
  50. ↑ Hannig, Christian; Hannig, Matthias; Attin, Thomas (2005). "Enzymes in the acquired enamel pellicle". European Journal of Oral Sciences. 113 (1): 2–13. doi:10.1111/j.1600-0722.2004.00180.x. ISSN 0909-8836. PMID 15693823.
  51. ↑ Kirstilä V, Lenander-Lumikari M, Tenuovo J (1994). "Effects of a lactoperoxidase-system-containing toothpaste on dental plaque and whole saliva in vivo". Acta Odontol Scand. 52 (6): 346–353. doi:10.3109/00016359409029032. PMID 7887144.
  52. ↑ Marino R, Torretta S, Capaccio P, Pignataro L, Spadari F (2010). "Different therapeutic strategies for burning mouth syndrome: preliminary data". J Oral Pathol Med. 39 (8): 611–616. doi:10.1111/j.1600-0714.2010.00922.x. PMID 20701667.
  53. ↑ Shin K, Yaegaki K, Murata T, Ii H, Tanaka T, Aoyama I, Yamauchi K, Toida T, Iwatsuki K (2011). "Effects of a composition containing lactoferrin and lactoperoxidase on oral malodor and salivary bacteria: a randomized, double-blind, crossover, placebo-controlled clinical trial". Clin Oral Investig. 15 (4): 485–493. doi:10.1007/s00784-010-0422-x. PMID 20512389.
  54. ↑ Gil-Montoya JA, Guardia-Lopéz I, Gonzaléz-Moles MA (2008). "Evaluation of the clinical efficacy of a mouthwash and oral gel containing the antimicrobial proteins lactoperoxidase, lysozyme and lactoferrin in elderly patients with dry mouth – a pilot study". Gerodontology. 25 (1): 3–9. doi:10.1111/j.1741-2358.2007.00197.x. PMID 18194332.
  55. ↑ Nagy K, Urban E, Fazwkas O, Thurzo L, Nagy E (2007). "Controlled study of lactoperoxidase gel on oral flora and saliva in irradiated patients with oral cancer". J Craniofac Surg. 18 (5): 1157–1164. doi:10.1097/scs.0b013e3180de6311. PMID 17912104.
  56. ↑ Shahdad SA, Taylor C, Barclay SC, Steeb IN, Preshaw PM (2005). "A double-blind, crossover study of Biotène Oralbalance and BioXtra systems as salivary substitutes in patients with post- radiotherapy xerostomia". Eur J Cancer Care (Engl). 14 (4): 319–326. doi:10.1111/j.1365-2354.2005.00587.x. PMID 16098116.
  57. ↑ Matear DW, Barbaro J (2005). "Effectiveness of saliva substitute products in the treatment of dry mouth in the elderly: a pilot study". J R Soc Promot Health. 125 (1): 35–41. doi:10.1177/146642400512500113. PMID 15712851.

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