Defensin

Defensin
Example defensins with alpha helix in red, beta strands in blue, disulphide bonds in yellow (PDB: 1MR4, 2KOZ, 1FJN, 2LXZ, 1IJV, 2RNG​)
Identifiers
SymbolDefensin
Pfam clanCL0075
OPM superfamily54
OPM protein6cs9

Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate[1] and invertebrate[2] animals, plants,[3][4] and fungi.[5] They are host defense peptides, with members displaying either direct antimicrobial activity, immune signaling activities, or both. They are variously active against bacteria, fungi and many enveloped and nonenveloped viruses. They are typically 18-45 amino acids in length, with three or four highly conserved disulphide bonds.

In animals, they are produced by cells of the innate immune system and epithelial cells, whereas in plants and fungi they are produced by a wide variety of tissues. An organism usually produces many different defensins, some of which are stored inside the cells (e.g. in neutrophil granulocytes to kill phagocytosed bacteria), and others are secreted into the extracellular medium. For those that directly kill microbes, their mechanism of action varies from disruption of the microbial cell membrane to metabolic disruption.

Varieties

Characteristic disulphide linkages
Trans-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to two different secondary structure elements (motif = CC). On the right, an example structure (PDB: 1IJV​).
Cis-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to the same alpha helix (motif = CxC...CxxxC). On the right, an example structure (PDB: 1MRR4​).

The name 'defensin' was coined in the mid-1980s, though the proteins have been called 'Cationic Antimicrobial Proteins,' 'Neutrophil peptides,' 'Gamma thionins' amongst others.[6]

Proteins called 'defensins' are not all evolutionarily related to one another.[7] Instead fall into two broad superfamilies, each of which contains multiple families.[7][8] One superfamily, the trans-defensins, contains the defensins found in humans and other vertebrates,[9][10] as well as some invertebrates.[11][12] The other superfamily, cis-defensins, contains the defensins found in invertebrates, plants, and fungi.[13][14][15] The superfamilies and families are determined by the overall tertiary structure, and each family usually has a conserved pattern of disulphide bonds.[9][16] All defensins form small and compact folded structures, typically with a high positive charge, that are highly stable due to the multiple disulphide bonds. In all families, the underlying genes responsible for defensin production are highly polymorphic.[citation needed]

Trans-defensins

Vertebrate defensins are primarily α-defensins and β-defensins. Some primates additionally have the much smaller θ-defensins. In general, both α- and β-defensins are encoded by two-exon genes, where the first exon encodes for a hydrophobic leader sequence (removed after translation) and the cysteine-rich sequence (the mature peptide). The disulfide linkages formed by the cysteines have been suggested to be essential for activities related to innate immunity in mammals, but are not necessarily required for antimicrobial activity.[17][18] Theta defensins form a single beta-hairpin structure and represent a distinct group. Only alpha and beta-defensins are expressed in humans.[19]

Table of human defensins
Type Gene Symbol Gene Name Protein Name Description
α-defensins DEFA1 Defensin, alpha 1 Neutrophil defensin 1 Are expressed primarily in neutrophils as well as in NK cells and certain T-lymphocyte subsets. DEFA5 and DEFA6 are expressed in Paneth cells of the small intestine, where they may regulate and maintain microbial balance in the intestinal lumen.
DEFA1B Defensin, alpha 1B Defensin, alpha 1
DEFA3 Defensin, alpha 3, neutrophil-specific Neutrophil defensin 3
DEFA4 Defensin, alpha 4, corticostatin Neutrophil defensin 4
DEFA5 Defensin, alpha 5, Paneth cell-specific Defensin-5
DEFA6 Defensin, alpha 6, Paneth cell-specific Defensin-6
β-defensins DEFB1 Defensin, beta 1 Beta-defensin 1 Are the most widely distributed, being secreted by leukocytes and epithelial cells of many kinds. For example, they can be found on the tongue, skin, cornea, salivary glands, kidneys, esophagus, and respiratory tract. It has been suggested (but also challenged) that some of the pathology of cystic fibrosis arises from the inhibition of β-defensin activity on the epithelial surfaces of the lungs and trachea due to higher salt content.
DEFB2 Defensin, beta 2 Beta-defensin 2
DEFB3 Defensin, beta 3 Beta-defensin 3
DEFB103A Defensin, beta 103B Beta-defensin 103
... ... ...
DEFB106A Defensin, beta 106A Beta-defensin 106A
DEFB106B Defensin, beta 106B Beta-defensin 106B
DEFB107B Defensin, beta 107A Beta-defensin 107
DEFB110 Defensin, beta 110 Beta-defensin 110
... ... ...
DEFB136 Defensin, beta 136 Beta-defensin 136
θ-defensins DEFT1P Defensin, theta 1 pseudogene not expressed in humans Are rare, and thus far have been found only in the leukocytes of the rhesus macaque[20] and the olive baboon, Papio anubis, the gene coding for it is corrupted in humans and other primates.[21][22]

Although the most well-studied defensins are from vertebrates, a family of trans-defensins called 'big defensins' are found in molluscs, arthropods and lancelets.[7][8]

Cis-defensins

Arthropod defensins are the best-characterised defensins from invertebrates (especially those from insects).[23] Other invertebrates known to produce defensins from this protein superfamily include molluscs, annelids and cnidaria.[24]

Plant defensins were discovered in 1990 and have subsequently been found in most plant tissues with antimicrobial activities, with both antifungal and antibacterial examples.[25] They have been identified in all major groups of vascular plants, but not in ferns, mosses or algae.[25]

Fungal defensins were first identified in 2005.[26] Studied examples mainly have anti-bacterial activities and have been found in both main divisions of fungi (Ascomycota and Basidiomycota), as well as in the more basal groups of Zygomycota and Glomeromycota.[27]

Bacterial defensins have also been identified, but are by far the least studied. They include variants with only four cysteines, whereas defensins from eukaryote defensins almost all have six or eight.[28]

In addition to the defensins involved in host defence, there are a number of related Defensin-Like Peptides (DLPs) that have evolved to have other activities.

Toxins

There appear to have been multiple evolutionary recruitments of defensins to be toxin proteins used in the venoms of animals;[29] they act via a completely different mechanism to their antimicrobial relatives, from binding directly to ion channels to disrupting nerve signals. Examples include the crotamine toxin in snake venom,[30] many scorpion toxins,[31] some sea anemone toxins,[10] and one of the toxins in platypus venom.[29] Indeed, an insect defensin has been experimentally converted into a toxin by deletion of a small loop that otherwise sterically hindered interactions with the ion channels.[32]

Signalling

In vertebrates, some α- and β-defensins are involved in signalling between the innate immune and adaptive immune systems.[33][34] In plants, a specialised family of DLPs is involved in signalling to detect if self-pollination has occurred and induce self-incompatibility to prevent inbreeding.[35]

Enzyme inhibitors

Some antimicrobial defensins also have enzyme inhibitory activity, and some DLPs function primarily as enzyme inhibitors, acting as antifeedants (discouraging animals from eating them).[36][37][38]

Function

In immature marsupials, because their immune system is underdeveloped at the time of birth, defensins play a major role in defense against pathogens. [citation needed] They are produced in the milk of the mother as well as by the young marsupial in question.

In human breast milk, defensins play a central role in neonate immunity.[39]

The human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin,[40] retrocyclin, was created by 'fixing' the pseudogene, and it was shown to be effective against HIV[41] and other viruses, including herpes simplex virus and influenza A. They act primarily by preventing these viruses from entering their target cells.

Also interesting is the effect of alpha-defensins on the exotoxin produced by anthrax (Bacillus anthracis). Chun Kim et al. showed how anthrax, which produces a metalloprotease lethal factor (LF) protein to target MAPKK, is vulnerable to human neutrophil protein-1 (HNP-1). This group showed HNP-1 to behave as a reversible noncompetitive inhibitor of LF.[42]

They have generally been considered to contribute to mucosal health; however, it is possible that these peptides can be considered biological factors that can be upregulated by bioactive compounds present in human breast milk. In this sense, the intestinal production of antimicrobial peptides as hBD2 and hBD4 by trefoil from milk might play an important role on neonate colonization, thereby enhancing the immune response of newborns against pathogens with which they may come in contact.[39][43]

Pathology

The alpha defensin peptides are increased in chronic inflammatory conditions.

Alpha defensin are increased in several cancers, including colorectal cancer.[44]

An imbalance of defensins in the skin may contribute to acne.[45]

A reduction of ileal defensins may predispose to Crohn's disease.[46][47]

In one small study, a significant increase in alpha defensin levels was detected in T cell lysates of schizophrenia patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings. The authors suggested that alpha-defensin levels might prove a useful marker for schizophrenia risk.[48]

Defensins are found in the human skin during inflammatory conditions like psoriasis[49] and also during wound healing.

Applications

Defensins

At present, the widespread spread of antibiotic resistance requires the search and development of new antimicrobial drugs. From this point of view, defensins (as well as antimicrobial peptides in general) are of great interest. It was shown that defensins have pronounced antibacterial activity against a wide range of pathogens.[50] In addition, defensins can enhance the effectiveness of conventional antibiotics.[50]

Defensin-mimetics

Defensin mimetics, also called host defense peptide (HDP) mimetics, are completely synthetic, non-peptide, small molecule structures that mimic defensins in structure and activity.[51] Similar molecules, such as brilacidin, are being developed as antibiotics,[52] anti-inflammatories for oral mucositis,[53][54] and antifungals, especially for candidiasis.[55][56][57]

See also

References

  1. ^ Hazlett L, Wu M (January 2011). "Defensins in innate immunity". Cell and Tissue Research. 343 (1): 175–88. doi:10.1007/s00441-010-1022-4. PMID 20730446. S2CID 2234617.
  2. ^ Tassanakajon A, Somboonwiwat K, Amparyup P (February 2015). "Sequence diversity and evolution of antimicrobial peptides in invertebrates". Developmental and Comparative Immunology. Specific immunity in invertebrates. 48 (2): 324–41. doi:10.1016/j.dci.2014.05.020. PMID 24950415.
  3. ^ Thomma BP, Cammue BP, Thevissen K (December 2002). "Plant defensins". Planta. 216 (2): 193–202. Bibcode:2002Plant.216..193T. doi:10.1007/s00425-002-0902-6. PMID 12447532. S2CID 19356421.
  4. ^ Sathoff AE, Samac DA (May 2019). "Antibacterial Activity of Plant Defensins". Molecular Plant-Microbe Interactions. 32 (5): 507–514. doi:10.1094/mpmi-08-18-0229-cr. PMID 30501455.
  5. ^ Wu J, Gao B, Zhu S (August 2014). "The fungal defensin family enlarged". Pharmaceuticals. 7 (8): 866–80. doi:10.3390/ph7080866. PMC 4165938. PMID 25230677.
  6. ^ Lehrer RI (September 2004). "Primate defensins". Nature Reviews. Microbiology. 2 (9): 727–38. doi:10.1038/nrmicro976. PMID 15372083. S2CID 8774156.
  7. ^ a b c Shafee TM, Lay FT, Hulett MD, Anderson MA (September 2016). "The Defensins Consist of Two Independent, Convergent Protein Superfamilies". Molecular Biology and Evolution. 33 (9): 2345–56. doi:10.1093/molbev/msw106. PMID 27297472.
  8. ^ a b Shafee TM, Lay FT, Phan TK, Anderson MA, Hulett MD (February 2017). "Convergent evolution of defensin sequence, structure and function". Cellular and Molecular Life Sciences. 74 (4): 663–682. doi:10.1007/s00018-016-2344-5. PMC 11107677. PMID 27557668. S2CID 24741736.
  9. ^ a b Hollox EJ, Abujaber R (2017). "Evolution and Diversity of Defensins in Vertebrates". In Pontarotti P (ed.). Evolutionary Biology: Self/Nonself Evolution, Species and Complex Traits Evolution, Methods and Concepts. Springer International Publishing. pp. 27–50. doi:10.1007/978-3-319-61569-1_2. ISBN 978-3-319-61569-1.
  10. ^ a b Mitchell ML, Shafee T, Papenfuss AT, Norton RS (July 2019). "Evolution of cnidarian trans-defensins: Sequence, structure and exploration of chemical space". Proteins. 87 (7): 551–560. doi:10.1002/prot.25679. hdl:11343/285595. PMID 30811678. S2CID 73469576.
  11. ^ Zhu S, Gao B (2013). "Evolutionary origin of β-defensins". Developmental and Comparative Immunology. 39 (1–2): 79–84. doi:10.1016/j.dci.2012.02.011. PMID 22369779.
  12. ^ Montero-Alejo V, Corzo G, Porro-Suardíaz J, Pardo-Ruiz Z, Perera E, Rodríguez-Viera L, Sánchez-Díaz G, Hernández-Rodríguez EW, Álvarez C, Peigneur S, Tytgat J, Perdomo-Morales R (February 2017). "Panusin represents a new family of β-defensin-like peptides in invertebrates". Developmental and Comparative Immunology. 67: 310–321. doi:10.1016/j.dci.2016.09.002. PMID 27616720. S2CID 19734223.
  13. ^ Dias RD, Franco OL (October 2015). "Cysteine-stabilized αβ defensins: From a common fold to antibacterial activity". Peptides. Festschrift to highlight the career of Abba J. Kastin as a founding editor, researcher, and educator in the peptide field. 72: 64–72. doi:10.1016/j.peptides.2015.04.017. PMID 25929172. S2CID 17846143.
  14. ^ Shafee T, Anderson MA (March 2019). "A quantitative map of protein sequence space for the cis-defensin superfamily" (PDF). Bioinformatics. 35 (5): 743–752. doi:10.1093/bioinformatics/bty697. PMID 30102339. S2CID 51968286.
  15. ^ Zhu S (February 2008). "Discovery of six families of fungal defensin-like peptides provides insights into origin and evolution of the CSalphabeta defensins". Molecular Immunology. 45 (3): 828–38. doi:10.1016/j.molimm.2007.06.354. PMID 17675235.
  16. ^ Wang YP, Lai R (February 2010). "[Insect antimicrobial peptides: structures, properties and gene regulation]". Dong Wu Xue Yan Jiu = Zoological Research. 31 (1): 27–34. doi:10.3724/sp.j.1141.2010.01027. hdl:1807/64439. PMID 20446450. S2CID 4692675.
  17. ^ Varkey J, Singh S, Nagaraj R (November 2006). "Antibacterial activity of linear peptides spanning the carboxy-terminal beta-sheet domain of arthropod defensins". Peptides. 27 (11): 2614–23. doi:10.1016/j.peptides.2006.06.010. PMID 16914230. S2CID 21104756.
  18. ^ Varkey J, Nagaraj R (November 2005). "Antibacterial activity of human neutrophil defensin HNP-1 analogs without cysteines". Antimicrobial Agents and Chemotherapy. 49 (11): 4561–6. doi:10.1128/AAC.49.11.4561-4566.2005. PMC 1280114. PMID 16251296.
  19. ^ Dhople V, Krukemeyer A, Ramamoorthy A (September 2006). "The human beta-defensin-3, an antibacterial peptide with multiple biological functions". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1758 (9): 1499–512. doi:10.1016/j.bbamem.2006.07.007. PMID 16978580. S2CID 36461159.
  20. ^ Tran D, Tran P, Roberts K, Osapay G, Schaal J, Ouellette A, Selsted ME (March 2008). "Microbicidal properties and cytocidal selectivity of rhesus macaque theta defensins". Antimicrobial Agents and Chemotherapy. 52 (3): 944–53. doi:10.1128/AAC.01090-07. PMC 2258523. PMID 18160518.
  21. ^ Garcia AE, Selsted M (March 2008). "Olive baboon θ-defensins". The FASEB Journal. 22 (1 Suppl): 673.11. doi:10.1096/fasebj.22.1_supplement.673.11. S2CID 89807163.
  22. ^ Garcia AE, Osapay G, Tran PA, Yuan J, Selsted ME (December 2008). "Isolation, synthesis, and antimicrobial activities of naturally occurring theta-defensin isoforms from baboon leukocytes". Infection and Immunity. 76 (12): 5883–91. doi:10.1128/IAI.01100-08. PMC 2583559. PMID 18852242.
  23. ^ Koehbach J (2017). "Structure-Activity Relationships of Insect Defensins". Frontiers in Chemistry. 5: 45. Bibcode:2017FrCh....5...45K. doi:10.3389/fchem.2017.00045. PMC 5506212. PMID 28748179.
  24. ^ Greco S, Gerdol M, Edomi P, Pallavicini A (January 2020). "Molecular Diversity of Mytilin-Like Defense Peptides in Mytilidae (Mollusca, Bivalvia)". Antibiotics. 9 (1): 37. doi:10.3390/antibiotics9010037. PMC 7168163. PMID 31963793.
  25. ^ a b Parisi K, Shafee TM, Quimbar P, van der Weerden NL, Bleackley MR, Anderson MA (April 2019). "The evolution, function and mechanisms of action for plant defensins". Seminars in Cell & Developmental Biology. 88: 107–118. doi:10.1016/j.semcdb.2018.02.004. PMID 29432955. S2CID 3543741.
  26. ^ Mygind PH, Fischer RL, Schnorr KM, Hansen MT, Sönksen CP, Ludvigsen S, Raventós D, Buskov S, Christensen B, De Maria L, Taboureau O, Yaver D, Elvig-Jørgensen SG, Sørensen MV, Christensen BE, Kjaerulff S, Frimodt-Moller N, Lehrer RI, Zasloff M, Kristensen HH (October 2005). "Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus". Nature. 437 (7061): 975–80. Bibcode:2005Natur.437..975M. doi:10.1038/nature04051. PMID 16222292. S2CID 4423851.
  27. ^ Wu J, Gao B, Zhu S (August 2014). "The fungal defensin family enlarged". Pharmaceuticals. 7 (8): 866–80. doi:10.3390/ph7080866. PMC 4165938. PMID 25230677.
  28. ^ Dash TS, Shafee T, Harvey PJ, Zhang C, Peigneur S, Deuis JR, Vetter I, Tytgat J, Anderson MA, Craik DJ, Durek T, Undheim EA (February 2019). "A Centipede Toxin Family Defines an Ancient Class of CSαβ Defensins". Structure. 27 (2): 315–326.e7. doi:10.1016/j.str.2018.10.022. PMID 30554841.
  29. ^ a b Whittington CM, Papenfuss AT, Bansal P, Torres AM, Wong ES, Deakin JE, Graves T, Alsop A, Schatzkamer K, Kremitzki C, Ponting CP, Temple-Smith P, Warren WC, Kuchel PW, Belov K (June 2008). "Defensins and the convergent evolution of platypus and reptile venom genes". Genome Research. 18 (6): 986–94. doi:10.1101/gr.7149808. PMC 2413166. PMID 18463304.
  30. ^ Batista da Cunha D, Pupo Silvestrini AV, Gomes da Silva AC, Maria de Paula Estevam D, Pollettini FL, de Oliveira Navarro J, Alves AA, Remédio Zeni Beretta AL, Annichino Bizzacchi JM, Pereira LC, Mazzi MV (May 2018). "Mechanistic insights into functional characteristics of native crotamine". Toxicon. 146: 1–12. doi:10.1016/j.toxicon.2018.03.007. hdl:11449/170828. PMID 29574214. S2CID 205440053.
  31. ^ Possani LD, Becerril B, Delepierre M, Tytgat J (September 1999). "Scorpion toxins specific for Na+-channels". European Journal of Biochemistry. 264 (2): 287–300. doi:10.1046/j.1432-1327.1999.00625.x. PMID 10491073.
  32. ^ Zhu S, Peigneur S, Gao B, Umetsu Y, Ohki S, Tytgat J (March 2014). "Experimental conversion of a defensin into a neurotoxin: implications for origin of toxic function". Molecular Biology and Evolution. 31 (3): 546–59. doi:10.1093/molbev/msu038. PMID 24425781.
  33. ^ Petrov V, Funderburg N, Weinberg A, Sieg S (December 2013). "Human β defensin-3 induces chemokines from monocytes and macrophages: diminished activity in cells from HIV-infected persons". Immunology. 140 (4): 413–20. doi:10.1111/imm.12148. PMC 3839645. PMID 23829433.
  34. ^ Semple F, Dorin JR (2012). "β-Defensins: multifunctional modulators of infection, inflammation and more?". Journal of Innate Immunity. 4 (4): 337–48. doi:10.1159/000336619. PMC 6784047. PMID 22441423.
  35. ^ Fobis-Loisy I, Ivanov R, Gaude T (2012). "The S-LOCUS CYSTEINE-RICH PROTEIN (SCR): A Small Peptide with a High Impact on the Evolution of Flowering Plants". Plant Signaling Peptides. Signaling and Communication in Plants. Vol. 16. Springer Berlin Heidelberg. pp. 77–92. doi:10.1007/978-3-642-27603-3_5. ISBN 978-3-642-27602-6.
  36. ^ Williams LK, Brayer GD (2015-11-25). "Porcine pancreatic alpha-amylase in complex with helianthamide, a novel proteinaceous inhibitor". doi:10.2210/pdb4x0n/pdb.
  37. ^ Zhao Q, Chae YK, Markley JL (2003-01-07). "Minimized NMR structure of ATT, an Arabidopsis trypsin/chymotrypsin inhibitor". doi:10.2210/pdb1jxc/pdb.
  38. ^ Pelegrini PB, Lay FT, Murad AM, Anderson MA, Franco OL (November 2008). "Novel insights on the mechanism of action of alpha-amylase inhibitors from the plant defensin family". Proteins. 73 (3): 719–29. doi:10.1002/prot.22086. PMID 18498107. S2CID 28378146.
  39. ^ a b Barrera GJ, Sanchez G, Gonzalez JE (November 2012). "Trefoil factor 3 isolated from human breast milk downregulates cytokines (IL8 and IL6) and promotes human beta defensin (hBD2 and hBD4) expression in intestinal epithelial cells HT-29". Bosnian Journal of Basic Medical Sciences. 12 (4): 256–64. doi:10.17305/bjbms.2012.2448. PMC 4362502. PMID 23198942.
  40. ^ retrocyclin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  41. ^ Münk C, Wei G, Yang OO, Waring AJ, Wang W, Hong T, Lehrer RI, Landau NR, Cole AM (October 2003). "The theta-defensin, retrocyclin, inhibits HIV-1 entry". AIDS Research and Human Retroviruses. 19 (10): 875–81. doi:10.1089/088922203322493049. PMID 14585219.
  42. ^ Kim C, Gajendran N, Mittrücker HW, Weiwad M, Song YH, Hurwitz R, Wilmanns M, Fischer G, Kaufmann SH (March 2005). "Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences". Proceedings of the National Academy of Sciences of the United States of America. 102 (13): 4830–5. Bibcode:2005PNAS..102.4830K. doi:10.1073/pnas.0500508102. PMC 555714. PMID 15772169.
  43. ^ Barrera GJ, Tortolero GS (2016). "Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins". Bratislavske Lekarske Listy. 117 (6): 332–9. doi:10.4149/bll_2016_066. PMID 27546365.
  44. ^ Albrethsen J, Bøgebo R, Gammeltoft S, Olsen J, Winther B, Raskov H (January 2005). "Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1-3) in colon cancer serum and tumours: a biomarker study". BMC Cancer. 5: 8. doi:10.1186/1471-2407-5-8. PMC 548152. PMID 15656915.
  45. ^ Philpott MP (November 2003). "Defensins and acne". Molecular Immunology. 40 (7): 457–62. doi:10.1016/S0161-5890(03)00154-8. PMID 14568392.
  46. ^ "Researchers discover a possible cause of chronic inflammations of Crohn Disease". Genomics & Genetics Weekly: 72. August 11, 2006.
  47. ^ Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, Feathers RW, Chu H, Lima H, Fellermann K, Ganz T, Stange EF, Bevins CL (December 2005). "Reduced Paneth cell alpha-defensins in ileal Crohn's disease". Proceedings of the National Academy of Sciences of the United States of America. 102 (50): 18129–34. Bibcode:2005PNAS..10218129W. doi:10.1073/pnas.0505256102. PMC 1306791. PMID 16330776.
  48. ^ Craddock RM, Huang JT, Jackson E, Harris N, Torrey EF, Herberth M, Bahn S (July 2008). "Increased alpha-defensins as a blood marker for schizophrenia susceptibility". Molecular & Cellular Proteomics. 7 (7): 1204–13. doi:10.1074/mcp.M700459-MCP200. PMID 18349140. S2CID 35381828.
  49. ^ Harder J, Bartels J, Christophers E, Schroder JM (February 2001). "Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic". The Journal of Biological Chemistry. 276 (8): 5707–13. doi:10.1074/jbc.M008557200. PMID 11085990. S2CID 9516726.
  50. ^ a b Bolatchiev A (2020-11-25). "Antibacterial activity of human defensins against Staphylococcus aureus and Escherichia coli". PeerJ. 8: e10455. doi:10.7717/peerj.10455. PMC 7698690. PMID 33304659.
  51. ^ "Press release: PolyMedix" (Press release). 2008-05-09. Business Wire
  52. ^ "PMX-30063 The First And Only Defensin Mimetic Systemic Antibiotic Drug In Human Clinical Trials". 2008.
  53. ^ Clinical trial number NCT02324335 for "Phase 2 Study to Evaluate the Safety & Efficacy of Brilacidin Oral Rinse in Patients With Head and Neck Cancer (Brilacidin)" at ClinicalTrials.gov
  54. ^ "Brilacidin-OM page". Cellceutix. Archived from the original on 2015-02-07. Retrieved 2015-03-02.
  55. ^ "Candidiasis". Cellceutix. Archived from the original on 2015-02-07. Retrieved 2015-03-02.
  56. ^ Diamond G, Scott R. "A Novel Therapeutic For Invasive Candiasis". Grantome. Fox Chase Chemical Diversity Center.
  57. ^ Ryan LK, Freeman KB, Masso-Silva JA, Falkovsky K, Aloyouny A, Markowitz K, Hise AG, Fatahzadeh M, Scott RW, Diamond G (July 2014). "Activity of potent and selective host defense peptide mimetics in mouse models of oral candidiasis". Antimicrobial Agents and Chemotherapy. 58 (7): 3820–7. doi:10.1128/AAC.02649-13. PMC 4068575. PMID 24752272.
Wikimedia Commons has media related to Defensin.

Read other articles:

International Football Association Board

International Football Association BoardLogo Discipline Calcio Calcio a 5 Beach soccer Fondazione1886 GiurisdizioneMondiale Sede Zurigo Sito ufficialewww.theifab.com, www.theifab.com/fr/, www.theifab.com/de/ e www.theifab.com/es/ Modifica dati su Wikidata · Manuale L'International Football Association Board (IFAB) è un organo internazionale (un'associazione di diritto svizzero), istituito a Londra nel 1886, che è composto di soli otto membri, indipendente dalla FIFA (dal gennaio ...

 

 

Daftar keuskupan di Iran

Daftar keuskupan di Iran adalah sebuah daftar yang memuat dan menjabarkan pembagian terhadap wilayah administratif Gereja Katolik Roma yang dipimpin oleh seorang uskup ataupun ordinaris di Iran. Konferensi para uskup Iran bergabung dalam Konferensi Waligereja Iran. Saat ini terdapat 6 buah yurisdiksi, terdiri atas 2 keuskupan agung metropolit, 2 keuskupan agung, dan 2 keuskupan suffragan. Daftar yurisdiksi Ritus Latin Yurisdiksi Tahta Suci Keuskupan Agung Isfahan: lowong Gereja Katolik Kaldea...

 

 

Escape Plan (film)

Escape PlanSutradaraMikael HåfströmProduser Mark Canton Randall Emmett Remington Chase Robbie Brenner Kevin King-Templeton Stepan Martirosyan Kelly Dennis Brandon Grimes SkenarioMiles ChapmanArnell JeskoCeritaMiles ChapmanPemeran Sylvester Stallone Arnold Schwarzenegger Jim Caviezel 50 Cent Sam Neill Faran Tahir Vinnie Jones Vincent D'Onofrio Caitriona Balfe Amy Ryan Penata musikAlex HeffesSinematograferBrendan GalvinPenyuntingElliot GreenbergPerusahaanproduksiAtmosphere Entertainment...

دوري السوبر الألباني 1961

يفتقر محتوى هذه المقالة إلى الاستشهاد بمصادر. فضلاً، ساهم في تطوير هذه المقالة من خلال إضافة مصادر موثوق بها. أي معلومات غير موثقة يمكن التشكيك بها وإزالتها. (نوفمبر 2019) دوري السوبر الألباني 1961 تفاصيل الموسم دوري السوبر الألباني  النسخة 24  البلد ألبانيا  المنظم اتحا�...

 

 

The F Word (British TV series)

This article is about the British cooking show. For the American cooking show, see The F Word (American TV series). For other uses, see F word. British TV series or programme The F WordGenreFood magazine/Cooking showStarringGordon RamsayGiles Coren (Series 1–2)Janet Street Porter(Series 2–5)Opening themeThe F Word by BabybirdCountry of originUnited KingdomOriginal languageEnglishNo. of series5No. of episodes51ProductionRunning time44 minutesOriginal releaseNetworkChannel 4Release27 Octobe...

 

 

جرينلاند والاتحاد الأوروبي

جرينلاند هي دولة تتمتع باستقلال ذاتي داخل مملكة الدنمارك (والتي تشمل أيضًا دول الدنمارك وجزر فارو)؛ وهي واحدة من الأقاليم والبلدان خارج الاتحاد الأوروبي (الأقاليم ذات العضوية الخاصة في الاتحاد الأوروبي) التابعة له والمرتبطة به. تتلقى جرينلاند تمويلًا من الاتحاد الأوروبي �...

Wide Open West

Telecommunications provider in the United States WOW! redirects here. For other uses, see Wow (disambiguation). WideOpenWest, Inc.Company typePublicTraded asNYSE: WOWRussell 2000 ComponentIndustryTelecommunicationsPredecessorAmericast, KnologyFoundedNovember 1996; 27 years ago (1996-11)Denver, Colorado, U.S.HeadquartersDenver, Colorado, U.S.Area servedAlabamaFloridaGeorgiaIllinoisIndianaMarylandMichiganOhio (1996-2021)South CarolinaTennesseeKey peopleTeresa Elder(P...

 

 

Nagato Uzumaki

Artikel ini menjelaskan karya atau unsur fiksi dalam gaya fiksi. Silakan memperbaiki artikel ini dan jelaskan juga dari sudut pandang non-fiksi. Karakter dalam seri NarutoNagato UzumakiPenampilan perdanaMangaBab #372AnimeNaruto Shippuden Eps. #128FilmRoad to Ninja: Naruto the MoviePermainan video • Naruto Shippuden Ultimate Ninja Heroes 3  • Naruto Shippuden Ultimate Ninja Storm 2Tampil diManga, Anime, Film dan PermainanPengisi suaraInggrisVic MignognaJepangMorita Junpei Informa...

 

 

2015 D.C. United season

D.C. United 2015 soccer seasonD.C. United2015 seasonGeneral managerDave KasperHead coachBen OlsenStadiumRFK StadiumMLSConference: 4thOverall: 8thMLS Cup PlayoffsConference SemifinalsU.S. Open CupFifth roundCONCACAF Champions League (14–15)QuarterfinalsCONCACAF Champions League (15–16)QuarterfinalsAtlantic CupRunner-upTop goalscorerLeague: Chris Rolfe (6)All: Jairo Arrieta (9)Highest home attendance21,517( vs. NYCFC)Lowest home attendanceLeague: 11,218(June 3 vs. Chicago)All: 8,137(Mar. 4...

Able seaman

Unlicensed member of the deck department of ship This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.Find sources: Able seaman – news · newspapers · books · scholar · JSTOR (January 2017) (Learn how and when to remove this template message) This article is about the civilian occupation. For the military rank, see Able seaman ...

 

 

Tinju pada Olimpiade Musim Panas 1984

Tinju pada Olimpiade Musim Panas 1984LokasiLos Angeles Memorial Sports ArenaLos Angeles, CaliforniaTanggal29 Juli hingga 11 Agustus 1984Peserta354 dari 81 negara← 19801988 → Tinju pada Olimpiade Musim Panas 1984 berlangsung di Memorial Sports Arena, Los Angeles, California sejak tanggal 29 Juli hingga 11 Agustus 1984. Edisi ini menandingkan 12 nomor yang seluruhnya untuk atlet putra. 354 atlet dari 81 negara bertanding dalam edisi ini.[1] Hasil Ter...

 

 

Alma Juventus Fano 1906 2016-2017

Voce principale: Alma Juventus Fano 1906. Alma Juventus Fano 1906Stagione 2016-2017Sport calcio Squadra Fano Allenatore Giovanni Cusatis (1ª-22ª), poi Agatino Cuttone (22ª-38ª) All. in seconda Massimo Scardovi(1ª-38ª) Presidente Claudio Gabellini Lega Pro17° StadioRaffaele Mancini 8.880 Abbonati981 Maggior numero di spettatori2.475 vs Mantova (2 aprile 2017) Minor numero di spettatori1.056 vs Lumezzane (11 dicembre 2016) Media spettatori1.693 2015-2016 2017-2018 Si invita a segui...

Kejatuhan Soeharto

Kejatuhan SoehartoBagian dari Reformasi Indonesia Searah jarum jam, dari atas: Presiden Indonesia Soeharto menyampaikan pengunduran diri dari jabatannya Para perusuh membakar perabot kantor di jalan-jalan Jakarta Mahasiswa memprotes pemerintah Mahasiswa Universitas Trisakti dan polisi pada bentrok Tanggal4–21 Mei 1998LokasiIndonesiaHasilKejatuhan Orde Baru Presiden Soeharto mengundurkan diri Peresmian B.J. Habibie sebagai presiden Pembentukan Kabinet Reformasi Pembangunan Referendum kemerde...

 

 

Vassal state

State subordinate to another state Part of the Politics seriesBasic forms of government List of forms of government List of countries by system of government Source of power Democracy (rule by many) Demarchy Direct Liberal Representative Social Socialist Others Oligarchy (rule by few) Anocracy Aristocracy Gerontocracy Kleptocracy Kritarchy Meritocracy Noocracy Particracy Plutocracy Stratocracy Technocracy Theocracy Autocracy (rule by one) Despotism Dictatorship Military dictatorship Tyranny A...

 

 

Assedio di Siracusa (212 a.C.)

Assedio di Siracusa (212 a.C.)parte della seconda guerra punicaArchimede dirige la difesa delle mura dell'antica SiracusaData214–212 a.C. LuogoSiracusa CausaImprovviso appoggio di Siracusa a Cartagine EsitoVittoria romana Modifiche territorialiConquista romana di Siracusa e dei suoi territori SchieramentiSiracusaCartagineRepubblica romana ComandantiSiracusani: IppocrateEpicideCartaginesi: ImilconeBomilcare[1]Claudio Marcello[2][3]Appio Claudio[3] Effettivi25....

约翰斯顿环礁

此條目可参照英語維基百科相應條目来扩充。 (2021年5月6日)若您熟悉来源语言和主题，请协助参考外语维基百科扩充条目。请勿直接提交机械翻译，也不要翻译不可靠、低品质内容。依版权协议，译文需在编辑摘要注明来源，或于讨论页顶部标记{{Translated page}}标签。 约翰斯顿环礁Kalama Atoll 美國本土外小島嶼 Johnston Atoll 旗幟颂歌：《星條旗》The Star-Spangled Banner約翰斯頓環礁�...

 

 

2016年美國總統選舉

2016年美國總統選舉 ← 2012 2016年11月8日 2020 → 538個選舉人團席位獲勝需270票民意調查投票率55.7%[1][2] ▲ 0.8 %   获提名人 唐納·川普 希拉莉·克林頓 政党 共和黨 民主党 家鄉州 紐約州 紐約州 竞选搭档 迈克·彭斯 蒂姆·凱恩 选举人票 304[3][4][註 1] 227[5] 胜出州/省 30 + 緬-2 20 + DC 民選得票 62,984,828[6] 65,853,514[6]...

 

 

الموسوعة الكاثوليكية

الموسوعة الكاثوليكيةAn International Work of Reference on the Constitution, Doctrine, Discipline, and History of the Catholic Church (بالإنجليزية) معلومات عامةاللغة الإنجليزية العنوان الأصلي The Catholic Encyclopedia (بالإنجليزية) البلد  الولايات المتحدة النوع الأدبي موسوعة الناشر D. Appleton & Company (en) تاريخ الإصدار 19 أبريل 1913 تعديل ...

007 - Vendetta privata

Questa voce o sezione sugli argomenti film d'azione e film thriller non cita le fonti necessarie o quelle presenti sono insufficienti. Puoi migliorare questa voce aggiungendo citazioni da fonti attendibili secondo le linee guida sull'uso delle fonti. Segui i suggerimenti dei progetti di riferimento 1, 2. 007 - Vendetta privataL'inseguimento finale in camionTitolo originaleLicence to Kill Paese di produzioneRegno Unito Anno1989 Durata133 min Rapporto2,35:1 Generespionaggio, azione,&#...

 

 

Lalotok

LalotokNama lahirAdolfo Maria Soares LayLahir Timor PortugisPengabdian Timor LesteDinas/cabang Falintil Pasukan Pertahanan Timor LestePangkat Letnan FDTLPerang/pertempuranPendudukan Indonesia di Timor Timur Letnan FDTL Lalotok[1] adalah tokoh militer Timor Leste. Dia pernah menjabat sebagai Komandan Seksi Falintil. Kepangkatan Lambang Pangkat Tanggal Letnan FDTL 2 Februari 2022 — sekarang Referensi ^ Jornal da República: Edisi 20 Desember 2006 (PDF; 403 kB), diakses pada 23 Maret 2...