list all the advantage, disadvantage, and the method for all AMPs peptides

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timer Asked: Mar 27th, 2017

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from these papers below write a summary make sure the include all the important point dont pilgrism and do it in this patern

List all the AMPs from literatures and discuss why againin-2 the one for your study.

Follow the format of Prospectus.

Objectives:

Hypothesis:

Methods:


make sure to include all the important point dont pilgrims



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INTERNATIONAL JOURNAL OF ONCOLOGY 46: 2181-2193, 2015 CecropinXJ inhibits the proliferation of human gastric cancer BGC823 cells and induces cell death in vitro and in vivo YAN-LING WU, LI-JIE XIA, JIN-YAO LI and FU-CHUN ZHANG Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Tianshan, Urumqi 830046, P.R. China Received December 19, 2014; Accepted February 5, 2015 DOI: 10.3892/ijo.2015.2933 Abstract. We have shown that an antimicrobial peptide (AMP) cecropinXJ isolated from the larvae of Bombyx mori selectively inhibits the proliferation of cancer cells. However, the mechanism remains to be determined. In the present study, we examined the antitumor activity of cecropinXJ against human gastric cancer BGC823 cells and explored the mechanism. The results showed that cecropinXJ inhibited the growth of gastric cancer BGC823 cells in vitro and in vivo. MTT and colony formation assays indicated that cecropinXJ suppressed cell proliferation and reduced colony formation of BGC823 cells in a dose- and time-dependent manner, but without inhibitory effect on normal gastric epithelia GES-1 cells. S-phase arrest in BGC823 cells was observed after treatment with cecropinXJ. Annexin V/PI staining suggested that cecropinXJ induced both early and late phases of apoptosis through activation of mitochondrial-mediated caspase pathway, upregulation of Bax expression and downregulation of Bcl-2 expression. Additionally, cecropinXJ treatment increased reactive oxygen species (ROS) production, disrupted the mitochondrial membrane potential (Δψm) and led to release of cytochrome c. Importantly, in vivo study showed that cecropinXJ significantly prevented the growth of xenograft tumor in the BGC823-bearing mice, possibly mediated by the induction of apoptosis and inhibition of angiogenesis. These results suggest that cecropinXJ may be a promising therapeutic candidate for the treatment of gastric cancer. Correspondence to: Professor Fu-Chun Zhang, Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, 666 Shengli Road, Tianshan, Urumqi 830046, P.R. China E-mail: zfcxju@xju.edu.cn Abbreviations: AMPs, antimicrobial peptides; ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B Key words: cecropinXJ, gastric cancer, antitumor, proliferation, apoptosis, mitochondrial-mediated pathway, angiogenesis Introduction Gastric cancer is one of the most common malignant tumors, >70% of new cases and deaths occur in developing countries each year (1). In China, the incidence and mortality rate of gastric cancer are increasing. Although there are distinct discrepancies in diagnosis, prognosis, and treatment efficacy for gastric cancer patients, the 5-year survival rate of gastric cancer is generally 3.3 mol% corresponding to > 10 wt.%) neutron in-plane scattering on mechanically aligned membrane systems indicates the presence of water filled cavities, which resemble ‘wormholes’ [47,59]. The model thus postulates that peptides and lipid form together well-defined pores [60]. The arguments in favour or contradicting such a mechanism have been discussed in considerable detail previously [21,61]. 1.2. Carpet model Based on experimental results obtained with the antibiotic peptide dermaseptin the carpet model has been proposed [19,22,62]. This 34-residue antibiotic peptide is rich in lysines and adopts an amphipathic α-helix (residues 1–27). It thereby resembles cecropins and magainins for which an in-plane alignment had been demonstrated [63,64]. The peptide partitions into acidic and zwitterionic membranes [62]. In the presence of negatively charged lipids and at high peptide concentrations dermaseptin is located at the membrane surface and it has been suggested to self-associate in a ‘carpet-like’ manner (Fig. 1B, back). The model further suggests that the membrane breaks into pieces when a threshold concentration of peptide is reached [65]. The presence of negatively charged lipids helps in the formation in a dense peptide carpet, as they help to reduce the repulsive electrostatic forces between positively charged peptides. Whereas the in-plane orientation of these peptides reflects the detergent-like properties of these amphipathic peptides, the 1531 carpet model describes the lysis of the membranes at high local peptide concentrations and reflects the morphological changes of the membrane after a threshold concentration at the membrane surface is reached (Fig. 2). Although high peptide densities have been observed at the surface of bacterial cells, the concentrations at the membrane itself remain a matter of speculation [66]. Furthermore, membrane-activities have been demonstrated at reduced peptide-to-lipid ratios. Indeed comparatively low peptide-to-lipid ratios are needed to dissipate the ionic gradient across cell membranes or to develop antibiotic activity [25,37,67]. Notably, it has been speculated that small openings are sufficient for ion release concomitantly with inhibition of respiration [25] when at the same time bigger pores and higher peptide-to-lipid ratios are required for osmolysis of red blood cells. In a similar manner single-channel recordings of cecropin or magainin require small amounts of peptide within the membrane as otherwise lysis occurs [55,56,68]. We therefore prefer to describe the activities of these peptides by a more general model which is based on their detergent-like properties [69–71]. 1.3. The ‘detergent-like’ model Represents the most generally applicable explanation for the membrane-activities of amphiphiles. The model is based on the intercalation of these molecules into the bilayer (Fig. 1A). Thereby, the nature of the molecules such as charge and hydrophobic volume strongly contribute to the variety of actions observed and the lipid polymorphism induced [72]. The interaction of detergents with lipid membranes in particular above the critical micelle concentration (cmc), where the molecules exist in their aggregated, micellar state is rather complex. However, it has to be noted that antimicrobial peptides can also exist as oligomers (Fig. 1A, top) and thus may exhibit different behaviour as compared to the monomeric peptides (see below). Let us consider those general features of detergent– lipid interactions, which are more related to the action of antimicrobial peptides. Whereas detergents at very low detergent-to-lipid ratios can have a neutral effect on model membranes, or can even result in their stabilization [73,74], openings might form temporarily at intermediate concentrations, and membrane disintegration becomes apparent at higher peptide-to-lipid ratios (Figs. 1B and 2). Disintegration of the bilayer takes into account the loss of the membrane barrier, dissipation of the transmembrane electrochemical gradient, loss of cytoplasmic constituents and concomitantly interference with the energy metabolism of living cells, all being observed also with antimicrobial peptides. However, it remains possible that, depending on the peptide and membrane composition, the peptides merely form small and transient openings (Figs. 1A and 2) which suffice for the diffusion of smaller molecules, including the peptides themselves in and out of the cell interior. The mechanism by which antimicrobial and cytolytic peptides finally damage the membrane will be determined by the peptide and lipid structure [42]. The step-wise changes in conductivity that have been observed for magainin 2 [55–57] or for cecropins [75] are 1532 B. Bechinger, K. Lohner / Biochimica et Biophysica Acta 1758 (2006) 1529–1539 Fig. 2. This figure shows a schematic phase diagram of antibiotic peptide/phospholipid mixtures. A variety of macroscopic phases are obtained as a function of peptide/ lipid ratios and lipid composition. Here two lipids with different molecular shapes are mixed and their effect on the macroscopic phase transition in the presence of antibiotic peptides is shown. For a complete description of antibiotic activities other parameters such as temperature, pH, or cholesterol concentration would have to be considered. puzzling observations, which are on first view difficult to reconcile with an alignment of these peptide helices along the membrane interface. Interestingly, however, step-wise conductivity increases have also been observed in the presence of detergents [76,77], in pure lipid membranes [78–80], or when small unilamellar phospholipid vesicles are added to planar lipid bilayers [81]. On a molecular level one could thus imagine that the temporal and local fluctuations of the peptide/detergent density, related to their lateral and translational diffusion along interfacial localizations, causes stochastic accumulations of peptide/detergent in time and space. When high enough local densities are reached a decrease in ohmic resistance occurs [21]. Alternatively, electroporation of the membrane has been suggested for NK-lysine an amphipathic helical peptide lying on the surface of the membrane. In this case the high local electric fields are sufficient for transient pore formation [82]. An interesting feature of the detergent-like model is the potential aggregation of the peptides into micelles in aqueous solution (Fig. 1A, top), whereby an equilibrium between monomeric peptides and peptide aggregates has to be taken into account that will result in concentration dependent effects. For example, tetrameric aggregates have been observed for melittin under specific conditions [83] and larger aggregates depending on pH and peptide concentration have been reported for δ-lysin [84,85]. Self-assembly of peptides was also observed for natural and synthetic acylated antimicrobial peptides [86– 88]. Such peptide micelles might interact with the lipid bilayer, e.g. by carrying away lipid molecules which would also result in transient openings. On the other hand such peptide micelles could insert (or form) in the lipid bilayer (Fig. 1A), thereby forming structures that resemble pores without, however, being well defined in shape or size [89]. The lipopeptaibol trichogin B. Bechinger, K. Lohner / Biochimica et Biophysica Acta 1758 (2006) 1529–1539 GA IV isolated from the soil fungus Trichoderma longibrachiatum [90] may be an example for such a mechanism. Leakage and light scattering experiments suggest that within the explored concentration range membrane perturbation of this peptide is due to pore formation of the peptide aggregates and not to micellization [88]. Furthermore, the ability to selfassociate in aqueous medium may be important for target cell selectivity [86,91]. The role of pre-assembly was tested using monomeric diastereomeric cationic peptides and their covalently linked pentameric bundles [92]. In contrast to the peptide aggregates that expressed similar potent antifungal and high antimicrobial activity as well as haemolytic activity independent on peptide length, the monomeric peptides showed length dependent antimicrobial activity and were devoid of haemolytic activity. A complete description of the peptide–membrane interactions and the resulting membrane morphologies would need to take into account a wide variety of parameters and conditions. These include the peptide-to-lipid ratio, the detailed membrane composition, temperature, hydration and buffer composition. As with detergents this can be done by establishing phase diagrams (Fig. 2). Notably, the detergent-like properties of amphipathic peptides are not in contradiction but include the above mentioned wormhole and carpet models, in fact these latter models should be considered ‘special cases’ where the conditions are such that these kind of supramolecular structures are observed within a much more complex phase diagram. It therefore seems tedious to argue about the ‘correct model’ as all of them might occur depending on the detailed conditions. Notably, the extensive plasticity of peptide/detergent–lipid complexes opens up the possibility that a peptide induces a certain macromolecular structure when interacting with the membranes of one organism, but a different one when interacting with another species. On the other hand the mutagenesis of the peptide sequence causes shifts in the phase diagram and therefore also affects the biological mechanisms. In the following we have assembled a number of experimental results which illustrate the detergent-like properties of amphipathic peptides. When the permeability changes of membranes are investigated the leakage of fluorescence dyes takes place at magainin concentrations of approximately 3 mol % which is equivalent to 81 g/mole lipid. This latter value is very similar to those observed for the permeability increases in the presence of the detergents Triton-X100 and octyl glucoside [76,93]. Furthermore, the macroscopic phase properties as monitored by proton-decoupled 31P solid-state NMR spectroscopy exhibits interesting parallels when amphipathic peptides, short chain lipids, lysolipids and detergents are compared to each other [70,71]. Pore formation due to the increased membrane tension has also been suggested for other amphipathic helical peptides [94] and cecropin B activity on bacterial cells was compared to that of quartenary detergents [95]. When the molecular shape of amphipathic helices and detergents are compared to each other it becomes evident that, when intercalated into a lipid bilayer, neither of them fills the volume at the level of the fatty acyl chains and in the lipid head 1533 group region equally well (Fig. 3). Whereas the peptide acts as a spacer at the level of the lipid headgroup it does not occupy the corresponding volume at the level of the fatty acyl chains creating a void in the hydrophobic region of the membrane bilayer [21,42,70]. This parallels the behaviour described for charged alkyl compounds, which are one of the simplest, among the variety of detergent molecules being also anchored at the lipid–water interface with their polar headgroup (for a review see [72]). Systematic studies using PC model membranes revealed that molecules with short alkyl chains (C6–12) are located in the more ordered plateau region of the acyl chain region of the phospholipids inducing voids below their terminal methyl groups. Since the formation of such free volume is energetically unfavourable [96], the hydrocarbon chains must eliminate these voids by chain bends, increased trans-gauche isomerization [97] or chain interdigitation as found for very short chain amphiphiles like alcohols (e.g. [98]) thus affecting the phospholipids' acyl chain packing. Similar effects were observed also for non-ionic surfactants such as N-alkyl-N,Ndimethylamine-N-oxides [99] which were shown to exhibit antimicrobial activity [100,101]. Increasing the size of the polar headgroup would lead to a molecular shape of the compound that can be described by a cone which would further promote the formation of voids. Amphipathic peptides thus exhibit effects similar to those observed with cone- or wedge-shaped molecules. Intercalation of peptides into the membrane interface therefore creates voids Fig. 3. The molecular shape of lipids and in-plane oriented amphipathic peptides is illustrated. Whereas lipids such as POPC are considered to exhibit a cylindrical overall molecular shape, the decreased size of the PE head group results in an inverted cone structure. On the other hand monoacyl-phospholipids, detergents or in-plane oriented amphipathic peptides predominantly fill the space at the head group region/lipid interface thereby resembling a cone. This model should be considered only as a first order conceptual approach to the real situation. Notably, the ‘molecular shape’ of the amphipathic molecule reflects the geometrical as well as the interaction space of these molecules. Therefore charge and hydrogen interactions between the lipids and the peptide have to be considered. Furthermore, in-plane oriented peptides can reside as monomers or as side-by-side oligomers in the membrane (e.g. [125]). 1534 B. Bechinger, K. Lohner / Biochimica et Biophysica Acta 1758 (2006) 1529–1539 in the hydrophobic membrane region and in addition imposes curvature strain on the lipid bilayer [102]. On the other hand the head group of phosphatidylethanolamine occupies a smaller area in the interfacial region when compared to the hydrophobic membrane interior. Therefore, this lipid represents an inverted cone structure. Due to their shape, mixing cone and invertedcone molecules release the strain and lipid bilayers that exhibit a tendency to form hexagonal phases e.g. at increased temperatures are stabilized by the insertion of amphipathic peptides [37,103]. Stabilization of phosphatidylethanolamine bilayers was also observed for a number of detergents such as Triton X100, deoxycholate or octylglucoside which exhibit a cone shaped molecular geometry [73]. Considering the large variety of conditions it seems impossible to establish a complete phase diagram for peptide– lipid interactions. However, over the years a considerable amount of data has been collected for melittin. Its overall amphipathic character composed of a cluster of cationic amino acids at the C-terminus and a stretch of hydrophobic amino acids, resembles the features of many detergents being characterized by a polar/charged headgroup and a hydrophobic moiety. This peptide is too lytic to be used as an antibiotic but it can nevertheless illustrate the complexity of such interactions. There is experimental evidence that melittin inserts into the membrane interface [104]. The possibility remains that a small proportion also adopts a transmembrane alignment in the presence of POPC but not POPG [105,106]. Melittin was found to exhibit pronounced effects on the phase behaviour of DPPC already at very low peptide concentrations (lipid-to-peptide molar ratio of 1000/1) [107,108]. A similar concentration dependent behaviour was reported for the detergent cetyltrimethylammonium chloride [74]. Since these effects cannot be accounted for only by local perturbations around the sites of interaction, long range effects beyond the immediate neighbourhood of the incorporated peptide must be involved. Therefore, it was suggested that the peptide-affected domains create line defects in an ordered lipid lattice [104]. Such a defect-like action at low peptide concentrations may be explained by shifting the percolation balance of coexisting gel- and fluid-like states [109]. However, at high melittin concentrations (lipid-to-peptide molar ratio of 15/1), diskshaped particles were found for the DMPC/melittin mixture [110,111], suggesting a detergent-like solubilization of the membrane under these experimental conditions. Below the gel to fluid phase transition of the pure lipid the presence of intermediate amounts of melittin (< 5mol%) results in the reversible disintegration of the bilayer into disks (cf. Fig. 2) [110,112,113]. It should be noted that some of the mixed peptide/phospholipid phases exhibit meta-stable properties. Therefore in the presence of melittin or magainins the transitions between one phase to another might take many hours even months [70,114, A. Ramamoorthy, personal communication]. The idea of gradual membrane disintegration is also supported by data gained on δ-lysin/PC multilamellar vesicles [115,116]. This peptide from S. aureus is, like melittin, 26 residues in size and surface-active. It lyses erythrocytes and many other types of mammalian cells, as well as intracellular organelles and bacterial protoplasts [117]. Similarly to the DPPC/melittin system, the addition of small quantities (lipid-topeptide molar ratio ≥ 1000/1) of peptide had only minor but significant effects on the phase behaviour of DPPC or DMPC bilayers. Increasing the peptide concentration to molar lipid-topeptide ratios lower than 125/1 promoted the formation of two populations of lipid particles, which could be separated by centrifugation. Thereby, small-angle X-ray scattering measurements confirmed that the pellet consists of multilamellar vesicles, while disk-shaped lipid–peptide aggregates were found in the supernatant, the predominant aggregate form at high peptide concentration [116]. Interestingly, the structural parameters of the DMPC/δ-lysin discoidal aggregates (diameter of about 14 nm and a bilayer thickness of 5.2nm) correspond well with the hydrodynamic radius of 6.9 nm estimated for the disk-shape particles of DMPC/melittin from gel-filtration experiments [110]. Modelling of the X-ray data suggested a peptide ring of about 1 nm thickness surrounding the discoidal lipid bilayer (illustrated in Fig. 2). These data support the idea that lytic peptides like detergents may have concentrationdependent effects on the membrane structure inducing bilayer perturbations of long-range order at low peptide concentrations and exhibiting a detergent-like solubilization of the membrane at high peptide concentrations. Pore formation, which has also been reported for δ-lysin [118], is not necessarily in contradiction to this proposal, but may either reflect a transient state or occur at distinct environmental conditions (Fig. 2). Pore formation might be particularly sensitive to the lipid class composing the membrane. Whereas melittin and δ-lysin disrupt PC bilayers into small structures, the peptides exhibit bilayerstabilizing effects when mixed with phosphatidylethanolamine membranes, which in the absence of peptide show a tendency for the inverse hexagonal phase (HII) [119]. A different behaviour is observed when melittin is inserted into charged phospholipids such as cardiolipin, DOPA or eggPG. In these cases a preference for inverted macroscopic phases is observed (HII or cubic) [120,121]. Fluorescence spectroscopy indicates that the macroscopic phase properties depend not only on the molecular shape of the lipid but also on the insertion depth of the peptide [122]. Interestingly, the presence of negative surface charge densities stabilizes PC lipid bilayers in the presence of melittin [106,111,123,124]. Thus the positioning and topology of melittin, and concomitantly its effect on membrane structure, are all strongly dependent on a wide variety of parameters that determine the local environment. Much less data are available for the peptide–lipid interactions involving antibiotic peptides. However, comparable correlations between the molecular shape of the phospholipids and macroscopic phase transitions have been observed for magainin or its analogue MSI-78 [70,71]. The peptides have been shown to be oriented parallel to the membrane surface using solid-state NMR spectroscopy [64] and MSI-78 to form antiparallel dimers, when solubilized in dodecylphosphocholine (DPC) micelles [125]. The latter observation suggests that magainin activity may be also modulated by oligomerization. Fluorescence energy transfer measurements indicate that the hydrophobic regions of B. Bechinger, K. Lohner / Biochimica et Biophysica Acta 1758 (2006) 1529–1539 magainin 2 are located approximately 10 Å from the bilayer center [126]. The peptide or its analogue MSI-78 thus acts like a wedge, which augments the curvature of the membrane. By inserting in-plane peptides into the headgroup region the bilayer packing is disturbed at an estimated radius around the peptide of approximately 50 Å resulting in a reduction in the average bilayer thickness [127–130]. A current atomic force microscopy study on DMPC bilayers and the magainin analogue MSI-78 also revealed that the membrane thickness is not reduced uniformly over the entire bilayer area [130]. Deuterium or 13C solid-state NMR measurements indicate a decrease in order parameter at the lipid bilayer interior for both magainin and MSI78 [131,132]. More recent investigations indicate that in mixed PC/PS lipid membranes cationic amphipathic peptides preferentially interact with the acidic phosphatidylserine [133,134]. A preferential interaction with the negatively charged lipid component in mixed model membranes was also observed earlier for human neutrophil peptide, HNP-2 [135], PGLa [53] or nisin [136] resulting in charge segregation. Such a behaviour can be expected because of the cationic nature of the peptides, and is typical for a large number of antimicrobial peptides, such as e.g. the α-helical peptides belonging to the magainin-family [35,137] and buforin II [138], the β-sheet peptides tachyplesin [139] and protegrin-1 [54,140], the cyclic peptides gramicidin S [141] and rhesus theta defensin, RTD-1 [142] as well as nisin Z [143]. There is also evidence that other biologically active amphipathic molecules, such as cardiotoxin [144] and synthetic peptides [145] interact with model membranes inducing lateral separation of phospholipids into co-existing domains. Additional support for the detergent-like model arises from the observation that antibiotic or model peptides too short to span the membrane exhibit channel-like activities as well [146– 153]. In particular the model is in perfect agreement with the experimentally observed in-plane orientation of amphipathic peptides [45,64,126]. The membrane lipid composition can thus have pronounced effects on the membrane-disrupting activities of amphipathic peptides. This is reflected by shifts in the borders within the peptide–membrane phase diagram or by the occurrence of different macroscopic phases when one diagram is compared to another. The lipid composition thereby modulates the sensitivity of the membrane to a given peptide [42,53,54,154]. For example, the alignment and the dynamics of the C-terminal helical domain of pardaxin are a function of the phosphatidylcholine fatty acyl chain composition [51,52]. Furthermore, cholesterol which is only present in eukaryotic cells changes the interactions of cationic peptides with the membrane [68,155]. Cholesterol affects the fluidity and the dipole potential of phospholipid membranes. Furthermore, its capacity to form hydrogen bonds with the peptide has also been suggested to reduce antibiotic activity [156]. However, recent experiments on δ-lysin showed that in ternary lipid systems mimicking mammalian cell membranes the peptide binds preferentially to the liquid-disordered domain suggesting that there is no specific interaction between δ-lysin and cholesterol and sphingomyelin, respectively, emphasizing the importance of membrane properties in lipid–peptide interactions [157]. As a result of peptide 1535 accumulation peptide aggregates may form that become orientationally ordered, which in turn may have an impact on several processes such as peptide translocation across membranes [158]. Moreover, peptide enriched lipid domains will form especially in the presence of anionic lipids that differ significantly in their local properties from the membrane bulk phase [42]. This may result in packing defects giving rise to increased membrane permeability. In addition, exclusion of certain lipids, e.g. segregation of anionic lipids, from areas of the cell membrane due to their preferential interaction with the cationic peptides may affect membrane structure and integrity [133,134]. Thus, it is evident from the discussion above that the molecular mechanism of membrane permeation and disruption obviously depends on a number of parameters such as the nature of the peptides and membrane lipids, peptide concentration and environmental conditions. Acknowledgements We are grateful to the members of our laboratories for their important contributions to this subject as well as to many friends and colleagues for ongoing discussions on this issue. 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