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Antimicrobial Peptides from Fish

Department of Pediatrics and Graduate School of Biomedical Sciences, Rutgers New Jersey Medical School, Newark, NJ 07101, USA
Department of Oral Biology, University of Florida, Box 100424, Gainesville, FL 32610, USA
Author to whom correspondence should be addressed.
Pharmaceuticals 2014, 7(3), 265-310;
Original submission received: 15 January 2014 / Revised: 6 February 2014 / Accepted: 18 February 2014 / Published: 3 March 2014


Antimicrobial peptides (AMPs) are found widely distributed through Nature, and participate in the innate host defense of each species. Fish are a great source of these peptides, as they express all of the major classes of AMPs, including defensins, cathelicidins, hepcidins, histone-derived peptides, and a fish-specific class of the cecropin family, called piscidins. As with other species, the fish peptides exhibit broad-spectrum antimicrobial activity, killing both fish and human pathogens. They are also immunomodulatory, and their genes are highly responsive to microbes and innate immuno-stimulatory molecules. Recent research has demonstrated that some of the unique properties of fish peptides, including their ability to act even in very high salt concentrations, make them good potential targets for development as therapeutic antimicrobials. Further, the stimulation of their gene expression by exogenous factors could be useful in preventing pathogenic microbes in aquaculture.

1. Introduction

Antimicrobial peptides (AMPs) represent a broad category of different families of highly conserved peptides widely found throughout Nature, which exhibit broad-spectrum antimicrobial activity in vitro and in vivo. While vertebrate antimicrobial peptides were initially discovered in amphibians, humans and rabbits in the mid-1980s [1,2,3], The antimicrobial activity of fish peptides was not described for another decade. Initially, a toxic peptide from the Moses sole fish Pardachirus marmoratus, called pardaxin, was characterized in 1980 [4], but its antimicrobial activity wasn’t observed until 1996 [5]. Shortly thereafter, Cole et al. described a peptide isolated from the skin secretions of the winter flounder (Pleuronectes americanus) [6] using antimicrobial activity as a screening method. Since then, the field has progressed as with other vertebrate species, with the identification of homologous peptides in the piscidin family (unique to fish, but homologous to cecropins), as well as the defensin, cathelicidin, and hepcidin families, which are found in many other species. Many of the peptides were identified by purification of the peptides with antibiotic activity, although as with other species, the increased use of bioinformatics techniques has allowed the identification of even more peptides [7]. The results of the research described here demonstrate that AMPs from fish exhibit many if not all of the same characteristics as other vertebrate AMPs, like broad-spectrum (but often species-specific) antimicrobial activities, as well as immunomodulatory functions. In addition, there appear to be interesting differences, specific to fish, that have evolved to address the unique aquatic environments and microbes encountered by these species. There has also been a recent effort to study the potential for using these peptides as therapeutic agents, both in human medicine and in aquaculture. Below we will examine the various peptide families (whose members are shown in Table 1), and discuss their role in host defense and potential for future use.
Table 1. Characterized antimicrobial peptides from fish, by species. Listed is the number of peptides of each family [reference].
Table 1. Characterized antimicrobial peptides from fish, by species. Listed is the number of peptides of each family [reference].
Common nameScientific nameHabitat
American plaiceHippoglossoides platessoidesMarine2 [8]
Antarctic toothfishDissostichus mawsoniMarine 3 [9]
Atlantic codGadus morhuaMarine and brackish2 [10]1 [11]1 [12]1 [13]1 [14]
Antarctic eelpoutLycodichthys dearborniMarine 2 [9]
Atlantic hagfishMyxine glutinosaMarine 3 [15]
Atlantic salmonSalmo salarMarine, brackish and freshwater 2 [16]2 [17]1 [18]
AyuPlecoglossus altivelisMarine, brackish and freshwater 1 [19]1 [20]
BarramundiLates calcariferMarine, brackish and freshwater 2 [21]
Black porgyAcanthopagrus schlegeliiMarine and brackish 7 [22,23]
Black rockfishSebastes schlegeliiMarine 2 [24]
Blotched snakeheadChanna maculataFreshwater 1 [25]
Blue catfishIctalurus furcatusFreshwater and brackish 1 [26]
Blunt snout breamMegalobrama amblycephalaFreshwater 1 [27]
Brook troutSalvelinus fontinalisMarine, brackish and freshwater 2 [28]
Brown troutSalmo trutta farioMarine, brackish and freshwater 1 [28]
Channel catfishIctalurus punctatusFreshwater 1 [26] 1 [29]
Chinese loachParamisgurnus dabryanusFreshwater 1 [30]
Common carpCyprinus carpio L.Freshwater and brackish 2 [31]1 [32]
European seabassDicentrarchus labraxMarine, brackish and freshwater1 [33] 1 [34]
Gilthead seabreamSparus aurataMarine and brackish 1 [35]1 [36]
GraylingThymallus thymallusFreshwater and brackish 1 [28]
Half-smooth tongue soleCynoglossus semilaevisMarine, brackish and freshwater 1 [37]
Atlantic halibutHippoglossus hippoglossusMarine1 [8] 1 [38]
Hybrid striped bassMorone saxatilis x M. chrysopsMarine, brackish and freshwater4 [39,40,41] 1 [42]
IcefishChionodraco hamatusMarine1 [43]
Olive flounderParalichthys olivaceusMarine 2 [16]
Japanese rice fishOryzias latipesFreshwater and brackish 1 [16]
Japanese pufferfishTakifugu rubripesMarine, brackish and freshwater 1 [44]
Japanese seabassLateolabrax japonicusMarine, brackish and freshwater 1 [45]
Largemouth bassMicropterus salmoidesFreshwater 2 [46]
Large yellow croakerPseudosciaena croceaMarine and brackish1 [47] 1 [48,49]
Mandarin fishSiniperca chuatsiFreshwater1 [50]1 [51]
Maori chiefNotothenia angustataMarine 5 [9]
MedakaOryzias melastigmaFreshwater and brackish 1 [52]2 [53]
Miiuy croakerMiichthys miiuyMarine and brackish 1 [54]
Mud dabLimanda limandaMarine1 [55]
Mud loachMisgurnus mizolepisFreshwater [56]
Olive flounderParalichthys olivaceusMarine 5 [57]
Orange-spotted grouperEpinephelus coioidesMarine and brackish1 [58]2 [59,60]3 [61,62]
Pacific mutton hamletAlphestes immaculatusMarine 1 [63]
Rainbow troutOncorhynchus mykissMarine, brackish and freshwater 4 [64,65] 2 [17]3 [66,67,68,69]
Redbanded seabreamPagrus aurigaMarine 4 [70]
Red sea breamChrysophrys majorMarine1 [71] 1 [72]
RockbreamOplegnathus fasciatusMarine 4 [73]
Sea bassDicentrarchus labraxMarine, brackish and freshwater 1 [74]
SeahorseHippocampus kudaMarine and brackish1 [75]
Smallmouth bassMicropterus dolomieuFreshwater 2 [46]
SnowtroutSchizothorax richardsoniiFreshwater 1 [76]
Spotted-green pufferfishTetraodon nigroviridisFreshwater and brackish 2 [44]
Sunshine bassMarine, brackish and freshwater 1 [69]
Thick-lipped lenokBrachymystax lenokFreshwater 1 [77]
TilapiaOreochromis mossambicusFreshwater and brackish5 [78] 3 [79]
TurbotScophthalmus maximusMarine and brackish 2 [80,81]
Winter flounderPleuronectesamericanusMarine6 [6,82,83] 5 [16]
Witch flounderGlyptocephalus cynoglossusMarine5 [8]
Yellowtail flounderPleuronectes ferrugineaMarine1 [8]
ZebrafishDanio rerioFreshwater 3 [44]2 [84]

2. Piscidins

Piscidins and pleurocidins comprise a family of linear, amphipathic AMPs, evolutionarily related to similarly structured peptides found in amphibian skin and insects [85]. The first member of the family identified was a 25-residue peptide isolated and characterized from skin mucous secretions of the winter flounder, Pleuronectes americanus, called pleurocidin [6]. Further research identified other homologous pleurocidins in related species [8,83]. These were shown to exhibit an amphipathic, α-helical structure, similar to magainins and cecropins. A similarly structured peptide was identified in the loach, Misgurunus anguillicaudatus, called misgurin [86], and a family of peptides, termed piscidins, were identified in the mast cells of the hybrid striped bass [87], as well as numerous other fish taxa [88]. Other similar peptides, including moronecidin, epinecidin, dicentracin, have been identified [33,41,89]. An alignment of primary amino acid sequences of some members of this class are shown in Figure 1. The similarities of the mature peptide predicted secondary structure [6,41,78,90] as well as an analysis of their gene structures [33,50] suggested that they all belong to the same evolutionarily related family, which we will refer to as the piscidins. In addition, positive selection has been found influencing evolution of these peptides, where the highest diversity is found in the mature peptide that suggest adaptation for attacking new pathogens or strains that are coevolving with the host [91,92].
Figure 1. Alignment of piscidins. Mature peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. The Drosophila cecropin A1 sequences is provided for comparison as a representative member of the cecropin family.
Figure 1. Alignment of piscidins. Mature peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. The Drosophila cecropin A1 sequences is provided for comparison as a representative member of the cecropin family.
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Alignment of primary amino acid sequences shows that piscidins as a group have little direct sequence identity (Figure 1), but are as a group predicted to possess an amphipatic α-helical structure [6,41,78,90]. However, CD spectroscopy of the piscidin from brooding pouch suggests that it might have a β-sheet or β-strand motif instead of α-helix [75]. Their gene structure is composed of four exons and three introns, encoding a peptide precursor containing a signal peptide, a mature piscidin and a carboxy-terminal prodomain [41,50,82]. However, in tilapia and grouper a three-exon/two-intron and five-exon/four-intron structure, respectively was found [78,89]. Moreover, multiple piscidin isoforms have been found in the same species [78,83].
Piscidins exhibit potent antimicrobial activity against a variety of microorganisms. They are widely active against bacteria Gram-positive and -negative species, with the best antibacterial values obtained against several Streptococcus, Pseudomonas, Bacillus and Vibrio species (for a full listing of fish antimicrobial peptides and their activities, see Supplementary Table S1). Interestingly, chrysophsin-3 was observed to kill the three stages of Bacillus anthracis (sporulated, germinated and vegetative), being able to penetrate and kill the spores without full germination [93]. Piscidins have also been shown to possess anti-fungal activity [47,94,95], anti-parasitic activity [47,96,97,98], and anti-viral activity [99,100]. An interesting study showed that piscidin-2 was highly potent against the water mold Saprolegnia sp. (Oomycetes) with a MIC within the physiological piscidin-2 levels [98].
Piscidins are mainly expressed in gill, skin and intestine, although can be also found in head-kidney and spleen [10,43,47,50,58,101,102]. However, in Atlantic cod piscidin was found to be ubiquitous, being detected in chondrocytes, heart, oocytes, exocrine and endocrine glands, swim bladder, and other tissues [103]. Nevertheless, the expression profiles vary depending on the isoform [39,78,83]. Moreover, specifically among the cell types where piscidin has shown to be expressed are mast cells, rodlet cells, phagocytic granulocytes and eosinophilic granular cells [43,88,102,104,105]. Interestingly, there is evidence that granulocytes can destroy bacteria in phagosome by intracellular release of piscidin, meaning that piscidin can act against extra and intracellular bacteria [102]. In addition, pleurocidin expression is expressed at 13 days post-hatch in the winter flounder, which is suggested to play an important role in defense during development [101].
Like AMP genes from mammals, piscidin genes can be induced by a variety of stimuli, including Gram-positive and -negative bacteria [78], bacteria cell components like LPS [43,50,58] or the bacterial antigen ASAL [10]. The LPS-mediated induction of epinecidin-1 in zebrafish was shown to require hepatocyte nuclear factor 1 [89]. Furthermore, piscidin genes are induced by parasites [47,104,106], viruses [107], and poly I:C [43,58]. Another study demonstrated that high biomass density (i.e., a higher concentration of fish per volume water in an experimental tank) used as an acute stressor component, led to an to up-regulation of dicentracin in gills and skin as well [74].
Besides microorganisms, piscidin-mediated anti-tumor activity has been shown by the growth inhibition and/or killing of a variety of different cancer-derived cell lines like A549 [108], HT1080 [108,109,110], U937 [111], HL60 [112], U937 [110], HeLa [110] and different breast cancer-derived cell lines including MDA-MB-468, T47-D, SKBR3, MCF7, MCF7-TX400 (paclitaxel-resistant MCF7), MDA-MB-231 and 4T1 [113]. Furthermore, pleurocidin is able to kill breast cancer xenografts in NOD SCID mice, where cell death was caused by mitochondrial membrane damage and ROS production [113]. In addition, disruption of cancer cell membrane has been also shown to occur [110]. Moreover, in vitro inhibition of proliferation of U937 and HT1080 was suggested to occur by inducing apoptosis in response to cytokine production like TNF-α, IL-10, IL-15, IL-6, the tumor suppressor p53 [111], and caspases [110]. Also, pleurocidin showed the ability to inhibit HT1080 migration in a dose-dependent manner [109] as well as the rapid killing of a human leukemia cell line [112]. In contrast, pleurocidin showed no lysis of human dermal fibroblasts, umbilical vein endothelial cells and erythrocytes [113].
Several studies have shown that piscidin can disrupt the plasma membranes and cause cellular material efflux by pore formation [114,115]. However, use of membrane models has suggested that membrane composition is an important factor in the lytic capacity of piscidin to disrupt cell membranes [116]. In addition, using site-specific high-resolution solid-state NMR orientational restraints and circular dichroism it was shown that piscidin-1 and -3 induce a membrane-AMP interaction by parallel orientation of the α-helical in membrane model surfaces where fast and large amplitude backbone motions occur [117,118]. Moreover, at very low inhibitory concentrations piscidin does not cause significant cell membrane damage but is capable to inhibit macromolecular synthesis in bacteria [119]. Against fungi, pleurocidin was active against C. albicans by causing protoplast regeneration and membrane disruption [95,112] and it has been suggested to cause oxidative stress, triggering apoptosis in C. albicans by inducing intracellular reactive oxygen species (ROS) and activation of metacaspases, leading to externalization of phosphatidylserine [94].
Among other attractive features of piscidin includes their ability to retain antibacterial activity at high salt concentrations [41], thermostability (piscidin from seahorse brooding pouch retained full activity after exposing from 20–80 °C for 30 min, and only 20% loss of activity when boiling at 100 °C for 30 min) [75], and relatively low cytotoxicity against mammalian cells [120]. However, in tilapia some piscidin isoforms were hemolytic for tilapia red blood cells. The peptide with the greatest hemolysis activity was also the one with the best antibacterial activity, which is associated with the amphiphilic α-helical cationic structure [78].
The immunomodulatory capacity of piscidins is another feature that has been widely assessed. In fish, they are able to modulate the expression of pro-inflammatory and other immune-related genes like IL-1β, IL-10, IL-22, IL-26, TNF-α, IFN-γ, NF-κB, lysozyme, NOS2, MyD88, TLR4a, TLR1, TLR3, [121,122,123,124,125]. Moreover, in mice this immunomodulatory effect also has been observed, with the modulation of the genes encoding IL-6, IL-10, IL-12, MCP-1, TNF-α, IFN-γ and IgG1 [126,127,128]. Recently, some pleurocidins have shown to be able stimulate human mast cell chemotaxis increasing Ca2+ mobilization, and inducing the production of pro-inflammatory cytokines (like CCL2, 1β/CCL4) in mast cells, which was suggested to occur through G-proteins. In addition, it is able to cause mast cells to adhere, migrate, degranulate, and release cysteinyl leukotrienes and prostaglandin D2 [129].
Overall, it appears that piscidins represent an evolutionarily conserved family of peptides, which, while unique to fish, exhibit broad homology to the linear, amphipathic classes of antimicrobial peptides found in many other species.

3. β-Defensins

A general term for cysteine-rich, cationic antimicrobial peptides found in plants, fungi, invertebrates and vertebrates [130,131,132], defensins exhibit a general conformation made by cysteine-stabilized α-helical and β–sheet folds (reviewed in [131,133]). In mammals three types of defensins have been identified based on their structure, α-, β-, and θ-defensins (last one found only in certain nonhuman primates, including the rhesus macacque) [130,134,135]. However in fish, sequence and structural analysis have revealed that fish defensins are solely β-defensin-like proteins [35,44,51,64] including the conserved 6-cyteine motif (Figure 2). To date, up to four genes and five isoforms of defensins have been found in a single species [57,65], apparently as result of gene duplication events that had occurred in vertebrate β-defensins [133]. Fish defensins were first identified in zebrafish, Fugu and tetraodon by a database mining approach [44], but currently defensins have been identified in many other marine and freshwater fish species (see Table 1). Interestingly, a phylogenetic analysis using defensins from human and fish revealed that hBD-4 is the only human defensin that clustered with fish defensins, suggesting possible similar biological properties [35].
The human β-defensin gene has two exons and one intron, fairly typical of most β-defensin genes. Furthermore, mammalian β-defensins are translated as prepeptides, with the mature peptide sequence immediately downstream from the signal sequence [136]. However, in fish three exons and two introns are found [65], encoding a prepropeptide (including signal peptide, propeptide and mature peptide) comprised of 60 to 77 amino acids, and a mature peptide from 38 to 45 amino acids with cationic nature with a pI around 8 (except for those in olive flounder, which are around 4, indicating anionic nature [57]). Due its cationic nature they present a net positive charge that can go from +1 to +5. As with all vertebrate β-defensins, there are six conserved cysteines, although in human and birds these are located in a single exon, while in fish they span two exons [57].
Figure 2. Alignment of β-defensins. Precursor peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. The bovine β-defensin, Tracheal Antimicrobial Peptide (TAP) is shown for comparison. The conserved β-defensin cysteine spacing is shown in the consensus line. The first residue of the mature peptide region (based on the isolated TAP sequence) is denoted with an asterisk.
Figure 2. Alignment of β-defensins. Precursor peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. The bovine β-defensin, Tracheal Antimicrobial Peptide (TAP) is shown for comparison. The conserved β-defensin cysteine spacing is shown in the consensus line. The first residue of the mature peptide region (based on the isolated TAP sequence) is denoted with an asterisk.
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Fish β-defensins have proven to be active against both Gram-negative and -positive bacteria (for specific inhibitory values see Supplementary Table S1), although with rather moderate activity. Exceptions to those reports of MICs in the high µM range are Planococcus citreus (Gram-positive) [11] and Aeromonas hydrophila (Gram-negative) [52], with low MIC values. Other studies using supernatant of lysates HEK293T cells transfected with β-defensins from the Chinese loach or the gilthead seabream showed significant growth inhibition of the Gram-negative A. hydrophila and the Gram-positive B. subtilis [30,35]. Moreover, β-defensins are also active against fish-specific viruses such as Singapore grouper iridovirus (SGIV), viral nervous necrosis virus (VNNV), haemorrhagic septicaemia virus (VHSV), and the frog-specific Rana grylio virus (RGV) [59,60,64]. In addition it has been shown that the α-defensin human defensin-1 (HD-1) is highly active against VHSV, a salmonid rhabdovirus, causing its inactivation and inhibition [137]. However, no assessment has been carried out testing fish-derived defensins against human viruses so far, nor about their potential mechanism of action. Similarly, there are no published studies examining the activity of fish defensins against parasites. A small number of studies demonstrate the activity of human defensins against parasites, showing, for example, that HD-1 is capable to destroy the parasite Trypanosoma cruzi by pore formation and induction of nuclear and mitochondrial DNA fragmentation [138], and that hd-5 is able to reduce Toxoplasma gondii viability by aggregation [139]. This is an area with great potential both for fish and human biology. As with parasites, there are no studies related to the antifungal activity of fish defensins, in spite of the many studies showing such activity of β-defensins from other species (e.g., those described in [140,141,142].
In addition to their antimicrobial activities, β-defensins have been shown to exhibit multiple immunomodulatory activities (reviewed in [143]). For example, recombinant mBD4 and hBD2 (both β-defensins in mice and human, respectively) have shown to possess chemotactic activity for CCR6-expressing cells (which include monocytes, dendritic cells and T-lymphocytes), which was confirmed using its chemokine ligand CCL20 that competed with these β-defensins [144]. Similar activity has been observed in a fish homologue. β-defensins from the gilthead seabream exhibited chemotactic activity, showing the capacity to attract head-kidney leukocytes [35]. There is evidence of CCR6 mammalian orthologs in zebrafish [145] and rainbow trout [146] that may help address the mechanism. In addition, chemotactic capacity of HNP1 (human α-defensin) towards trout leucocytes has been shown [147]. Furthermore, a β-defensin from Atlantic cod is capable of stimulating antimicrobial activity in phagocytes [11]. Together, the studies suggest that fish β-defensins function similarly to their mammalian counterparts, contributing to the innate host defense in multiple ways.
In mammals, β-defensin expression was initially identified and studied predominantly in skin and mucosal membranes from respiratory, gastrointestinal and genitourinary tracts (reviewed in [148]. More recently, however, numerous β-defensin isoforms have been identified in sperm, with associations to reproduction being demonstrated [149]. While some β-defensins (mostly hBD-1 and its homologue) are constitutively expressed, the expression of most β-defensins can be induced by a variety of factors, including many innate immune mediators and microbe-associated molecular patterns (reviewed in [150]). Furthermore, their expression is observed not only in adult tissues, but during embryonic development as well [151,152]. In fish, constitutive expression seems to start early in the development probably as part of the need of defense in vulnerable stages that rely significantly in the innate immune response [11,57]. However, it is hard to establish specific expression patterns, because this appears to vary between species and isoform [31,44,59,60,65], although in most of the characterized fish β-defensins, skin is one of the tissues with the highest basal expression [31,35,44,65], a widely distributed feature among vertebrate defensins [148,153]. After skin, head-kidney and spleen are the tissues with also high expression, which are the main immune organs in fish [51,52,65]. Nevertheless, in some studies some isoforms of fish β-defensins have shown to possess a widespread constitutive expression [30,52,65]. Furthermore, high expression in eye has been found, suggesting a relevant role in ocular infections [30,52]. In addition, a study in the orange-spotted grouper suggest a relationship of fish β-defensin and reproduction endocrine regulation, finding an isoform that is exclusively expressed in pituitary and testis, where such expression is up-regulated from intersexual gonad to testis in sex reversal, and a deeper analysis proved that the pituitary-specific POU1F1 transcription binding site and the testis-specific SRY site are responsible for this phenomenon [60]. Fish β-defensin genes are induced by a variety of stimuli including cell wall components like LPS [52,59], β-glucans [31] and peptidoglycan [154]. They are stimulated by bacterial challenges from A. hydrophila [30], Y. ruckeri [65], V. anguillarum [11] and E. tarda [57]; and by viral challenges, including SGIV [59] or the TLR-3 agonist poly(I:C), to emulate a viral infection [59,65]. In addition, supplemented diets with the diatom Naviluca sp. and the lactobacillus Lactobacillus sakei have shown to induced β-defensin in gilthead seabream [155]. Thus, β-defensins in fish are true orthologues, exhibiting both structural and functional similarities to mammalian peptides, as well as their patterns of expression. This further supports the hypothesis that β-defensins are an ancient and highly conserved mechanism of host defense in animal species [133].

4. Hepcidins

Hepcidins are cysteine-rich peptides with antimicrobial activity that were first discovered in humans [156,157]. Since then, hepcidins have been identified in many other vertebrates including reptiles, amphibians and fish. Although, in birds the existence of a hepcidin needs to be better confirmed [158]. Fish hepcidin was first identified and isolated from the hybrid striped bass [42] and since then hepcidins have been identified in at least 37 fish species. The general structure of human hepcidin is a β-sheet-composed harpin-shaped with four disulfide bridges (formed by eight cysteines) with an unusual vicinal bridge at the hairpin turn [159], which is also the general structure in fish hepcidin [76,79]. However, sequence analysis of fish hepcidins has shown the presence of hepcidins containing 7, 6 or 4 cysteines [9,48].
Fish hepcidin genes have undergone duplication and diversification processes that have produced multiple gene copies [9], and up to eight copies have been identified [22,34,73]. Hepcidin genes are composed of three exons and two introns encoding a signal peptide, a prodomain and a mature peptide [22,34,72]. The pre-prohepcidin size can range from 81 to 96 amino acids, and the mature hepcidin from 19 to 31, with a molecular weight around 2–3 kDa. Representative sequences are shown in Figure 3. An average pI generally above 8 demonstrates their cationic nature. However, a predicted low pI of 5.4 of the orange-spotted grouper, indicates the existence of anionic hepcidin [61].
Figure 3. Alignment of hepcidins. Representative precursor peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. Human hepcidin is shown for comparison. The first residue of the mature peptide region is denoted with an asterisk.
Figure 3. Alignment of hepcidins. Representative precursor peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. Human hepcidin is shown for comparison. The first residue of the mature peptide region is denoted with an asterisk.
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Fish have two types of hepcidins, HAMP1 and HAMP2. However, although HAMP1 is present in actinopterygian and non-actinopterygian fish, HAMP2 has been only found in actinopterygian fish [54,63,158]. Moreover, a phylogenetic study has shown positive Darwinian selection in HAMP2 (but not HAMP1 and its mammalian orthologue) that suggest adaptive evolution probably associated with the host-pathogen interaction in different environments [9,54,160].
Hepcidin expression can be detected as early as in the fertilized egg in blunt snout bream [27] or at 8 h after fertilization in channel catfish [26]. However, in winter flounder and tongue sole it was not detected until day 5 and 6, respectively (larvae stage) [16,37]. Nevertheless, it has been shown that hepcidin isoforms have different expression pattern and kinetics in larval development [70]. In addition, different hepcidin types in a single species can have different rates of expression within the same tissue [80] that can be affected by different stimuli [24,70,73,79]. Interestingly, some isoforms have high basal hepcidin expression in liver, but some have not, where the highest expression often occurs in spleen, kidney and intestine [9,70,73,79].
Similar to other AMP genes, fish hepcidins can be induced by exposure to both Gram-positive and Gram-negative bacteria [12,19,25,26,27,34,36,37,42,48,53,56,61,63,72,73,161,162,163,164,165,166]. Moreover, fungi like Saccharomyces cerevisiae [36,61], and tumor cell lines like L-1210 and SAF-1 have shown to induce hepcidin expression as well [36]. Hepcidin genes in fish are also induced by viruses [36,61,73,165], and poly I:C [12,36,164], as well as mitogens [36]. Moreover, environmental estrogenic endocrine disrupting chemicals like 17β-estradiol down-regulates one of the hepcidin isoforms expression in liver in largemouth bass [46].
In humans, hepcidin acts as a type II actue-phase protein [167]. Related to this, time-course experiments under bacterial challenge of fish have shown that the highest expression of hepcidin occurs at 3–6 h and decay after that [23,32,163]. Also, the expression of hepcidin occurs along with other acute phase response proteins like IL-1β, serum amyloid A and precerebellin after infection with Yersinia ruckeri in rainbow trout [168]. Related to this, mud loach infected with Gram-negative bacteria showed a high IL-1β-like gene expression-mediated response [56]. Together, these results suggest that hepcidins can also act as a type II acute phase protein, and function as part of a broad innate immune response in fish.
Fish hepcidins are active against a wide variety of bacteria, both Gram-positive and -negative at the low µM range, including potent activity against a large number of fish pathogens (see Supplementary Table S1 for a complete listing). This includes rapid killing kinetics against S. aureus and Pseudomonas stutzeri [23,62]. Furthermore, synergy between bass hepcidin and moronecidin against S. iniae and Y. enterocolitica has been demonstrated [161]. In addition, they are active against a number of viruses [80,99,169,170,171], and a recent study indicates that human Hepc25 is able to affect HCV replication in cell culture by inducing STAT3 activation leading to an antiviral state of the cell [172]. In contrast, their quantified activity against fungi appears to be rather low [23,48,161].
A few studies have tried to elucidate the mechanism of action of hepcidin against bacteria. With human Hepc25, the lack of SYTOX uptake showed that membrane permeabilization does not occur [173] in contrast to most antimicrobial peptides [150]. Similar results have been observed with fish peptides, using light emission kinetics, which showed that Medaka recombinant pro-hepcidin and synthetic hepcidin also do not cause membrane permeabilization in E. coli [171]. However, human Hepc25 has shown binding to DNA with high efficiency in a retardation assay [173].
Fish hepcidins have also shown the capacity of affect cancer cells viability. For example, tilapia hepcidin TH2-3, have shown inhibition of proliferation and migration of human fibrosarcoma cell line HT1080a in a concentration-dependent manner. Furthermore, TH2-3 was able to cause cell membrane disruption in HT1080 and results also suggest that TH2-3 down-regulates c-Jun leading to apoptosis [174]. TH1-5 inhibit the proliferation of tumor cells (HeLa, HT1080 and HepG2) altering membrane structure and inducing apoptosis at low dose. Also, TH1-5 showed modulation of immune-related genes [175]. A study with medaka hepcidin showed 40% decrease in HepG2 cell viability by addition of 25 and 5 μM of synthetic mature Om-hep1 and recombinant pro-Om-hep1 (prohepcidin), respectively [171]. Interestingly, Pro-Omhep1 has better anti-tumor activity compared with Om-hep1, using HepG2 cells [171].
Fish hepcidins have also shown the ability to modulate the expression of different immune-related genes not only in fish but also in mice. Transgenic zebrafish expressing TH1-5 showed upregulation of IL-10, IL-21, IL-22, lysozyme, TLR-1, TLR-3, TNF-α and NF-κB [176]. However, TH2-3 showed to downregulate some of those upregulated by TH1-5 [177]. In the same context, TH2-3 reduced the amount of TNF-α, IL-1α, IL-1β, IL-6 and COX-2 in mouse macrophages challenged with LPS [178]. Related to this, in turbot it has been shown that hepcidin is able to increase the activation of NF-κB (which control a variety of inflammatory cytokines) through an undetermined yet signaling pathway [165]. TH2-3 have also shown to be able to modulate protein kinase C isoforms in the mouse macrophage RAW264.7 cell line [179], and was also capable to induce morphology changes in these cells similar to PMA-induced changes [179]. Moreover, TH1-5 modulates the expression of certain interferons and annexin (viral-responsive genes) in pancreatic necrosis virus-infected fish [170].
However, despite the potential antimicrobial and immunomodulatory effect, hepcidin is better known for being a key iron regulator controlling ferroportin, which is able to degrade by its internalization, which decrease iron transfer into blood [180]. In fish, although ferroportin internalization by hepcidin has not been proven yet, there is evidence suggesting that fish hepcidin also controls iron [34,56,73,80,162,165,166,181]. It may also serve as a pleiotropic sensor for other divalent metals, because it is up-regulated by exposure to other metals like copper [56] and cadmium [182], which can be considered waterborne or toxic.

5. Cathelicidins

Unusual among the AMPs, cathelicidins share little sequence homology between the mature peptides. Rather, they are defined by a homologous N-terminal region of the precursor peptide, called a cathelin domain, found just after a conserved signal domain (reviewed in [183]). The active, mature peptide is released upon protolytic cleavage by elastase and possibly other enzymes [184]. In mammals, the mature AMP sequence varies greatly, not only between species but also among the often multiple cathelicidin peptides within a single species. In general, however, all mammalian cathelicidin mature peptides are cationic and exhibit an amphipathic characteristic, as well as broad-spectrum antimicrobial activity in vitro. As can be seen by the alignment of primary amino acid sequences in Figure 4, there are significant sequence similarities in the C-terminal region, and in several short domains, which are highly cationic and glycine-rich.
The first cathelicidins identified in fish were initially isolated as antimicrobial peptides from the Atlantic hagfish, Myxine glutinosa [15]. Upon sequence analysis of the cDNA that encoded these peptides, it was discovered that they exhibited homology to cathelicidins, previously only found in mammals to this point. As cathelicidins were discovered in other more conventional fish species, primarily by sequence homology from the cathelin region (e.g., [17,28,77,185]), or more recently by peptide isolation [186], new patterns emerged. In some of the more recently studied fish cathelicidins, while a high degree of homology is maintained in the cathelin domain (see [185] for a comprehensive alignment), there appears to be a higher degree of sequence similarity of the mature peptide than seen in mammals. Thus, fish cathelicidins can now be subdivided into two classes—the linear peptides, and those that exhibit a characteristic disulphide bond. In contrast to mammalian cathelicidins, there is significant sequence homology among members of the classes (up to 90%), and little homology between the classes. In addition, the recently identified cathelicidins found in cod appear to comprise a third class, based on sequence homology between themselves, and a lack of homology with either of the other two classes [185]. An alignment of representative fish cathelicidins is shown in Figure 4.
Figure 4. Alignment of fish cathelicidins. Mature peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. Characteristic cysteine residues found in certain classes of fish cathelicidins are underlined. As, Atlantic salmon; Rt, Rainbow trout; Cs, Chinook salmon; Btr, Brown trout; Ac, Arctic char; Bt, Brook trout; Je, Japanese eel.
Figure 4. Alignment of fish cathelicidins. Mature peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. Characteristic cysteine residues found in certain classes of fish cathelicidins are underlined. As, Atlantic salmon; Rt, Rainbow trout; Cs, Chinook salmon; Btr, Brown trout; Ac, Arctic char; Bt, Brook trout; Je, Japanese eel.
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As cathelicidin peptides are purified from more species, their in vitro antibacterial activities appear to exhibit significant variability with respect to selectivity, depending on the species. For example, cod cathelicidin (codCATH) is highly active against those Gram-negative bacterial species examined, but almost inactive against the Gram-positive species. It also exhibits potent antifungal activity against C. albicans [13]. In contrast, the hagfish cathelicidins are active against both Gram-positive and -negative bacteria, but inactive against Candida [15]. Even more specifically, rainbow trout cathelicidins are active against Y. ruckeri, while Atlantic salmon cathelicidins are not [187]. Thus, the variability in the mature peptide sequence of these molecules appears to direct the antimicrobial activities, and is probably a result of an evolutionary divergence to address specific pathogens.
Based on their antimicrobial activity, most of the work to elucidate their role in vivo has examined the expression of the cathelicidin genes in the various fish species with respect to induction by innate immune regulators, such as bacteria and to different pathogen-associated molecular patterns (PAMPs). Importantly, cathelicidin expression is observed early in embryonic development, suggesting that its role in immunity is present early on [186]. In vitro, both bacteria and bacterial DNA were sufficient to induce cathelicidin expression in a cultured embryonic salmon cell line [188], suggesting that like mammalian cathelicidins, the fish homologs play a similar role in antibacterial host defense. Surprisingly, purified LPS (that is, treated with DNase I) could not induce the gene. This regulation has been further elucidated by the demonstration of a wide variability of the Chinook salmon embryonic cell line’s response to different bacteria and to poly I:C, LPS and flagellin [189]. Further in vitro evidence of this role was demonstrated by the induction of rainbow trout cathelicidin in a macrophage cell line from that species by IL-6, an important mediator of the innate immune response [190], and by a novel TNF-α isoform [191]. Similarly, stimulation of a cell line from Atlantic cod with poly I:C induced expression of the gmCath1 (from cod) gene promoter [192]. In addition to bacteria and their products, trout cell lines were shown to induce cathelicidin gene expression upon incubation with the oomycete Saprolegnia parasitica [193].
In vivo studies further support this hypothesis. When ayu were injected with live pathogenic bacteria, there was a time-dependent induction of cathelicidin expression in numerous tissues, including gill, liver, spleen and intestine [20]. Further, Atlantic salmon and rainbow trout infected with Y. ruckeri led to an induction in cathelicidin expression [187,194]. In the Atlantic cod, a difference in inducibility was observed. Cathelicidin experession in the gills was induced by a 3-h incubation with Aeromonas salmonicida, but not V. anguillarum, suggesting a more complex role is played by these peptides in host defense.
In mammals, cathelicidins have been demonstrated to exhibit multiple activities, both immune and non-immune, well in excess of their in vitro antimicrobial activities (reviewed in [195]). While research in fish has not approached this level, a recent study demonstrated that two Atlantic salmon cathelicidins induced the rapid and transient expression of IL-8 in peripheral blood leukocytes [187]. This suggests that the immunomodulatory activities seen by mammalian cathelicidins may be shared by their fish counterparts, and may thus be an evolutionarily conserved mechanism of innate immune regulation.

6. Histone-Derived Peptides

While examining an amphibian species for novel antimicrobial peptides, Park et al. [196] described a new peptide from the Asian toad, Bufo bufo gargarizans, which they called Buforin I. This turned out to be identical to the N-terminal portion of histone 2A. This led to the demonstration of antimicrobial activity of histone fragments from numerous species (reviewed in [197]), suggesting that these proteolytic fragments are part of an ancient innate immune mechanism. Histone-derived AMPs have been identified in a number of fish species, with broad-spectrum activity against both human and fish pathogens (reviewed in [198]), including water molds [199] and a parasitic dinoflagellate [69]. They are expressed and secreted in fish skin, and found in other tissues, including gill, speen and the gut. They are not limited to the N-terminus of the histones, as was found for the Buforin peptide, but can be found as fragments of both termini, from histones H1, H2A, H2B and H6 (see Figure 5). Further evidence that they play a role in host defense of the fish comes from studies showing that expression of histone-derived AMP genes are induced under conditions of stress in specific tissues of different fish species [74,200].
Figure 5. Alignment of histone-derived peptides. Representative peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. Since the sequences are homolgous to different histone peptide fragments, there is no shared sequence homology.
Figure 5. Alignment of histone-derived peptides. Representative peptide sequences were obtained from published data and from the PubMed protein database, and were aligned using MacVector software. Since the sequences are homolgous to different histone peptide fragments, there is no shared sequence homology.
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7. Therapeutics

All AMPs have common characteristics that support their development as therapeutic antimicrobials. These include broad-spectrum activity against a wide variety of pathogens; potent activity under a wide range of conditions, including temperature and in secretions such as saliva; and a reduced capacity to the development of resistance by bacteria. The identification and characterization of peptides from fish has provided a unique contribution in this arena. While the structural characteristics of fish peptides do not appear particularly different from their mammalian, insect or amphibian homologues, there may be specific differences with respect to activity. It appears that overall their antimicrobial activities against human pathogens is in the same range as AMPs from other species. However, it is possible that they are more active against fish pathogens, as they most likely have evolved together with those pathogens. It is difficult to know this, however, as few studies have compared non-fish peptides with fish peptides against fish pathogens. One area where fish peptides may provide an advantage is in food preservation [201], as they are derived from a natural food source, and thus may be more amenable to being consumed.
Since many AMPs are sensitive to high salt concentrations [202,203,204], the ability of some fish AMPs to kill microbes even at extremely high salt concentrations, such as those found in the marine environment, make them important targets for investigation. Pleurocidin, for example, maintains its antibacterial activity even up to 300 mM NaCl [6], similar to other piscidins [41,205]. Understanding the structural foundation that supports this salt-independent activity could aid in the design of novel peptides [206] or mimetics that could address infections under a wide range of normal and abnormal salt concentrations, whether in serum, tear film hyperosmolarity, or in saliva to address dental caries [207]. In addition to their potential uses as antimicrobials, some fish AMPs have been observed to exhibit in vitro cytotoxic activity against a variety of cancer cells [113,208].
Different applications of piscidin have been promising. For example, epinecidin-1, when administrated orally or injected (in pre-, co- and post-infection) can significantly enhance survival in zebrafish and grouper that were challenged with Vibrio vulnificus [58,123,124]. Related to this, electrotransfer of epinecidin-1 in zebrafish and grouper muscle showed significant reduction in V. vulnificus and Streptococcus agalactiae bacterial counts [121,122,125]. Moreover, treatment of lethally-challenged methicillin-resistant S. aureus (MRSA) mice with epinecidin-1 allowed mice to survive by decreasing considerably the bacterial counts, where also there was evidence of wound closure and angiogenesis enhancement [128].
In oral disease treatment piscidins are also promising due to the potent effect of chrysophsin-1 in killing the cariogenic pathogen Streptococcus mutans [209]. Furthermore, pleurocidin also demonstrated anti-cariogenic activity by being able to kill both S. mutans and S. sobrinus, where killing of biofilms occurred in a dose-dependent manner. In addition, it showed to retained its activity in physiological or higher salt concentration, and was relatively stable in presence of human saliva and no hemolysis was found [207,210].
Epinecidin-1 showed to be a potential candidate for topical application that can prevent vaginal or skin infections due to the synergistic effect that possess with commercial cleaning solutions, where such effect was not affected by low pH or after being stored at room temperature and at 4 °C for up to 14 days [211]. The synergistic effect of pleurocidin and several antibiotics [212], bacteroricin [213] and histone-derived [214] has also been shown [212,213]. Furthermore, the creation of antimicrobial surfaces has been made by the immobilization of chrysophsin-1 resulting in a surface with antibacterial activity capable to killed around 82% of E. coli bacteria [215].
A recent interest finding is the ability of epinecidin-1 to create inactivated virus for vaccination purposes. Huang et al. found that mice injected with Epi-1-based inactivated Japanese encephalitis virus (JEV) reached 100% survival (in a dose-dependent manner), and the performance was better than the formalin-based JEV-inactivated vaccine. This was caused by the modulation of immune-related genes, including the increase of anti-JEV-neutralizing antibodies in serum, which suppressed the multiplication of JEV in brain sections [126].
Fish hepcidins are also under examination for development as therapeutics. One example of this is the study carried out by Pan et al. [216], where injections with pre-incubated tilapia hepcidin TH2-3 and 108 cfu of Vibrio vulnificus for 30 min enhanced the survival of infected and re-infected mice, obtaining up to 60% of survival with a dose of 40 μg/mice. In addition, TH2-3 also showed significant prophylactic effect by administration prior infection, where survival rates of 100% were obtained after 7 days of infection. Also, curative effects were shown when fish were first infected and later injected with 40 μg/mice of TH2-3, obtaining survival rates up to 50%. But more interesting, was the fact that TH2-3 had better bacteriostatic effect than tetracycline in controlling the bacterial burden in blood, although in liver there was no significant difference, demonstrating the capacity of TH2-3 to control multiplication of V. vulnificus in mice. Although the direct in vivo TH2-3-mediated killing was not confirmed, a microarray analysis showed that TH2-3 clearly altered the gene expression profiles improving the host response in mice [216]. In addition, a transgenic zebrafish expressing TH2-3 showed to be able to decrease V. vulnificus burden significantly, but not S. agalactiae [177]. Zebrafish expressing TH1-5 exhibited enhanced bacterial resistance by decreasing the bacterial burden of both same pathogens [176]. In addition, TH1-5 has showed to be effective at increasing survival and decreasing the number of infectious bacteria in ducks challenged with Riemerella anatipestifer, which also showed to be able to modulate the expression of immune-related genes [114].
However, as with other AMPs, they share the similar problems that hinder their further development, especially for use in human medicine. These include a tendency to be inactivated in the body, increased expense of peptide synthesis, and sensitivity to protease digestion. Attempts to address these issues with fish peptides, include the identification of smaller peptide fragments that might exhibit better activity with smaller molecules [217], and the observation of high levels of synergy with bacterial AMPs [213,214], as well as conventional antibiotics [218] allowing for reduced concentrations. One strategy that may have some success is the design of small molecule peptide mimetics that incorporate the structural characteristics of the peptides necessary for their activity (reviewed in [219]). Initial in vitro and in vivo results with molecules designed from magainins and defensins have been encouraging, demonstrating antibacterial [220] and antifungal [221] activities, as well as immunomodulatory activity [222]. Another strategy that has been examined extensively in other species (reviewed in [223]) is the use of exogenous agents to modulate the expression of endogenous AMPs in the fish. Terova et al. have demonstrated the induction of an AMP initially isolated from sea bass [33] by feeding them a cell wall extract from S. cerevisiae [224], suggesting a novel method for enhancing the natural defense mechanism of the fish. Incorporation of an enhancer of AMP expression in the diet could be a cost-effective part of an overall strategy of modulating the innate immune system of the fish to control infection in aquaculture (reviewed in [198]).

8. Conclusions

The comprehensive characterization of AMPs from fish, on the structural, genetic and functional levels, has provided a wealth of information. Examination of AMPs in a single species, such as the Atlantic cod, where members of all five groups of AMPs have been identified can help understand the role of these peptides in innate host defense of the fish. Studies on the similarities and differences with peptides from non-fish species contribute to our understanding of the evolutionary relationships of innate host defense mechanisms among vertebrates. Furthermore, they can provide important information for the better design of novel therapeutic agents, both for microbial infections as well as cancer and other conditions. Unique for the field of fish AMPs is the potential application to aquaculture. The constant risk of large-scale microbial infection that can lead to significant economic losses demands new strategies to prevent or treat these pathogens. Many of the studies described above have demonstrated that specific fish AMPs have potent activity against fish pathogens. Furthermore, other studies have shown that some pathogens induce potent innate immune responses in the fish. Complicating this is the evolutionary battle with the pathogens. For example, challenge of Atlantic cod with the pathogen V. anguillarum induces the expression of a β-defensin, which is antibacterial against other species, but not the inducing V. anguillarum [11]. Thus, the large body of work described above provides a solid foundation for strong future work to better understand both the role of these peptides in host defense of the fish, as well as the development of these peptides and their derivatives as potential therapeutics.


GD is funded by US Public Health Service Grants R01 DE22723 and R21 AI100379.

Author Contributions

Both authors contributed to the writing and editing of this review

Conflicts of Interest

The authors declare no conflict of interest.

Supplementary Files

Table S1. Antimicrobial activity of fish AMPs. Bacteria and fungi included MICs (μM, or μg/mL will be indicated) values, MLCs (μM), vLD90 (virtual 90% lethal dose, mg/mL [mean ± SEM]) or IC50 (μM). If values are not included antimicrobial activity was assessed by inhibitory halo (IH) and size in millimeter was not presented, if so, is indicated. If isoforms were tested, the best performance value was used. For parasites, the minimum protozoacidal concentration (PCmin) or MIC is indicated. Habitat of microorganisms are indicated (freshwater, marine or other).
Table S1. Antimicrobial activity of fish AMPs. Bacteria and fungi included MICs (μM, or μg/mL will be indicated) values, MLCs (μM), vLD90 (virtual 90% lethal dose, mg/mL [mean ± SEM]) or IC50 (μM). If values are not included antimicrobial activity was assessed by inhibitory halo (IH) and size in millimeter was not presented, if so, is indicated. If isoforms were tested, the best performance value was used. For parasites, the minimum protozoacidal concentration (PCmin) or MIC is indicated. Habitat of microorganisms are indicated (freshwater, marine or other).
Gram negative
Escherichia coli39.0 ± 3.7 (vLD90) [60]
32.6 ± 1.5 (vLD90) [52]
IH [10]
5–10 μM (MIC) [50]
2–10 μM (MIC) [117]
50 μg/mL (MIC) [40]
2.2–3.3 μM (MIC) [6]
5 μM (MIC) [43]
3–6 μM (MIC) [47]
2 μg/mL (MIC) [83]
3 μM (MIC) [75]
1 μg/mL (MIC) [8]
5–10 μM (MIC) [23]
>96 μM (MIC) [62]
6-12 μM (MIC) [171]
18.66 (IC50) [36]
11 μM (MIC) [161]
12–24 μM (MIC) [48]
>8.18 μM (MIC) [37]
34.56 mm2 (IH) [49]
<1 μg/mL (MIC) [187]
1 μg/mL (MIC) [225]
2–4 μg/mL (MIC) [77]
5 μg/mL (MIC) [186]
1 μg/mL(MIC) [29]
>10 μg/mL(MIC) [14]
2.5 μg/mL (MIC) [38]
XXFreshwater and others
Plesiomonas shigelloides 11 μM (MIC) [161] XXFreshwater
Klebsiella pneumoniae 12.6 μg/mL (MIC) [82]
2.5–5 μM (MIC) [41]
22 μM (MIC) [161]18.8 μM (MIC) [77] XOther
Klebsiella oxytoca 5–10 μM (MIC) [41]
12.5 μg/mL (MIC) [58]
>44 μM (MIC) [161] XOther
Shigella sonnei 5–10 μM (MIC) [41]>44 μM (MIC) [161] XOther
Shigella flexneri 3.1 μg/mL (MIC) [40]
2.5–5 μM (MIC) [41]
>96 μM (MIC) [62]
22 μM (MIC) [161]
XFreshwater and others
Yersinia enterocolitica 2.5–5 μM (MIC) [41]
100 μM (MIC) [58]
22 μM (MIC) [161] XXFreshwater and others
Yersinia ruckeri 20–40 μM (MIC) [50] X Freshwater
Aeromonas salmonicida>50 μM (MIC) [11]17.7–35 μM (MIC) [6]
2 μg/mL (MIC) [83]
1 μg/mL (MIC) [8]
5 μM (MLC) [71]
>44 μM (MIC) [161]9.4 μg/mL (MIC)[77]
1–5 μg/mL (MIC) [225]
50 μg/mL (MIC) [20]
10 μg/mL (MIC) [186]
20 μg/mL (MIC) [38]
>1.2 μg/mL (MIC) [66]
X Freshwater and marine
Aeromonas hydrophila13.4 ± 0.7 [52]
IH [51]
1.05 μg/mL (MIC) [78]
19.78 μg/mL (MIC) [78]
>21.4 μg/mL (MIC) [78]
>160 [50]
>20 [41]
>96 [47]
10–20 μM (MIC) [23]
>96 μM (MIC) [62]
1.5–3 μM (MIC) [171]
>44 μM (MIC) [161]
3–6 μM (MIC) [48]
31.66 mm2 (IH) [49]
XXFreshwater and others
Aeromonas sobria59.4 ± 8.8 [60]10–20 μM (MIC) [50] 2.5 μM (MIC) [38]XXFreshwater and others
Aeromonas punctata 10–20 μM (MIC) [50] X Freshwater and others
Vibrio anguillarum>50 μM (MIC) [11]
58.2 ± 23.4 (vLD90) [60]
21.1 ± 1 (vLD90) [52]
20–40 μM (MIC) [50]
6.3 μg/mL (MIC) [40]
1.25 μM (MLC) [71]
2.92 μM (MIC) [37]5 μM (MIC) [187]
0.5–2.5 μM (MIC) [225]
5 μM (MIC) [186]
X Marine
Vibrio parahaemolyticus >60 μM (MIC) [23]
>96 μM (MIC) [62]
>48 μM (MIC) [171]
3–6 μM (MIC) [48]
5.84 μM (MIC) [37]
94.25 mm2 (IH) [49]
25 [20] XXMarine
Vibrio fluvialis43.0 ± 10 (vLD90) [60]
35.1 ± 2.7 (vLD90) [52]
>96 μM (MIC) [62]
123.11 mm2 (IH) [49]
3.1 μg/mL (MIC) [20] XXMarine
Vibrio harveyi 12.5 μg/mL (MIC) [58]
5 μM (MLC) [71]
20–40 μM (MIC) [23]
>96 μM (MIC) [62]
6–12 μM (MIC) [48]
5.84 μM (MIC) [37]
113.10 mm2 (IH) [49]
6.2 μg/mL (MIC) [20] X Marine
Vibrio alginolyticus 0.03 μg/mL (MIC) [78]
1.24 μg/mL (MIC) [78]
2.68 μg/mL (MIC) [78]
>60 μM (MIC) [23]
>96 μM (MIC) [62]
>48 μM (MIC) [171]
12–24 μM (MIC) [48]
118.06 mm2 (IH) [49]
Vibrio vulnificus 0.03 μg/mL (MIC) [78]
0.62 μg/mL (MIC) [78]
0.67 μg/mL (MIC) [78]
6.25 μg/mL (MIC) [58]
2.5 μM (MLC) [71]
20 μM (MIC) [61,163] XXMarine
Vibrio cholera 2.5–5 μM (MIC) [41] XXFreshwater, marine and others
Vibrio damsela 48 μM (MIC) [75] XXMarine
Vibrio penaeicida 5 μM (MLC) [71] Marine
Salinivibrio costicola 3.125 μg/mL (MIC) [58] Marine and others
Edwardsiella tarda >44 μM (MIC) [161]
2.92 μM (MIC) [37]
XXMarine and freshwater
Riemerella anatipestifer 6.25 μg/mL (MIC) [114]25 μg/mL (MIC) [114] Other
Pseudomonas aeruginosa44.5 ± 11.8 [60]0.52 μg/mL (MIC) [78]
>19.78 μg/mL (MIC) [78]
10.70 μg/mL (MIC) [78]
60 μg/mL (MIC) [58]
1 μg/mL (MIC) [83]
28 μg/mL (MIC) [82]
>35 μM (MIC) [6]
5–10 μM (MIC) [41]
>44 μM (MIC) [161]
>96 μM (MIC) [62]
12.5 μg/mL (MIC) [20]
1–4 μg/mL (MIC) [77]
XXFreshwater, marine and others
Pseudomonas fluorescens 10–20 μM (MIC) [50]
1.5–3 μM (MIC) [47]
24–48 μM (MIC) [62] 20 μM (MIC) [38]XXFreshwater and others
Pseudomonas stutzeri <1.5 μM (MIC) [62]
3–6 μM (MIC) [171]
Enterobacter cloacae 10–20 μM (MIC) [41]
100 μg/mL (MIC) [58]
>44 μM (MIC) [161] XXFreshwater and others
Enterobacter aerogenes 10–20 μM (MIC) [41]
25 μg/mL (MIC) [58]
Salmonella arizonae 10–20 μM (MIC) [41]>44 μM (MIC) [161] XOther
Salmonella choleraesuis 10–20 μM (MIC) [41]
6 μM (MIC) [75]
>44 μM (MIC) [161] XOther
Salmonella typhimurium 8.8–17.7 μM (MIC) [6]
10–20 μM (MIC) [41]
2 μg/mL (MIC) [83]
1 μg/mL (MIC) [8]
>44 μM (MIC) [161] 2 μM (MIC) [29] XOther
Serratia marcescens >35 μM (MIC) [6]
>20 μM (MIC) [41]
>44 μM (MIC) [161] 4 μM (MIC) [29] XOther
Cytophaga columnare 40–80 μM (MIC) [50] X Freshwater
Cytophaga aquatilis 2.2–4.4 μM (MIC) [6] X Freshwater
Proteus vulgaris 2–10 μM (MIC) [117]X XXFreshwater and others
Photobacterium damsela subsp. piscidida 1.5 μg/mL (MIC) [40] X Marine and freshwater
Pasteurella haemolytica 4.4–8.8 μM (MIC) [6] XOther
Burkholderia cepacia >20 μM (MIC) [41] XFreshwater and others
Moraxella catarrhalis 2.5–5 μM (MIC) [41] XOther
Neisseria gonorrhoeae >20 μM (MIC) [41] XOther
Psychrobacter sp. 10 μM (MIC) [43] Marine and others
Morganella morganii 12 μM (MIC) [75] XOther
Enterococcus faecium 15 μM (MIC) [75] XOther
Gram positive
Micrococcus luteus25–50 μM (MIC) [11]
296.5 ± 65.5 (vLD90) [60]
311 ± 15.6 (vLD90) [52]
10–20 μM (MIC) [41]
3.125 μg/mL (MIC) [58]
>96 μM (MIC) [62]
1.5–3 μM (MIC) [48]
2.5–5 μM (MIC) [23]
24–48 μM (MIC) [62]
34.56 mm2 (IH) [49]
XFreshwater and others
Staphylococcus aureus358.5 ± 46.5 (vLD90) [60]
229.8 ± 12.8 (vLD90) [52]
IH [51]
0–2 μM (MIC) [117]
3.1 μg/mL (MIC) [40]
17.7–35 μM (MIC) [6]
62.5 μg/mL (MIC) [82]
1.25–2.5 μM (MIC) [41]
6–12 μM (MIC) [47]
6.25 μg/mL (MIC) [58]
8 μg/mL (MIC) [83]
1.5 μM (MIC) [75]
1.25–2.5 μM (MIC) [53]
1.5–3 μM (MIC) [62]
1.5–3 μM (MIC) [171]
>44 μM (MIC) [161]
3–6 μM (MIC) [48]
1.25–2.5 μM (MIC) [23]
>8.18 μM (MIC) [37]
47.12 mm2 (IH) [49]
11–45 μM (MIC) [77]2μM (MIC) [29] XOther
Staphylococcus epidermidis 5–10 μM (MIC) [41]
12.5 μg/mL (MIC) [58]
8 μg/mL (MIC) [83]
4 μg/mL (MIC) [8]
20–40 μM (MIC) [23]
>96 μM (MIC) [62]
6–12 μM (MIC) [48]
10 μM (MIC) [38] XOther
Staphylococcus saprophiticus 5–10 μM (MIC) [41]
7.5 μM (MIC) [75]
Staphylococcus haemolyticus 7.5 μM (MIC) [75] XOther
Staphylococcus xylosus >20 μM (MIC) [41]
50 μg/mL (MIC) [58]
Staphylococcus warneri 15 μM (MIC) [75] Other
Bacillus subtilis 1.1–2.2 μM (MIC) [6]
0.75–1.5 μM (MIC) [47]
48 μM (MIC) [75]
5–10 μM (MIC) [23]
>96 μM (MIC) [62]
11.41 (IC50) [36]
3–6 μM (MIC) [48]
28.86 mm2 (IH) [49]
11 μg/mL (MIC) [29]
0.6 μg/mL (MIC) [66]
1.3 μg/mL (MIC) [38]
Bacillus cereus17.5 ± 4 (vLD90) [60]0–2 μM (MIC) [117]
5 μM (MIC) [43]
40–60 μM (MIC) [23]
>96 μM (MIC) [62]
12–24 μM (MIC) [48]
Corynebacterium glutamicum 2.5–5 μM (MIC) [23]
48–96 μM (MIC) [62]
3–6 μM (MIC) [171]
1.5–3 μM (MIC) [48]
Planococcus citreus0.4–0.8 μM (MIC) [11] 0.08 μg/mL (MIC) [66] Marine
Enterococcus faecalis 8.39 μg/mL (MIC) [78]>44 μM (MIC) [161] XOther
9.89 μg/mL (MIC) [78]
>21.41 μg/mL (MIC) [78]
3.1 μg/mL (MIC) [40]
>256 μM (MIC) [210]
2.5–5 μM (MIC) [41]
8-16 μg/mL (MIC) [209]
Listeria monocytogenes 2.5–5 μM (MIC) [41]
25 μg/mL (MIC) [58]
Streptococcus agalactiae 0.13 μg/mL (MIC) [78] XXFreshwater, marine and others
0.31 μg/mL (MIC) [78]
0.33 μg/mL (MIC) [78]
1.25–2.5 μM (MIC) [41]
12.5 μg/mL (MIC) [58]
Streptococcus iniae 3.1 μg/mL (MIC) [40]
1.25–2.5 μM (MIC) [41]
1.5 μM (MLC) [71]
XXFreshwater, marine and others
Streptococcus mutans 2.2 μM (MIC) [207]
8 μg/mL (MIC) [210]
4 μg/mL (MIC) [209]
1 μg/mL (MIC) [29] XOther
Streptococcus sobrinus 8 μg/mL (MIC) [210]
4 μg/mL (MIC) [209]
Streptococcus sanguinis 32 μg/mL (MIC) [210]
4–8 μg/mL (MIC) [209]
Streptococcus gordonii 8 μg/mL (MIC) [210]
8 μg/mL (MIC) [209]
Streptococcus bovis 1.25–2.5 μM (MIC) [41] XOther
Streptococcus equisimilis 2.5–5 μM (MIC) [41] XOther
Streptococcus mitis 1.25–2.5 μM (MIC) [41] XOther
Streptococcus pneumoniae 1.25–2.5 μM (MIC) [41]
12.5 μg/mL (MIC) [58]
Streptococcus pyogenes 1.25–2.5 μM (MIC) [41]
25 μg/mL (MIC) [58]
Lactococcus garviae 3.1 μg/mL (MIC) [40]
5 μM (MLC) [71]
XXMarine and others
Leucothrix mucor >35 μM (MIC) [6] X Marine
Lactobacillus acidophilus 128 μg/mL (MIC) [210]
4–8 μg/mL (MIC) [209]
Lactobacillus casei 32 μg/mL (MIC) [210]
4 μg/mL (MIC) [209]
Lactobacillus fermenti 2 μg/mL (MIC) [210]
4 μg/mL (MIC) [209]
Actinomyces viscosus 8 μg/mL (MIC) [209] XOther
Actinomyces naeslundii 8 μg/mL (MIC) [209] XOther
Aspergillus fumigatus 50–100 μM (MIC) [41] XOther
Aspergillus niger 48–96 μM (MIC) [47]20–40 μM (MIC) [23]
44 μM (MIC) [161]
12–24 μM (MIC) [48]
Fusarium graminearum 20–40 μM (MIC) [23]
12–24 μM (MIC) [48]
Fusarium solani 20–40 μM (MIC) [23]
12–24 μM (MIC) [48]
Fusarium oxysporum 0.78–1.56 μM (MIC) [41] XXFreshwater, marine and others
Fusarium culmorum 0.39–0.78 [41] Other
Candida albicans 15.4 μg/mL (MIC) [82]
10–20 μM (MIC) [41]
24–48 μM (MIC) [47]
8 μg/mL (MIC) [83]
96 μM (MIC) [75]
4 μg/mL (MIC) [8]
5 μM (MIC) [115]
6.25 μM (MIC) [226]
>60 μM (MIC) [23]
>96 μM (MIC) [62]
>44 μM (MIC) [161]
>48 μM (MIC) [48]
2.3 [77]
2.5 [186]
Candida glabrata 10–20 μM (MIC) [41] XOther
Candida lusitania 10–20 μM (MIC) [41]
Candida tropicalis 10–20 μM (MIC) [41] XOther
Saccharomyces cerevisiae 384 μM (MIC) [75]
5 μM (MIC) [115]
Pichia pastoris >60 μM (MIC) [23]
>96 μM (MIC) [62]
>48 μM (MIC) [48]
Saprolegnia sp 12.5–25 μg/mL (MOC) [98] X Freshwater and others
Neurospora crassa 1.56–3.12 μM (MIC) [41] Other
Trichosporon beigelii 2.5 μM (MIC) [115]
1.56 μM (MIC) [226]
Malassezia furfur 6.25 μM (MIC) [226] XOther
Trichomonas vaginalis 12.5 μg/mL (MIC) [115] XOther
Trichodina 12.5–100 μg/mL (PCmin) [97] X Freshwater and marine
Cryptocaryon theront 12.5 μg/mL (PCmin) [97] X Marine
Amyloodinium dinospore 6.3 μg/mL (PCmin) [97] X Marine
Ichthyophthirius theront 6.3 μg/mL (PCmin) [97] X Freshwater
VHSV[64] [80] X Marine
NNV[59][227][99,169] X Marine
IPNV [170] X Marine
RGV[60] X Marine and Freshwater
SGIV[59] [61] X Marine
CCV [100] X Freshwater
FV3 [100] Other


  1. Ganz, T.; Selsted, M.E.; Szklarek, D.; Harwig, S.S.; Daher, K.; Bainton, D.F.; Lehrer, R.I. Defensins. Natural peptide antibiotics of human neutrophils. J. Clin. Investig. 1985, 76, 1427–1435. [Google Scholar] [CrossRef]
  2. Lehrer, R.I.; Selsted, M.E.; Szklarek, D.; Fleischmann, J. Antibacterial activity of microbicidal cationic proteins 1 and 2, natural peptide antibiotics of rabbit lung macrophages. Infect. Immun. 1983, 42, 10–14. [Google Scholar]
  3. Zasloff, M. Magainins, a class of antimicrobial peptides from Xenopus skin: Isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc. Natl. Acad. Sci. USA 1987, 84, 5449–5453. [Google Scholar] [CrossRef]
  4. Primor, N.; Tu, A.T. Conformation of pardaxin, the toxin of the flatfish Pardachirus marmoratus. Biochim. Biophys. Acta 1980, 626, 299–306. [Google Scholar] [CrossRef]
  5. Oren, Z.; Shai, Y. A class of highly potent antibacterial peptides derived from pardaxin, a pore-forming peptide isolated from Moses sole fish Pardachirus marmoratus. Eur. J. Biochem. 1996, 237, 303–310. [Google Scholar]
  6. Cole, A.M.; Weis, P.; Diamond, G. Isolation and characterization of pleurocidin, an antimicrobial peptide in the skin secretions of winter flounder. J. Biol. Chem. 1997, 272, 12008–12013. [Google Scholar] [CrossRef]
  7. Tessera, V.; Guida, F.; Juretic, D.; Tossi, A. Identification of antimicrobial peptides from teleosts and anurans in expressed sequence tag databases using conserved signal sequences. FEBS J. 2012, 279, 724–736. [Google Scholar] [CrossRef]
  8. Patrzykat, A.; Gallant, J.W.; Seo, J.K.; Pytyck, J.; Douglas, S.E. Novel antimicrobial peptides derived from flatfish genes. Antimicrob. Agents Chemother. 2003, 47, 2464–2470. [Google Scholar] [CrossRef]
  9. Xu, Q.; Cheng, C.H.; Hu, P.; Ye, H.; Chen, Z.; Cao, L.; Chen, L.; Shen, Y.; Chen, L. Adaptive evolution of hepcidin genes in antarctic notothenioid fishes. Mol. Biol. Evol. 2008, 25, 1099–1112. [Google Scholar] [CrossRef]
  10. Browne, M.J.; Feng, C.Y.; Booth, V.; Rise, M.L. Characterization and expression studies of Gaduscidin-1 and Gaduscidin-2; paralogous antimicrobial peptide-like transcripts from Atlantic cod (Gadus morhua). Dev. Comp. Immunol. 2011, 35, 399–408. [Google Scholar] [CrossRef]
  11. Ruangsri, J.; Kitani, Y.; Kiron, V.; Lokesh, J.; Brinchmann, M.F.; Karlsen, B.O.; Fernandes, J.M. A novel beta-defensin antimicrobial peptide in Atlantic cod with stimulatory effect on phagocytic activity. PLoS One 2013, 8, e62302. [Google Scholar]
  12. Solstad, T.; Larsen, A.N.; Seppola, M.; Jorgensen, T.O. Identification, cloning and expression analysis of a hepcidin cDNA of the Atlantic cod (Gadus morhua L.). Fish Shellfish Immunol. 2008, 25, 298–310. [Google Scholar] [CrossRef]
  13. Broekman, D.C.; Zenz, A.; Gudmundsdottir, B.K.; Lohner, K.; Maier, V.H.; Gudmundsson, G.H. Functional characterization of codCath, the mature cathelicidin antimicrobial peptide from Atlantic cod (Gadus morhua). Peptides 2011, 32, 2044–2051. [Google Scholar] [CrossRef]
  14. Bergsson, G.; Agerberth, B.; Jornvall, H.; Gudmundsson, G.H. Isolation and identification of antimicrobial components from the epidermal mucus of Atlantic cod (Gadus morhua). FEBS J. 2005, 272, 4960–4969. [Google Scholar] [CrossRef]
  15. Uzzell, T.; Stolzenberg, E.D.; Shinnar, A.E.; Zasloff, M. Hagfish intestinal antimicrobial peptides are ancient cathelicidins. Peptides 2003, 24, 1655–1667. [Google Scholar] [CrossRef]
  16. Douglas, S.E.; Gallant, J.W.; Liebscher, R.S.; Dacanay, A.; Tsoi, S.C. Identification and expression analysis of hepcidin-like antimicrobial peptides in bony fish. Dev. Comp. Immunol. 2003, 27, 589–601. [Google Scholar] [CrossRef]
  17. Chang, C.I.; Zhang, Y.A.; Zou, J.; Nie, P.; Secombes, C.J. Two cathelicidin genes are present in both rainbow trout (Oncorhynchus mykiss) and atlantic salmon (Salmo salar). Antimicrob. Agents Chemother. 2006, 50, 185–195. [Google Scholar] [CrossRef]
  18. Richards, R.C.; O’Neil, D.B.; Thibault, P.; Ewart, K.V. Histone H1: An antimicrobial protein of Atlantic salmon (Salmo salar). Biochem. Biophys. Res. Commun. 2001, 284, 549–555. [Google Scholar] [CrossRef]
  19. Chen, M.Z.; Chen, J.; Lu, X.J.; Shi, Y.H. Molecular cloning, sequence analysis and expression pattern of hepcidin gene in ayu (Plecoglossus altivelis). Dongwuxue Yanjiu 2010, 31, 595–600. [Google Scholar]
  20. Lu, X.J.; Chen, J.; Huang, Z.A.; Shi, Y.H.; Lv, J.N. Identification and characterization of a novel cathelicidin from ayu, Plecoglossus altivelis. Fish Shellfish Immunol. 2011, 31, 52–57. [Google Scholar] [CrossRef]
  21. Barnes, A.C.; Trewin, B.; Snape, N.; Kvennefors, E.C.; Baiano, J.C. Two hepcidin-like antimicrobial peptides in Barramundi Lates calcarifer exhibit differing tissue tropism and are induced in response to lipopolysaccharide. Fish Shellfish Immunol. 2011, 31, 350–357. [Google Scholar] [CrossRef]
  22. Yang, M.; Wang, K.J.; Chen, J.H.; Qu, H.D.; Li, S.J. Genomic organization and tissue-specific expression analysis of hepcidin-like genes from black porgy (Acanthopagrus schlegelii B). Fish Shellfish Immunol. 2007, 23, 1060–1071. [Google Scholar] [CrossRef]
  23. Yang, M.; Chen, B.; Cai, J.J.; Peng, H.; Ling, C.; Yuan, J.J.; Wang, K.J. Molecular characterization of hepcidin AS-hepc2 and AS-hepc6 in black porgy (Acanthopagrus schlegelii): Expression pattern responded to bacterial challenge and in vitro antimicrobial activity. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2011, 158, 155–163. [Google Scholar] [CrossRef]
  24. Kim, Y.O.; Park, E.M.; Nam, B.H.; Kong, H.J.; Kim, W.J.; Lee, S.J. Identification and molecular characterization of two hepcidin genes from black rockfish (Sebastes schlegelii). Mol. Cell. Biochem. 2008, 315, 131–136. [Google Scholar] [CrossRef]
  25. Gong, L.C.; Wang, H.; Deng, L. Molecular characterization, phylogeny and expression of a hepcidin gene in the blotched snakehead Channa maculata. Dev. Comp. Immunol. 2014, 44, 1–11. [Google Scholar] [CrossRef]
  26. Bao, B.; Peatman, E.; Li, P.; He, C.; Liu, Z. Catfish hepcidin gene is expressed in a wide range of tissues and exhibits tissue-specific upregulation after bacterial infection. Dev. Comp. Immunol. 2005, 29, 939–950. [Google Scholar] [CrossRef]
  27. Liang, T.; Ji, W.; Zhang, G.R.; Wei, K.J.; Feng, K.; Wang, W.M.; Zou, G.W. Molecular cloning and expression analysis of liver-expressed antimicrobial peptide 1 (LEAP-1) and LEAP-2 genes in the blunt snout bream (Megalobrama amblycephala). Fish Shellfish Immunol. 2013, 35, 553–563. [Google Scholar] [CrossRef]
  28. Scocchi, M.; Pallavicini, A.; Salgaro, R.; Bociek, K.; Gennaro, R. The salmonid cathelicidins: A gene family with highly varied C-terminal antimicrobial domains. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2009, 152, 376–381. [Google Scholar] [CrossRef]
  29. Park, I.Y.; Park, C.B.; Kim, M.S.; Kim, S.C. Parasin I, an antimicrobial peptide derived from histone H2A in the catfish, Parasilurus asotus. FEBS Lett. 1998, 437, 258–262. [Google Scholar] [CrossRef]
  30. Chen, Y.; Zhao, H.; Zhang, X.; Luo, H.; Xue, X.; Li, Z.; Yao, B. Identification, expression and bioactivity of Paramisgurnus dabryanus beta-defensin that might be involved in immune defense against bacterial infection. Fish Shellfish Immunol. 2013, 35, 399–406. [Google Scholar] [CrossRef]
  31. Marel, M.; Adamek, M.; Gonzalez, S.F.; Frost, P.; Rombout, J.H.; Wiegertjes, G.F.; Savelkoul, H.F.; Steinhagen, D. Molecular cloning and expression of two beta-defensin and two mucin genes in common carp (Cyprinus carpio L.) and their up-regulation after beta-glucan feeding. Fish Shellfish Immunol. 2012, 32, 494–501. [Google Scholar] [CrossRef]
  32. Li, H.; Zhang, F.; Guo, H.; Zhu, Y.; Yuan, J.; Yang, G.; An, L. Molecular characterization of hepcidin gene in common carp (Cyprinus carpio L.) and its expression pattern responding to bacterial challenge. Fish Shellfish Immunol. 2013, 35, 1030–1038. [Google Scholar] [CrossRef]
  33. Salerno, G.; Parrinello, N.; Roch, P.; Cammarata, M. cDNA sequence and tissue expression of an antimicrobial peptide, dicentracin; a new component of the moronecidin family isolated from head kidney leukocytes of sea bass, Dicentrarchus labrax. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2007, 146, 521–529. [Google Scholar] [CrossRef]
  34. Rodrigues, P.N.; Vazquez-Dorado, S.; Neves, J.V.; Wilson, J.M. Dual function of fish hepcidin: Response to experimental iron overload and bacterial infection in sea bass (Dicentrarchus labrax). Dev. Comp. Immunol. 2006, 30, 1156–1167. [Google Scholar] [CrossRef]
  35. Cuesta, A.; Meseguer, J.; Esteban, M.A. Molecular and functional characterization of the gilthead seabream beta-defensin demonstrate its chemotactic and antimicrobial activity. Mol. Immunol. 2011, 48, 1432–1438. [Google Scholar] [CrossRef]
  36. Cuesta, A.; Meseguer, J.; Esteban, M.A. The antimicrobial peptide hepcidin exerts an important role in the innate immunity against bacteria in the bony fish gilthead seabream. Mol. Immunol. 2008, 45, 2333–2342. [Google Scholar] [CrossRef]
  37. Wang, Y.; Liu, X.; Ma, L.; Yu, Y.; Yu, H.; Mohammed, S.; Chu, G.; Mu, L.; Zhang, Q. Identification and characterization of a hepcidin from half-smooth tongue sole Cynoglossus semilaevis. Fish Shellfish Immunol. 2012, 33, 213–219. [Google Scholar] [CrossRef]
  38. Birkemo, G.A.; Luders, T.; Andersen, O.; Nes, I.F.; Nissen-Meyer, J. Hipposin, a histone-derived antimicrobial peptide in Atlantic halibut (Hippoglossus hippoglossus L.). Biochim. Biophys. Acta 2003, 1646, 207–215. [Google Scholar] [CrossRef]
  39. Salger, S.A.; Reading, B.J.; Baltzegar, D.A.; Sullivan, C.V.; Noga, E.J. Molecular characterization of two isoforms of piscidin 4 from the hybrid striped bass (Morone chrysops x Morone saxatilis). Fish Shellfish Immunol. 2011, 30, 420–424. [Google Scholar] [CrossRef]
  40. Noga, E.J.; Silphaduang, U.; Park, N.G.; Seo, J.K.; Stephenson, J.; Kozlowicz, S. Piscidin 4, a novel member of the piscidin family of antimicrobial peptides. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2009, 152, 299–305. [Google Scholar] [CrossRef]
  41. Lauth, X.; Shike, H.; Burns, J.C.; Westerman, M.E.; Ostland, V.E.; Carlberg, J.M.; van Olst, J.C.; Nizet, V.; Taylor, S.W.; Shimizu, C.; et al. Discovery and characterization of two isoforms of moronecidin, a novel antimicrobial peptide from hybrid striped bass. J. Biol. Chem. 2002, 277, 5030–5039. [Google Scholar] [CrossRef]
  42. Shike, H.; Lauth, X.; Westerman, M.E.; Ostland, V.E.; Carlberg, J.M.; van Olst, J.C.; Shimizu, C.; Bulet, P.; Burns, J.C. Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge. Eur. J. Biochem. 2002, 269, 2232–2237. [Google Scholar] [CrossRef]
  43. Buonocore, F.; Randelli, E.; Casani, D.; Picchietti, S.; Belardinelli, M.C.; de Pascale, D.; de Santi, C.; Scapigliati, G. A piscidin-like antimicrobial peptide from the icefish Chionodraco hamatus (Perciformes: Channichthyidae): Molecular characterization, localization and bactericidal activity. Fish Shellfish Immunol. 2012, 33, 1183–1191. [Google Scholar] [CrossRef]
  44. Zou, J.; Mercier, C.; Koussounadis, A.; Secombes, C. Discovery of multiple beta-defensin like homologues in teleost fish. Mol. Immunol. 2007, 44, 638–647. [Google Scholar] [CrossRef]
  45. Ren, H.L.; Wang, K.J.; Zhou, H.L.; Yang, M. Cloning and organisation analysis of a hepcidin-like gene and cDNA from Japan sea bass, Lateolabrax japonicus. Fish Shellfish Immunol. 2006, 21, 221–227. [Google Scholar] [CrossRef]
  46. Robertson, L.S.; Iwanowicz, L.R.; Marranca, J.M. Identification of centrarchid hepcidins and evidence that 17beta-estradiol disrupts constitutive expression of hepcidin-1 and inducible expression of hepcidin-2 in largemouth bass (Micropterus salmoides). Fish Shellfish Immunol. 2009, 26, 898–907. [Google Scholar] [CrossRef]
  47. Niu, S.F.; Jin, Y.; Xu, X.; Qiao, Y.; Wu, Y.; Mao, Y.; Su, Y.Q.; Wang, J. Characterization of a novel piscidin-like antimicrobial peptide from Pseudosciaena crocea and its immune response to Cryptocaryon irritans. Fish Shellfish Immunol. 2013, 35, 513–524. [Google Scholar] [CrossRef]
  48. Wang, K.J.; Cai, J.J.; Cai, L.; Qu, H.D.; Yang, M.; Zhang, M. Cloning and expression of a hepcidin gene from a marine fish (Pseudosciaena crocea) and the antimicrobial activity of its synthetic peptide. Peptides 2009, 30, 638–646. [Google Scholar] [CrossRef]
  49. Zhang, J.; Yan, Q.; Ji, R.; Zou, W.; Guo, G. Isolation and characterization of a hepcidin peptide from the head kidney of large yellow croaker, Pseudosciaena crocea. Fish Shellfish Immunol. 2009, 26, 864–870. [Google Scholar] [CrossRef]
  50. Sun, B.J.; Xie, H.X.; Song, Y.; Nie, P. Gene structure of an antimicrobial peptide from mandarin fish, Siniperca chuatsi (Basilewsky), suggests that moronecidins and pleurocidins belong in one family: The piscidins. J. Fish Dis. 2007, 30, 335–343. [Google Scholar] [CrossRef]
  51. Wang, G.; Li, J.; Zou, P.; Xie, H.; Huang, B.; Nie, P.; Chang, M. Expression pattern, promoter activity and bactericidal property of beta-defensin from the mandarin fish Siniperca chuatsi. Fish Shellfish Immunol. 2012, 33, 522–531. [Google Scholar] [CrossRef]
  52. Zhao, J.G.; Zhou, L.; Jin, J.Y.; Zhao, Z.; Lan, J.; Zhang, Y.B.; Zhang, Q.Y.; Gui, J.F. Antimicrobial activity-specific to Gram-negative bacteria and immune modulation-mediated NF-kappaB and Sp1 of a medaka beta-defensin. Dev. Comp. Immunol. 2009, 33, 624–637. [Google Scholar]
  53. Bo, J.; Cai, L.; Xu, J.H.; Wang, K.J.; Au, D.W. The marine medaka Oryzias melastigma—A potential marine fish model for innate immune study. Mar. Pollut. Bull. 2011, 63, 267–276. [Google Scholar] [CrossRef]
  54. Xu, T.; Sun, Y.; Shi, G.; Wang, R. Miiuy croaker hepcidin gene and comparative analyses reveal evidence for positive selection. PLoS One 2012, 7, e35449. [Google Scholar]
  55. Brocal, I.; Falco, A.; Mas, V.; Rocha, A.; Perez, L.; Coll, J.M.; Estepa, A. Stable expression of bioactive recombinant pleurocidin in a fish cell line. Appl. Microbiol. Biotechnol. 2006, 72, 1217–1228. [Google Scholar] [CrossRef]
  56. Nam, Y.K.; Cho, Y.S.; Lee, S.Y.; Kim, B.S.; Kim, D.S. Molecular characterization of hepcidin gene from mud loach (Misgurnus mizolepis; Cypriniformes). Fish Shellfish Immunol. 2011, 31, 1251–1258. [Google Scholar] [CrossRef]
  57. Nam, B.H.; Moon, J.Y.; Kim, Y.O.; Kong, H.J.; Kim, W.J.; Lee, S.J.; Kim, K.K. Multiple beta-defensin isoforms identified in early developmental stages of the teleost Paralichthys olivaceus. Fish Shellfish Immunol. 2010, 28, 267–274. [Google Scholar] [CrossRef]
  58. Pan, C.Y.; Chen, J.Y.; Cheng, Y.S.; Chen, C.Y.; Ni, I.H.; Sheen, J.F.; Pan, Y.L.; Kuo, C.M. Gene expression and localization of the epinecidin-1 antimicrobial peptide in the grouper (Epinephelus coioides), and its role in protecting fish against pathogenic infection. DNA Cell Biol. 2007, 26, 403–413. [Google Scholar] [CrossRef]
  59. Guo, M.; Wei, J.; Huang, X.; Huang, Y.; Qin, Q. Antiviral effects of beta-defensin derived from orange-spotted grouper (Epinephelus coioides). Fish Shellfish Immunol. 2012, 32, 828–838. [Google Scholar] [CrossRef]
  60. Jin, J.Y.; Zhou, L.; Wang, Y.; Li, Z.; Zhao, J.G.; Zhang, Q.Y.; Gui, J.F. Antibacterial and antiviral roles of a fish beta-defensin expressed both in pituitary and testis. PLoS One 2010, 5, e12883. [Google Scholar]
  61. Zhou, J.G.; Wei, J.G.; Xu, D.; Cui, H.C.; Yan, Y.; Ou-Yang, Z.L.; Huang, X.H.; Huang, Y.H.; Qin, Q.W. Molecular cloning and characterization of two novel hepcidins from orange-spotted grouper, Epinephelus coioides. Fish Shellfish Immunol. 2011, 30, 559–568. [Google Scholar] [CrossRef]
  62. Qu, H.; Chen, B.; Peng, H.; Wang, K. Molecular cloning, recombinant expression, and antimicrobial activity of EC-hepcidin3, a new four-cysteine hepcidin isoform from Epinephelus coioides. Biosci. Biotechnol. Biochem. 2013, 77, 103–110. [Google Scholar] [CrossRef]
  63. Masso-Silva, J.; Diamond, G.; Macias-Rodriguez, M.; Ascencio, F. Genomic organization and tissue-specific expression of hepcidin in the pacific mutton hamlet, Alphestes immaculatus (Breder, 1936). Fish Shellfish Immunol. 2011, 31, 1297–1302. [Google Scholar] [CrossRef]
  64. Falco, A.; Chico, V.; Marroqui, L.; Perez, L.; Coll, J.M.; Estepa, A. Expression and antiviral activity of a beta-defensin-like peptide identified in the rainbow trout (Oncorhynchus mykiss) EST sequences. Mol. Immunol. 2008, 45, 757–765. [Google Scholar]
  65. Casadei, E.; Wang, T.; Zou, J.; Gonzalez Vecino, J.L.; Wadsworth, S.; Secombes, C.J. Characterization of three novel beta-defensin antimicrobial peptides in rainbow trout (Oncorhynchus mykiss). Mol. Immunol. 2009, 46, 3358–3366. [Google Scholar] [CrossRef]
  66. Fernandes, J.M.; Kemp, G.D.; Molle, M.G.; Smith, V.J. Anti-microbial properties of histone H2A from skin secretions of rainbow trout, Oncorhynchus mykiss. Biochem. J. 2002, 368, 611–620. [Google Scholar] [CrossRef]
  67. Fernandes, J.M.; Molle, G.; Kemp, G.D.; Smith, V.J. Isolation and characterisation of oncorhyncin II, a histone H1-derived antimicrobial peptide from skin secretions of rainbow trout, Oncorhynchus mykiss. Dev. Comp. Immunol. 2004, 28, 127–138. [Google Scholar] [CrossRef]
  68. Fernandes, J.M.; Saint, N.; Kemp, G.D.; Smith, V.J. Oncorhyncin III: A potent antimicrobial peptide derived from the non-histone chromosomal protein H6 of rainbow trout, Oncorhynchus mykiss. Biochem. J. 2003, 373, 621–628. [Google Scholar] [CrossRef]
  69. Noga, E.J.; Fan, Z.; Silphaduang, U. Histone-like proteins from fish are lethal to the parasitic dinoflagellate Amyloodinium ocellatum. Parasitology 2001, 123, 57–65. [Google Scholar]
  70. Martin-Antonio, B.; Jimenez-Cantizano, R.M.; Salas-Leiton, E.; Infante, C.; Manchado, M. Genomic characterization and gene expression analysis of four hepcidin genes in the redbanded seabream (Pagrus auriga). Fish Shellfish Immunol. 2009, 26, 483–491. [Google Scholar] [CrossRef]
  71. Iijima, N.; Tanimoto, N.; Emoto, Y.; Morita, Y.; Uematsu, K.; Murakami, T.; Nakai, T. Purification and characterization of three isoforms of chrysophsin, a novel antimicrobial peptide in the gills of the red sea bream, Chrysophrys major. Eur. J. Biochem. 2003, 270, 675–686. [Google Scholar] [CrossRef]
  72. Chen, S.L.; Xu, M.Y.; Ji, X.S.; Yu, G.C.; Liu, Y. Cloning, characterization, and expression analysis of hepcidin gene from red sea bream (Chrysophrys major). Antimicrob. Agents Chemother. 2005, 49, 1608–1612. [Google Scholar] [CrossRef]
  73. Cho, Y.S.; Lee, S.Y.; Kim, K.H.; Kim, S.K.; Kim, D.S.; Nam, Y.K. Gene structure and differential modulation of multiple rockbream (Oplegnathus fasciatus) hepcidin isoforms resulting from different biological stimulations. Dev. Comp. Immunol. 2009, 33, 46–58. [Google Scholar] [CrossRef]
  74. Terova, G.; Cattaneo, A.G.; Preziosa, E.; Bernardini, G.; Saroglia, M. Impact of acute stress on antimicrobial polypeptides mRNA copy number in several tissues of marine sea bass (Dicentrarchus labrax). BMC Immunol. 2011, 12, 69. [Google Scholar] [CrossRef]
  75. Sun, D.; Wu, S.; Jing, C.; Zhang, N.; Liang, D.; Xu, A. Identification, synthesis and characterization of a novel antimicrobial peptide HKPLP derived from Hippocampus kuda Bleeker. J. Antibiot. (Tokyo) 2012, 65, 117–121. [Google Scholar] [CrossRef]
  76. Chaturvedi, P.; Dhanik, M.; Pande, A. Characterization and structural analysis of hepcidin like antimicrobial peptide from schizothorax richardsonii (Gray). Protein J. 2014, 33, 1–10. [Google Scholar] [CrossRef]
  77. Li, Z.; Zhang, S.; Gao, J.; Guang, H.; Tian, Y.; Zhao, Z.; Wang, Y.; Yu, H. Structural and functional characterization of CATH_BRALE, the defense molecule in the ancient salmonoid, Brachymystax lenok. Fish Shellfish Immunol. 2013, 34, 1–7. [Google Scholar] [CrossRef]
  78. Peng, K.C.; Lee, S.H.; Hour, A.-L.; Pan, C.Y.; Lee, L.H.; Chen, J. Five different piscidins from nile tilapia, oreochromis niloticus: Analysis of their expressions and biological functions. PLoS One 2012, 7, e50263. [Google Scholar]
  79. Huang, P.H.; Chen, J.Y.; Kuo, C.M. Three different hepcidins from tilapia, Oreochromis mossambicus: Analysis of their expressions and biological functions. Mol. Immunol. 2007, 44, 1922–1934. [Google Scholar] [CrossRef]
  80. Pereiro, P.; Figueras, A.; Novoa, B. A novel hepcidin-like in turbot (Scophthalmus maximus L.) highly expressed after pathogen challenge but not after iron overload. Fish Shellfish Immunol. 2012, 32, 879–889. [Google Scholar] [CrossRef][Green Version]
  81. Chen, S.L.; Li, W.; Meng, L.; Sha, Z.X.; Wang, Z.J.; Ren, G.C. Molecular cloning and expression analysis of a hepcidin antimicrobial peptide gene from turbot (Scophthalmus maximus). Fish Shellfish Immunol. 2007, 22, 172–181. [Google Scholar] [CrossRef]
  82. Cole, A.M.; Darouiche, R.O.; Legarda, D.; Connell, N.; Diamond, G. Characterization of a fish antimicrobial peptide: Gene expression, subcellular localization, and spectrum of activity. Antimicrob. Agents Chemother. 2000, 44, 2039–2045. [Google Scholar] [CrossRef]
  83. Douglas, S.E.; Patrzykat, A.; Pytyck, J.; Gallant, J.W. Identification, structure and differential expression of novel pleurocidins clustered on the genome of the winter flounder, Pseudopleuronectes americanus (Walbaum). Eur. J. Biochem. 2003, 270, 3720–3730. [Google Scholar] [CrossRef]
  84. Shike, H.; Shimizu, C.; Lauth, X.; Burns, J.C. Organization and expression analysis of the zebrafish hepcidin gene, an antimicrobial peptide gene conserved among vertebrates. Dev. Comp. Immunol. 2004, 28, 747–754. [Google Scholar] [CrossRef]
  85. Tamang, D.G.; Saier, M.H., Jr. The cecropin superfamily of toxic peptides. J. Mol. Microbiol. Biotechnol. 2006, 11, 94–103. [Google Scholar] [CrossRef]
  86. Park, C.B.; Lee, J.H.; Park, I.Y.; Kim, M.S.; Kim, S.C. A novel antimicrobial peptide from the loach, Misgurnus anguillicaudatus. FEBS Lett. 1997, 411, 173–178. [Google Scholar] [CrossRef]
  87. Silphaduang, U.; Noga, E.J. Peptide antibiotics in mast cells of fish. Nature 2001, 414, 268–269. [Google Scholar] [CrossRef]
  88. Silphaduang, U.; Colorni, A.; Noga, E.J. Evidence for widespread distribution of piscidin antimicrobial peptides in teleost fish. Dis. Aquat. Org. 2006, 72, 241–252. [Google Scholar] [CrossRef]
  89. Pan, C.Y.; Chen, J.Y.; Ni, I.H.; Wu, J.L.; Kuo, C.M. Organization and promoter analysis of the grouper (Epinephelus coioides) epinecidin-1 gene. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2008, 150, 358–367. [Google Scholar] [CrossRef]
  90. Syvitski, R.T.; Burton, I.; Mattatall, N.R.; Douglas, S.E.; Jakeman, D.L. Structural characterization of the antimicrobial peptide pleurocidin from winter flounder. Biochemistry 2005, 44, 7282–7293. [Google Scholar] [CrossRef]
  91. Fernandes, J.M.O.; Ruangsri, J.; Kiron, V. Atlantic cod piscidin and its diversification through positive selection. PLoS One 2010, 5, e9501. [Google Scholar] [CrossRef][Green Version]
  92. Tennessen, J.A. Enhanced synonymous site divergence in positively selected vertebrate antimicrobial peptide genes. J. Mol. Evol. 2005, 61, 445–455. [Google Scholar] [CrossRef]
  93. Pinzon-Arango, P.A.; Nagarajan, R.; Camesano, T.A. Interactions of antimicrobial peptide chrysophsin-3 with Bacillus anthracis in sporulated, germinated, and vegetative states. J. Phys. Chem. B 2013, 117, 6364–6372. [Google Scholar] [CrossRef]
  94. Cho, J.; Lee, D.G. Oxidative stress by antimicrobial peptide pleurocidin triggers apoptosis in Candida albicans. Biochimie 2011, 93, 1873–1879. [Google Scholar] [CrossRef]
  95. Jung, H.J.; Park, Y.; Sung, W.S.; Suh, B.K.; Lee, J.; Hahm, K.S.; Lee, D.G. Fungicidal effect of pleurocidin by membrane-active mechanism and design of enantiomeric analogue for proteolytic resistance. Biochim. Biophys. Acta 2007, 1768, 1400–1405. [Google Scholar] [CrossRef]
  96. Pan, C.Y.; Chen, J.Y.; Lin, T.L.; Lin, C.H. In vitro activities of three synthetic peptides derived from epinecidin-1 and an anti-lipopolysaccharide factor against Propionibacterium acnes, Candida albicans, and Trichomonas vaginalis. Peptides 2009, 30, 1058–1068. [Google Scholar] [CrossRef]
  97. Colorni, A.; Ullal, A.; Heinisch, G.; Noga, E.J. Activity of the antimicrobial polypeptide piscidin 2 against fish ectoparasites. J. Fish Dis. 2008, 31, 423–432. [Google Scholar] [CrossRef]
  98. Zahran, E.; Noga, E.J. Evidence for synergism of the antimicrobial peptide piscidin 2 with antiparasitic and antioomycete drugs. J. Fish Dis. 2010, 33, 995–1003. [Google Scholar] [CrossRef]
  99. Wang, Y.D.; Kung, C.W.; Chen, J.Y. Antiviral activity by fish antimicrobial peptides of epinecidin-1 and hepcidin 1–5 against nervous necrosis virus in medaka. Peptides 2010, 31, 1026–1033. [Google Scholar] [CrossRef]
  100. Chinchar, V.G.; Bryan, L.; Silphadaung, U.; Noga, E.; Wade, D.; Rollins-Smith, L. Inactivation of viruses infecting ectothermic animals by amphibian and piscine antimicrobial peptides. Virology 2004, 323, 268–275. [Google Scholar] [CrossRef]
  101. Douglas, S.E.; Gallant, J.W.; Gong, Z.; Hew, C. Cloning and developmental expression of a family of pleurocidin-like antimicrobial peptides from winter flounder, Pleuronectes americanus (Walbaum). Dev. Comp. Immunol. 2001, 25, 137–147. [Google Scholar] [CrossRef]
  102. Mulero, I.; Noga, E.J.; Meseguer, J.; Garcia-Ayala, A.; Mulero, V. The antimicrobial peptides piscidins are stored in the granules of professional phagocytic granulocytes of fish and are delivered to the bacteria-containing phagosome upon phagocytosis. Dev. Comp. Immunol. 2008, 32, 1531–1538. [Google Scholar] [CrossRef]
  103. Ruangsri, J.; Fernandes, J.M.; Rombout, J.H.; Brinchmann, M.F.; Kiron, V. Ubiquitous presence of piscidin-1 in Atlantic cod as evidenced by immunolocalisation. BMC Vet. Res. 2012, 8, 46. [Google Scholar] [CrossRef][Green Version]
  104. Dezfuli, B.S.; Pironi, F.; Giari, L.; Noga, E.J. Immunocytochemical localization of piscidin in mast cells of infected seabass gill. Fish Shellfish Immunol. 2010, 28, 476–482. [Google Scholar] [CrossRef]
  105. Murray, H.M.; Gallant, J.W.; Douglas, S.E. Cellular localization of pleurocidin gene expression and synthesis in winter flounder gill using immunohistochemistry and in situ hybridization. Cell Tissue Res. 2003, 312, 197–202. [Google Scholar]
  106. Dezfuli, B.S.; Castaldelli, G.; Bo, T.; Lorenzoni, M.; Giari, L. Intestinal immune response of Silurus glanis and Barbus barbus naturally infected with Pomphorhynchus laevis (Acanthocephala). Parasite Immunol. 2011, 33, 116–23. [Google Scholar] [CrossRef]
  107. Dezfuli, B.S.; Lui, A.; Giari, L.; Castaldelli, G.; Mulero, V.; Noga, E.J. Infiltration and activation of acidophilic granulocytes in skin lesions of gilthead seabream, Sparus aurata, naturally infected with lymphocystis disease virus. Dev. Comp. Immunol. 2012, 36, 174–182. [Google Scholar] [CrossRef]
  108. Lin, W.J.; Chien, Y.L.; Pan, C.Y.; Lin, T.L.; Chen, J.Y.; Chiu, S.J.; Hui, C.F. Epinecidin-1, an antimicrobial peptide from fish (Epinephelus coioides) which has an antitumor effect like lytic peptides in human fibrosarcoma cells. Peptides 2009, 30, 283–290. [Google Scholar] [CrossRef]
  109. Lin, H.J.; Huang, T.C.; Muthusamy, S.; Lee, J.F.; Duann, Y.F.; Lin, C.H. Piscidin-1, an antimicrobial peptide from fish (hybrid striped bass morone saxatilis x M. chrysops), induces apoptotic and necrotic activity in HT1080 cells. Zool. Sci. 2012, 29, 327–332. [Google Scholar] [CrossRef]
  110. Hsu, J.C.; Lin, L.C.; Tzen, J.T.; Chen, J.Y. Characteristics of the antitumor activities in tumor cells and modulation of the inflammatory response in RAW264.7 cells of a novel antimicrobial peptide, chrysophsin-1, from the red sea bream (Chrysophrys major). Peptides 2011, 32, 900–910. [Google Scholar] [CrossRef]
  111. Chen, J.Y.; Lin, W.J.; Wu, J.L.; Her, G.M.; Hui, C.F. Epinecidin-1 peptide induces apoptosis which enhances antitumor effects in human leukemia U937 cells. Peptides 2009, 30, 2365–2373. [Google Scholar] [CrossRef]
  112. Morash, M.G.; Douglas, S.E.; Robotham, A.; Ridley, C.M.; Gallant, J.W.; Soanes, K.H. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents. Dis. Model. Mech. 2011, 4, 622–633. [Google Scholar] [CrossRef]
  113. Hilchie, A.L.; Doucette, C.D.; Pinto, D.M.; Patrzykat, A.; Douglas, S.; Hoskin, D.W. Pleurocidin-family cationic antimicrobial peptides are cytolytic for breast carcinoma cells and prevent growth of tumor xenografts. Breast Cancer Res. 2011, 13, R102. [Google Scholar] [CrossRef]
  114. Pan, C.Y.; Chow, T.Y.; Yu, C.Y.; Yu, C.Y.; Chen, J.C.; Chen, J.Y. Antimicrobial peptides of an anti-lipopolysaccharide factor, epinecidin-1, and hepcidin reduce the lethality of Riemerella anatipestifer sepsis in ducks. Peptides 2010, 31, 806–815. [Google Scholar] [CrossRef]
  115. Sung, W.S.; Lee, D.G. Pleurocidin-derived antifungal peptides with selective membrane-disruption effect. Biochem. Biophys. Res. Commun. 2008, 369, 858–861. [Google Scholar] [CrossRef]
  116. Rahmanpour, A.; Ghahremanpour, M.M.; Mehrnejad, F.; Moghaddam, M.E. Interaction of Piscidin-1 with zwitterionic versus anionic membranes: A comparative molecular dynamics study. J. Biomol. Struct. Dyn. 2013, 31, 1393–1403. [Google Scholar] [CrossRef]
  117. Chekmenev, E.Y.; Jones, S.M.; Nikolayeva, Y.N.; Vollmar, B.S.; Wagner, T.J.; Gor’kov, P.L.; Brey, W.W.; Manion, M.N.; Daugherty, K.C.; Cotten, M. High-field NMR studies of molecular recognition and structure-function relationships in antimicrobial piscidins at the water-lipid bilayer interface. J. Am. Chem. Soc. 2006, 128, 5308–5309. [Google Scholar] [CrossRef]
  118. Mason, A.J.; Bertani, P.; Moulay, G.; Marquette, A.; Perrone, B.; Drake, A.F.; Kichler, A.; Bechinger, B. Membrane interaction of chrysophsin-1, a histidine-rich antimicrobial peptide from red sea bream. Biochemistry 2007, 46, 15175–15187. [Google Scholar] [CrossRef]
  119. Patrzykat, A.; Friedrich, C.L.; Zhang, L.; Mendoza, V.; Hancock, R.E. Sublethal concentrations of pleurocidin-derived antimicrobial peptides inhibit macromolecular synthesis in Escherichia coli. Antimicrob. Agents Chemother. 2002, 46, 605–614. [Google Scholar] [CrossRef]
  120. Kim, J.K.; Lee, S.A.; Shin, S.; Lee, J.Y.; Jeong, K.W.; Nan, Y.H.; Park, Y.S.; Shin, S.Y.; Kim, Y. Structural flexibility and the positive charges are the key factors in bacterial cell selectivity and membrane penetration of peptoid-substituted analog of Piscidin 1. Biochim. Biophys. Acta 2010, 1798, 1913–1925. [Google Scholar]
  121. Lin, S.B.; Fan, T.W.; Wu, J.L.; Hui, C.F.; Chen, J.Y. Immune response and inhibition of bacterial growth by electrotransfer of plasmid DNA containing the antimicrobial peptide, epinecidin-1, into zebrafish muscle. Fish Shellfish Immunol. 2009, 26, 451–458. [Google Scholar] [CrossRef]
  122. Lee, L.H.; Hui, C.F.; Chuang, C.M.; Chen, J.Y. Electrotransfer of the epinecidin-1 gene into skeletal muscle enhances the antibacterial and immunomodulatory functions of a marine fish, grouper (Epinephelus coioides). Fish Shellfish Immunol. 2013, 35, 1359–1368. [Google Scholar] [CrossRef]
  123. Pan, C.Y.; Wu, J.L.; Hui, C.F.; Lin, C.H.; Chen, J.Y. Insights into the antibacterial and immunomodulatory functions of the antimicrobial peptide, epinecidin-1, against Vibrio vulnificus infection in zebrafish. Fish Shellfish Immunol. 2011, 31, 1019–1025. [Google Scholar] [CrossRef]
  124. Pan, C.Y.; Huang, T.C.; Wang, Y.D.; Yeh, Y.C.; Hui, C.F.; Chen, J.Y. Oral administration of recombinant epinecidin-1 protected grouper (Epinephelus coioides) and zebrafish (Danio rerio) from Vibrio vulnificus infection and enhanced immune-related gene expressions. Fish Shellfish Immunol. 2012, 32, 947–957. [Google Scholar] [CrossRef]
  125. Peng, K.C.; Pan, C.Y.; Chou, H.N.; Chen, J.Y. Using an improved Tol2 transposon system to produce transgenic zebrafish with epinecidin-1 which enhanced resistance to bacterial infection. Fish Shellfish Immunol. 2010, 28, 905–917. [Google Scholar] [CrossRef]
  126. Huang, H.N.; Pan, C.Y.; Rajanbabu, V.; Chan, Y.L.; Wu, C.J.; Chen, J.Y. Modulation of immune responses by the antimicrobial peptide, epinecidin (Epi)-1, and establishment of an Epi-1-based inactivated vaccine. Biomaterials 2011, 32, 3627–3636. [Google Scholar] [CrossRef]
  127. Lee, S.C.; Pan, C.Y.; Chen, J.Y. The antimicrobial peptide, epinecidin-1, mediates secretion of cytokines in the immune response to bacterial infection in mice. Peptides 2012, 36, 100–108. [Google Scholar] [CrossRef]
  128. Huang, H.N.; Rajanbabu, V.; Pan, C.Y.; Chan, Y.L.; Wu, C.J.; Chen, J.Y. Use of the antimicrobial peptide Epinecidin-1 to protect against MRSA infection in mice with skin injuries. Biomaterials 2013, 34, 10319–10327. [Google Scholar] [CrossRef]
  129. Pundir, P.; Catalli, A.; Leggiadro, C.; Douglas, S.E.; Kulka, M. Pleurocidin, a novel antimicrobial peptide, induces human mast cell activation through the FPRL1 receptor. Mucosal Immunol. 2014, 7, 177–187. [Google Scholar] [CrossRef]
  130. Bulet, P.; Stocklin, R.; Menin, L. Anti-microbial peptides: From invertebrates to vertebrates. Immunol. Rev. 2004, 198, 169–184. [Google Scholar] [CrossRef]
  131. Aerts, A.M.; Francois, I.E.; Cammue, B.P.; Thevissen, K. The mode of antifungal action of plant, insect and human defensins. Cell. Mol. Life Sci. 2008, 65, 2069–2079. [Google Scholar] [CrossRef]
  132. Zhu, S. Discovery of six families of fungal defensin-like peptides provides insights into origin and evolution of the CSalphabeta defensins. Mol. Immunol. 2008, 45, 828–838. [Google Scholar] [CrossRef]
  133. Zhu, S.; Gao, B. Evolutionary origin of beta-defensins. Dev. Comp. Immunol. 2013, 39, 79–84. [Google Scholar] [CrossRef]
  134. Liu, L.; Zhao, C.; Heng, H.H.; Ganz, T. The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: Two peptide families with differing disulfide topology share a common ancestry. Genomics 1997, 43, 316–320. [Google Scholar] [CrossRef]
  135. Tang, Y.Q.; Yuan, J.; Osapay, G.; Osapay, K.; Tran, D.; Miller, C.J.; Ouellette, A.J.; Selsted, M.E. A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins. Science 1999, 286, 498–502. [Google Scholar] [CrossRef]
  136. Beckloff, N.; Diamond, G. Computational analysis suggests beta-defensins are processed to mature peptides by signal peptidase. Protein Pept. Lett. 2008, 15, 536–540. [Google Scholar] [CrossRef]
  137. Falco, A.; Mas, V.; Tafalla, C.; Perez, L.; Coll, J.M.; Estepa, A. Dual antiviral activity of human alpha-defensin-1 against viral haemorrhagic septicaemia rhabdovirus (VHSV): Inactivation of virus particles and induction of a type I interferon-related response. Antivir. Res. 2007, 76, 111–123. [Google Scholar] [CrossRef]
  138. Madison, M.N.; Kleshchenko, Y.Y.; Nde, P.N.; Simmons, K.J.; Lima, M.F.; Villalta, F. Human defensin alpha-1 causes Trypanosoma cruzi membrane pore formation and induces DNA fragmentation, which leads to trypanosome destruction. Infect. Immun. 2007, 75, 4780–4791. [Google Scholar] [CrossRef]
  139. Tanaka, T.; Rahman, M.M.; Battur, B.; Boldbaatar, D.; Liao, M.; Umemiya-Shirafuji, R.; Xuan, X.; Fujisaki, K. Parasiticidal activity of human alpha-defensin-5 against Toxoplasma gondii. In Vitro Cell. Dev. Biol. Anim. 2010, 46, 560–565. [Google Scholar] [CrossRef]
  140. Krishnakumari, V.; Rangaraj, N.; Nagaraj, R. Antifungal activities of human beta-defensins HBD-1 to HBD-3 and their C-terminal analogs Phd1 to Phd3. Antimicrob. Agents Chemother. 2009, 53, 256–260. [Google Scholar] [CrossRef]
  141. Jiang, Y.; Wang, Y.; Wang, B.; Yang, D.; Yu, K.; Yang, X.; Liu, F.; Jiang, Z.; Li, M. Antifungal activity of recombinant mouse beta-defensin 3. Lett. Appl. Microbiol. 2010, 50, 468–473. [Google Scholar] [CrossRef]
  142. Aerts, A.M.; Thevissen, K.; Bresseleers, S.M.; Sels, J.; Wouters, P.; Cammue, B.P.; Francois, I.E. Arabidopsis thaliana plants expressing human beta-defensin-2 are more resistant to fungal attack: Functional homology between plant and human defensins. Plant Cell Rep. 2007, 26, 1391–1398. [Google Scholar] [CrossRef]
  143. Semple, F.; Dorin, J.R. Beta-Defensins: Multifunctional modulators of infection, inflammation and more? J. Innate Immun. 2012, 4, 337–348. [Google Scholar] [CrossRef]
  144. Rohrl, J.; Yang, D.; Oppenheim, J.J.; Hehlgans, T. Specific binding and chemotactic activity of mBD4 and its functional orthologue hBD2 to CCR6-expressing cells. J. Biol. Chem. 2010, 285, 7028–7034. [Google Scholar]
  145. Liu, Y.; Chang, M.X.; Wu, S.G.; Nie, P. Characterization of C-C chemokine receptor subfamily in teleost fish. Mol. Immunol. 2009, 46, 498–504. [Google Scholar]
  146. Dixon, B.; Luque, A.; Abos, B.; Castro, R.; Gonzalez-Torres, L.; Tafalla, C. Molecular characterization of three novel chemokine receptors in rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol. 2013, 34, 641–651. [Google Scholar]
  147. Falco, A.; Brocal, I.; Perez, L.; Coll, J.M.; Estepa, A.; Tafalla, C. In vivo modulation of the rainbow trout (Oncorhynchus mykiss) immune response by the human alpha defensin 1, HNP1. Fish Shellfish Immunol. 2008, 24, 102–112. [Google Scholar] [CrossRef]
  148. Lehrer, R.I.; Ganz, T. Defensins of vertebrate animals. Curr. Opin. Immunol. 2002, 14, 96–102. [Google Scholar] [CrossRef]
  149. Tollner, T.L.; Venners, S.A.; Hollox, E.J.; Yudin, A.I.; Liu, X.; Tang, G.; Xing, H.; Kays, R.J.; Lau, T.; Overstreet, J.W.; et al. A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility. Sci. Transl. Med. 2011, 3, 92–ra65. [Google Scholar]
  150. Diamond, G.; Beckloff, N.; Weinberg, A.; Kisich, K.O. The roles of antimicrobial peptides in innate host defense. Curr. Pharm. Des. 2009, 15, 2377–2392. [Google Scholar] [CrossRef]
  151. Dorschner, R.A.; Lin, K.H.; Murakami, M.; Gallo, R.L. Neonatal skin in mice and humans expresses increased levels of antimicrobial peptides: Innate immunity during development of the adaptive response. Pediatr. Res. 2003, 53, 566–572. [Google Scholar] [CrossRef]
  152. Huttner, K.M.; Brezinski-Caliguri, D.J.; Mahoney, M.M.; Diamond, G. Antimicrobial peptide expression is developmentally-regulated in the ovine gastrointestinal tract. J. Nutr. 1998, 128, 297S–299S. [Google Scholar]
  153. Ganz, T. Defensins: Antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 2003, 3, 710–720. [Google Scholar] [CrossRef]
  154. Casadei, E.; Bird, S.; Vecino, J.L.; Wadsworth, S.; Secombes, C.J. The effect of peptidoglycan enriched diets on antimicrobial peptide gene expression in rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol. 2013, 34, 529–537. [Google Scholar] [CrossRef]
  155. Reyes-Becerril, M.; Guardiola, F.; Rojas, M.; Ascencio-Valle, F.; Esteban, M.A. Dietary administration of microalgae Navicula sp. affects immune status and gene expression of gilthead seabream (Sparus aurata). Fish Shellfish Immunol. 2013, 35, 883–889. [Google Scholar] [CrossRef]
  156. Krause, A.; Neitz, S.; Magert, H.J.; Schulz, A.; Forssmann, W.G.; Schulz-Knappe, P.; Adermann, K. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000, 480, 147–150. [Google Scholar] [CrossRef]
  157. Park, C.H.; Valore, E.V.; Waring, A.J.; Ganz, T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 2001, 276, 7806–7810. [Google Scholar] [CrossRef]
  158. Hilton, K.B.; Lambert, L.A. Molecular evolution and characterization of hepcidin gene products in vertebrates. Gene 2008, 415, 40–48. [Google Scholar] [CrossRef]
  159. Hunter, H.N.; Fulton, D.B.; Ganz, T.; Vogel, H.J. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J. Biol. Chem. 2002, 277, 37597–37603. [Google Scholar]
  160. Padhi, A.; Verghese, B. Evidence for positive Darwinian selection on the hepcidin gene of Perciform and Pleuronectiform fishes. Mol. Divers. 2007, 11, 119–130. [Google Scholar] [CrossRef]
  161. Lauth, X.; Babon, J.J.; Stannard, J.A.; Singh, S.; Nizet, V.; Carlberg, J.M.; Ostland, V.E.; Pennington, M.W.; Norton, R.S.; Westerman, M.E. Bass hepcidin synthesis, solution structure, antimicrobial activities and synergism, and in vivo hepatic response to bacterial infections. J. Biol. Chem. 2005, 280, 9272–9282. [Google Scholar]
  162. Hu, X.; Camus, A.C.; Aono, S.; Morrison, E.E.; Dennis, J.; Nusbaum, K.E.; Judd, R.L.; Shi, J. Channel catfish hepcidin expression in infection and anemia. Comp. Immunol. Microbiol. Infect. Dis. 2007, 30, 55–69. [Google Scholar] [CrossRef]
  163. Pridgeon, J.W.; Mu, X.; Klesius, P.H. Expression profiles of seven channel catfish antimicrobial peptides in response to Edwardsiella ictaluri infection. J. Fish Dis. 2012, 35, 227–237. [Google Scholar] [CrossRef]
  164. Chiou, P.P.; Lin, C.M.; Bols, N.C.; Chen, T.T. Characterization of virus/double-stranded RNA-dependent induction of antimicrobial peptide hepcidin in trout macrophages. Dev. Comp. Immunol. 2007, 31, 1297–1309. [Google Scholar] [CrossRef]
  165. Yang, C.G.; Liu, S.S.; Sun, B.; Wang, X.L.; Wang, N.; Chen, S.L. Iron-metabolic function and potential antibacterial role of Hepcidin and its correlated genes (Ferroportin 1 and Transferrin Receptor) in turbot (Scophthalmus maximus). Fish Shellfish Immunol. 2013, 34, 744–755. [Google Scholar] [CrossRef]
  166. Alvarez, C.A.; Santana, P.A.; Guzman, F.; Marshall, S.; Mercado, L. Detection of the hepcidin prepropeptide and mature peptide in liver of rainbow trout. Dev. Comp. Immunol. 2013, 41, 77–81. [Google Scholar] [CrossRef]
  167. Nemeth, E.; Valore, E.V.; Territo, M.; Schiller, G.; Lichtenstein, A.; Ganz, T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003, 101, 2461–2463. [Google Scholar] [CrossRef]
  168. Skov, J.; Kania, P.W.; Holten-Andersen, L.; Fouz, B.; Buchmann, K. Immunomodulatory effects of dietary beta-1,3-glucan from Euglena gracilis in rainbow trout (Oncorhynchus mykiss) immersion vaccinated against Yersinia ruckeri. Fish Shellfish Immunol. 2012, 33, 111–120. [Google Scholar] [CrossRef]
  169. Chia, T.J.; Wu, Y.C.; Chen, J.Y.; Chi, S.C. Antimicrobial peptides (AMP) with antiviral activity against fish nodavirus. Fish Shellfish Immunol. 2010, 28, 434–439. [Google Scholar] [CrossRef]
  170. Rajanbabu, V.; Chen, J.Y. Antiviral function of tilapia hepcidin 1–5 and its modulation of immune-related gene expressions against infectious pancreatic necrosis virus (IPNV) in Chinook salmon embryo (CHSE)-214 cells. Fish Shellfish Immunol. 2011, 30, 39–44. [Google Scholar] [CrossRef]
  171. Cai, L.; Cai, J.J.; Liu, H.P.; Fan, D.Q.; Peng, H.; Wang, K.J. Recombinant medaka (Oryzias melastigmus) pro-hepcidin: Multifunctional characterization. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2012, 161, 140–147. [Google Scholar] [CrossRef]
  172. Liu, H.; Trinh, T.L.; Dong, H.; Keith, R.; Nelson, D.; Liu, C. Iron regulator hepcidin exhibits antiviral activity against hepatitis C virus. PLoS One 2012, 7, e46631. [Google Scholar]
  173. Hocquellet, A.; le Senechal, C.; Garbay, B. Importance of the disulfide bridges in the antibacterial activity of human hepcidin. Peptides 2012, 36, 303–307. [Google Scholar] [CrossRef]
  174. Chen, J.Y.; Lin, W.J.; Lin, T.L. A fish antimicrobial peptide, tilapia hepcidin TH2–3, shows potent antitumor activity against human fibrosarcoma cells. Peptides 2009, 30, 1636–1642. [Google Scholar] [CrossRef]
  175. Chang, W.T.; Pan, C.Y.; Rajanbabu, V.; Cheng, C.W.; Chen, J.Y. Tilapia (Oreochromis mossambicus) antimicrobial peptide, hepcidin 1–5, shows antitumor activity in cancer cells. Peptides 2011, 32, 342–352. [Google Scholar] [CrossRef]
  176. Pan, C.Y.; Peng, K.C.; Lin, C.H.; Chen, J.Y. Transgenic expression of tilapia hepcidin 1–5 and shrimp chelonianin in zebrafish and their resistance to bacterial pathogens. Fish Shellfish Immunol. 2011, 31, 275–285. [Google Scholar] [CrossRef]
  177. Hsieh, J.C.; Pan, C.Y.; Chen, J.Y. Tilapia hepcidin (TH)2-3 as a transgene in transgenic fish enhances resistance to Vibrio vulnificus infection and causes variations in immune-related genes after infection by different bacterial species. Fish Shellfish Immunol. 2010, 29, 430–439. [Google Scholar] [CrossRef]
  178. Rajanbabu, V.; Pan, C.Y.; Lee, S.C.; Lin, W.J.; Lin, C.C.; Li, C.L.; Chen, J.Y. Tilapia hepcidin 2-3 peptide modulates lipopolysaccharide-induced cytokines and inhibits tumor necrosis factor-alpha through cyclooxygenase-2 and phosphodiesterase 4D. J. Biol. Chem. 2010, 285, 30577–30586. [Google Scholar]
  179. Rajanbabu, V.; Chen, J.Y. The antimicrobial peptide, tilapia hepcidin 2-3, and PMA differentially regulate the protein kinase C isoforms, TNF-alpha and COX-2, in mouse RAW264.7 macrophages. Peptides 2011, 32, 333–341. [Google Scholar] [CrossRef]
  180. Ganz, T.; Nemeth, E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematol. Am. Soc. Hematol. Educ. Program. 2011, 2011, 538–542. [Google Scholar] [CrossRef]
  181. Fraenkel, P.G.; Gibert, Y.; Holzheimer, J.L.; Lattanzi, V.J.; Burnett, S.F.; Dooley, K.A.; Wingert, R.A.; Zon, L.I. Transferrin-a modulates hepcidin expression in zebrafish embryos. Blood 2009, 113, 2843–2850. [Google Scholar] [CrossRef]
  182. Chen, J.; Shi, Y.H.; Li, M.Y. Changes in transferrin and hepcidin genes expression in the liver of the fish Pseudosciaena crocea following exposure to cadmium. Arch. Toxicol. 2008, 82, 525–530. [Google Scholar] [CrossRef]
  183. Tomasinsig, L.; Zanetti, M. The cathelicidins—Structure, function and evolution. Curr. Protein Pept. Sci. 2005, 6, 23–34. [Google Scholar] [CrossRef]
  184. Shinnar, A.E.; Butler, K.L.; Park, H.J. Cathelicidin family of antimicrobial peptides: Proteolytic processing and protease resistance. Bioorg. Chem. 2003, 31, 425–436. [Google Scholar] [CrossRef]
  185. Maier, V.H.; Dorn, K.V.; Gudmundsdottir, B.K.; Gudmundsson, G.H. Characterisation of cathelicidin gene family members in divergent fish species. Mol. Immunol. 2008, 45, 3723–3730. [Google Scholar] [CrossRef]
  186. Broekman, D.C.; Frei, D.M.; Gylfason, G.A.; Steinarsson, A.; Jornvall, H.; Agerberth, B.; Gudmundsson, G.H.; Maier, V.H. Cod cathelicidin: Isolation of the mature peptide, cleavage site characterisation and developmental expression. Dev. Comp. Immunol. 2011, 35, 296–303. [Google Scholar] [CrossRef]
  187. Bridle, A.; Nosworthy, E.; Polinski, M.; Nowak, B. Evidence of an antimicrobial-immunomodulatory role of Atlantic salmon cathelicidins during infection with Yersinia ruckeri. PLoS One 2011, 6, e23417. [Google Scholar]
  188. Maier, V.H.; Schmitt, C.N.; Gudmundsdottir, S.; Gudmundsson, G.H. Bacterial DNA indicated as an important inducer of fish cathelicidins. Mol. Immunol. 2008, 45, 2352–2358. [Google Scholar] [CrossRef]
  189. Broekman, D.C.; Guethmundsson, G.H.; Maier, V.H. Differential regulation of cathelicidin in salmon and cod. Fish Shellfish Immunol. 2013, 35, 532–538. [Google Scholar] [CrossRef]
  190. Costa, M.M.; Maehr, T.; Diaz-Rosales, P.; Secombes, C.J.; Wang, T. Bioactivity studies of rainbow trout (Oncorhynchus mykiss) interleukin-6: Effects on macrophage growth and antimicrobial peptide gene expression. Mol. Immunol. 2011, 48, 1903–1916. [Google Scholar] [CrossRef]
  191. Hong, S.; Li, R.; Xu, Q.; Secombes, C.J.; Wang, T. Two types of TNF-alpha exist in teleost fish: Phylogeny, expression, and bioactivity analysis of type-II TNF-alpha3 in rainbow trout oncorhynchus mykiss. J. Immunol. 2013, 191, 5959–5972. [Google Scholar] [CrossRef]
  192. Shewring, D.M.; Zou, J.; Corripio-Miyar, Y.; Secombes, C.J. Analysis of the cathelicidin 1 gene locus in Atlantic cod (Gadus morhua). Mol. Immunol. 2011, 48, 782–787. [Google Scholar] [CrossRef]
  193. De Bruijn, I.; Belmonte, R.; Anderson, V.L.; Saraiva, M.; Wang, T.; van West, P.; Secombes, C.J. Immune gene expression in trout cell lines infected with the fish pathogenic oomycete Saprolegnia parasitica. Dev. Comp. Immunol. 2012, 38, 44–54. [Google Scholar] [CrossRef]
  194. Chettri, J.K.; Raida, M.K.; Kania, P.W.; Buchmann, K. Differential immune response of rainbow trout (Oncorhynchus mykiss) at early developmental stages (larvae and fry) against the bacterial pathogen Yersinia ruckeri. Dev. Comp. Immunol. 2012, 36, 463–474. [Google Scholar] [CrossRef]
  195. Choi, K.Y.; Chow, L.N.; Mookherjee, N. Cationic host defence peptides: Multifaceted role in immune modulation and inflammation. J. Innate Immun. 2012, 4, 361–370. [Google Scholar]
  196. Park, C.B.; Kim, M.S.; Kim, S.C. A novel antimicrobial peptide from Bufo bufo gargarizans. Biochem. Biophys. Res. Commun. 1996, 218, 408–413. [Google Scholar] [CrossRef]
  197. Parseghian, M.H.; Luhrs, K.A. Beyond the walls of the nucleus: The role of histones in cellular signaling and innate immunity. Biochem. Cell Biol. 2006, 84, 589–604. [Google Scholar] [CrossRef]
  198. Noga, E.J.; Ullal, A.J.; Corrales, J.; Fernandes, J.M. Application of antimicrobial polypeptide host defenses to aquaculture: Exploitation of downregulation and upregulation responses. Comp. Biochem. Physiol. Part D Genomics Proteomics 2011, 6, 44–54. [Google Scholar] [CrossRef]
  199. Robinette, D.; Wada, S.; Arroll, T.; Levy, M.G.; Miller, W.L.; Noga, E.J. Antimicrobial activity in the skin of the channel catfish Ictalurus punctatus: Characterization of broad-spectrum histone-like antimicrobial proteins. Cell. Mol. Life Sci. 1998, 54, 467–475. [Google Scholar] [CrossRef]
  200. Robinette, D.W.; Noga, E.J. Histone-like protein: A novel method for measuring stress in fish. Dis. Aquat. Org. 2001, 44, 97–107. [Google Scholar] [CrossRef]
  201. Burrowes, O.J.; Hadjicharalambous, C.; Diamond, G.; Lee, T.C. Evaluation of antimicrobial spectrum and cytotoxic activity of pleurocidin for food applicaitons. J. Food Sci. 2004, 69, 66–71. [Google Scholar]
  202. Bals, R.; Goldman, M.J.; Wilson, J.M. Mouse b-defensin 1 is a salt-sensitive antimicrobial peptide present in epithelia of the lung and urogenital tract. Infect. Immun. 1998, 66, 1225–1232. [Google Scholar]
  203. Lee, J.Y.; Yang, S.T.; Lee, S.K.; Jung, H.H.; Shin, S.Y.; Hahm, K.S.; Kim, J.I. Salt-resistant homodimeric bactenecin, a cathelicidin-derived antimicrobial peptide. FEBS J. 2008, 275, 3911–3920. [Google Scholar] [CrossRef]
  204. Tomita, T.; Hitomi, S.; Nagase, T.; Matsui, H.; Matsuse, T.; Kimura, S.; Ouchi, Y. Effect of ions on antibacterial activity of human beta defensin 2. Microbiol. Immunol. 2000, 44, 749–754. [Google Scholar] [CrossRef]
  205. Subramanian, S.; Ross, N.W.; MacKinnon, S.L. Myxinidin, a novel antimicrobial peptide from the epidermal mucus of hagfish, Myxine glutinosa L. Mar. Biotechnol. (N. Y.) 2009, 11, 748–757. [Google Scholar] [CrossRef]
  206. Olli, S.; Rangaraj, N.; Nagaraj, R. Effect of selectively introducing arginine and D-amino acids on the antimicrobial activity and salt sensitivity in analogs of human Beta-defensins. PLoS One 2013, 8, e77031. [Google Scholar]
  207. Mai, J.; Tian, X.L.; Gallant, J.W.; Merkley, N.; Biswas, Z.; Syvitski, R.; Douglas, S.E.; Ling, J.; Li, Y.H. A novel target-specific, salt-resistant antimicrobial peptide against the cariogenic pathogen Streptococcus mutans. Antimicrob. Agents Chemother. 2011, 55, 5205–5213. [Google Scholar] [CrossRef]
  208. Wu, S.P.; Huang, T.C.; Lin, C.C.; Hui, C.F.; Lin, C.H.; Chen, J.Y. Pardaxin, a fish antimicrobial peptide, exhibits antitumor activity toward murine fibrosarcoma in vitro and in vivo. Mar. Drugs 2012, 10, 1852–1872. [Google Scholar] [CrossRef]
  209. Wang, W.; Tao, R.; Tong, Z.; Ding, Y.; Kuang, R.; Zhai, S.; Liu, J.; Ni, L. Effect of a novel antimicrobial peptide chrysophsin-1 on oral pathogens and Streptococcus mutans biofilms. Peptides 2012, 33, 212–219. [Google Scholar] [CrossRef]
  210. Tao, R.; Tong, Z.; Lin, Y.; Xue, Y.; Wang, W.; Kuang, R.; Wang, P.; Tian, Y.; Ni, L. Antimicrobial and antibiofilm activity of pleurocidin against cariogenic microorganisms. Peptides 2011, 32, 1748–1754. [Google Scholar] [CrossRef]
  211. Pan, C.Y.; Rajanbabu, V.; Chen, J.Y.; Her, G.M.; Nan, F.H. Evaluation of the epinecidin-1 peptide as an active ingredient in cleaning solutions against pathogens. Peptides 2010, 31, 1449–1458. [Google Scholar] [CrossRef]
  212. Choi, H.; Lee, D.G. The influence of the N-terminal region of antimicrobial peptide pleurocidin on fungal apoptosis. J. Microbiol. Biotechnol. 2013, 23, 1386–1394. [Google Scholar] [CrossRef]
  213. Luders, T.; Birkemo, G.A.; Fimland, G.; Nissen-Meyer, J.; Nes, I.F. Strong synergy between a eukaryotic antimicrobial peptide and bacteriocins from lactic acid bacteria. Appl. Environ. Microbiol. 2003, 69, 1797–1799. [Google Scholar] [CrossRef]
  214. Patrzykat, A.; Zhang, L.; Mendoza, V.; Iwama, G.K.; Hancock, R.E. Synergy of histone-derived peptides of coho salmon with lysozyme and flounder pleurocidin. Antimicrob. Agents Chemother. 2001, 45, 1337–1342. [Google Scholar] [CrossRef]
  215. Ivanov, I.E.; Morrison, A.E.; Cobb, J.E.; Fahey, C.A.; Camesano, T.A. Creating antibacterial surfaces with the peptide chrysophsin-1. ACS Appl. Mater. Interfaces 2012, 4, 5891–5897. [Google Scholar] [CrossRef]
  216. Pan, C.Y.; Lee, S.C.; Rajanbabu, V.; Lin, C.H.; Chen, J.Y. Insights into the antibacterial and immunomodulatory functions of tilapia hepcidin (TH)2–3 against Vibrio vulnificus infection in mice. Dev. Comp. Immunol. 2012, 36, 166–173. [Google Scholar] [CrossRef]
  217. Souza, A.L.; Diaz-Dellavalle, P.; Cabrera, A.; Larranaga, P., Dalla-Rizza; de-Simone, S.G. Antimicrobial activity of pleurocidin is retained in Plc-2, a C-terminal 12-amino acid fragment. Peptides 2013, 45, 78–84. [Google Scholar] [CrossRef]
  218. Choi, H.; Lee, D.G. Antimicrobial peptide pleurocidin synergizes with antibiotics through hydroxyl radical formation and membrane damage, and exerts antibiofilm activity. Biochim. Biophys. Acta 2012, 1820, 1831–1838. [Google Scholar] [CrossRef]
  219. Som, A.; Vemparala, S.; Ivanov, I.; Tew, G.N. Synthetic mimics of antimicrobial peptides. Biopolymers 2008, 90, 83–93. [Google Scholar] [CrossRef]
  220. Beckloff, N.; Laube, D.; Castro, T.; Furgang, D.; Park, S.; Perlin, D.; Clements, D.; Tang, H.; Scott, R.W.; Tew, G.N.; et al. Activity of an antimicrobial peptide mimetic against planktonic and biofilm cultures of oral pathogens. Antimicrob. Agents Chemother. 2007, 51, 4125–4132. [Google Scholar] [CrossRef]
  221. Hua, J.; Yamarthy, R.; Felsenstein, S.; Scott, R.W.; Markowitz, K.; Diamond, G. Activity of antimicrobial peptide mimetics in the oral cavity: I. Activity against biofilms of Candida albicans. Mol. Oral Microbiol. 2010, 25, 418–425. [Google Scholar] [CrossRef]
  222. Hua, J.; Scott, R.W.; Diamond, G. Activity of antimicrobial peptide mimetics in the oral cavity: II. Activity against periopathogenic biofilms and anti-inflammatory activity. Mol. Oral Microbiol. 2010, 25, 426–432. [Google Scholar] [CrossRef]
  223. Hancock, R.E.; Nijnik, A.; Philpott, D.J. Modulating immunity as a therapy for bacterial infections. Nat. Rev. Microbiol. 2012, 10, 243–254. [Google Scholar]
  224. Terova, G.; Forchino, A.; Rimoldi, S.; Brambilla, F.; Antonini, M.; Saroglia, M. Bio-Mos: An effective inducer of dicentracin gene expression in European sea bass (Dicentrarchus labrax). Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2009, 153, 372–377. [Google Scholar] [CrossRef]
  225. Chang, C.I.; Pleguezuelos, O.; Zhang, Y.A.; Zou, J.; Secombes, C.J. Identification of a novel cathelicidin gene in the rainbow trout, Oncorhynchus mykiss. Infect. Immun. 2005, 73, 5053–5064. [Google Scholar] [CrossRef]
  226. Sung, W.S.; Lee, J.; Lee, D.G. Fungicidal effect and the mode of action of piscidin 2 derived from hybrid striped bass. Biochem. Biophys. Res. Commun. 2008, 371, 551–555. [Google Scholar] [CrossRef]
  227. Wang, Y.D.; Kung, C.W.; Chi, S.C.; Chen, J.Y. Inactivation of nervous necrosis virus infecting grouper (Epinephelus coioides) by epinecidin-1 and hepcidin 1-5 antimicrobial peptides, and downregulation of Mx2 and Mx3 gene expressions. Fish Shellfish Immunol. 2010, 28, 113–120. [Google Scholar] [CrossRef]

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Masso-Silva, J.A.; Diamond, G. Antimicrobial Peptides from Fish. Pharmaceuticals 2014, 7, 265-310.

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Masso-Silva JA, Diamond G. Antimicrobial Peptides from Fish. Pharmaceuticals. 2014; 7(3):265-310.

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Masso-Silva, Jorge A., and Gill Diamond. 2014. "Antimicrobial Peptides from Fish" Pharmaceuticals 7, no. 3: 265-310.

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