key: cord-0747876-qmj214tv
authors: Bellezza, Ilaria; Peirce, Matthew J.; Minelli, Alba
title: Cyclic Peptides in Neurological Disorders: The Case of Cyclo(His-Pro)
date: 2019-04-12
journal: Quorum Sensing
DOI: 10.1016/b978-0-12-814905-8.00010-1
sha: fdf3376c91559ca7269a1a31b2e67693d8439f1c
doc_id: 747876
cord_uid: qmj214tv

Communication between and within communities of cells or independent organisms is a crucial prerequisite for species survival. In response to variations in the extracellular environment, the collective behavior of cell populations can be coordinated by regulating community-level gene expression. This mechanism is strongly conserved during evolution, being shared both by bacterial communities and central nervous system cells. Notably, cyclic dipeptides (CDPs) are molecules that are implicated in these quorum sensing behaviors in both settings. Bacteria coordinate their collective behavior by producing CDPs (quorum sensing inducers) that enhance the capacity of individual members of the community to detect these signals and thus amplify the community-level response. In this review, we highlight recent data indicating that strikingly similar molecular mechanisms control communications between glial and neuronal cells to maintain homeostasis in the central nervous system, with a specific focus on the role of the thyrotropin-releasing hormone—derived CDP cyclo(His-Pro) in the protection against neurotoxic insults.

CDPs, also known as 2,5-diketopiperazines, are a family of small and biologically active molecules, mostly acting as QS effectors, that contain a family-defining CDP core/scaffold structure (Fig. 1) , and are produced by proteobacterial species as well as by humans (Bellezza et al., 2014a,b; Borthwick, 2012; Cornacchia et al., 2012; Minelli et al., 2008; Mishra et al., 2017; Prasad, 1995) . CDPs are a class of cyclic organic compounds in which the two nitrogen atoms of a piperazine 6-membered ring form amide linkages. The nomenclature of CDPs is indicated by the three-letter code for each of the two amino acids, plus a prefix to designate the absolute configuration (e.g., cyclo(L-Xaa-L-Yaa)). CDPs can be configured as both cis and trans-isoforms, but cis configurations are predominant (Eguchi and Kakuta, 1974) . Various amino acid modifications confer diversified chemical and biological functions. CDPs exhibit better biological activity than their linear counterparts due to their higher stability, protease resistance, and conformational rigidity, all factors that increase their ability to specifically interact with biological targets (Liskamp et al., 2011; Menegatti et al., 2013) . They constitute a large class of secondary metabolites produced by bacteria, fungi, plants, and animals (Borthwick, 2012; Giessen and Marahiel, 2014; Huang et al., 2010; Mishra et al., 2017; Prasad, 1995) . Indeed, approximately 90% of CDP producers are bacterial (Giessen and Marahiel, 2014) . The CDP scaffold can be synthesized either by purely chemically means using different solid phases or under reflux conditions in solution (Borthwick, 2012; Gonzalez et al., 2012) or, more naturally, by biosynthetic enzymes called nonribosomal peptide synthetases (NRPSs) and CDP synthases (CDPSs; Belin et al., 2012; Giessen and Marahiel, 2014) . Common chemical synthesis of CDPs includes the condensation of individual amino acids at high temperature. Dipeptides substituted with an amine at one terminus and an ester at the other can also spontaneously cyclize to form a CDP. However, conditions must be optimized in order to force a cyclization reaction and to limit racemization. This is the procedure most commonly used for the chemical synthesis of CDP. Cyclization of amino dipeptide esters can also be carried out under thermal conditions, normally by refluxing them in high boiling solvents such as toluene or xylene for 24 h (Borthwick, 2012) . In addition, CDPs are often products of unwanted side reactions or degradation products of oligo-and polypeptides in processed food and beverages (Borthwick and Da Costa, 2017; Prasad, 1995) . They are frequently formed during the chemical degradation of products in roasted coffee, stewed beef, and beer (Chen et al., 2009; Gautschi et al., 1997; Ginz and Engelhardt, 2000) . Nonenzymatic processes can also lead to the formation of functional CDPs in various organisms, as described for cyclo(L-His-L-Pro) (Bellezza et al., 2014a,b; Minelli et al., 2008) . In mammals, cyclo(His-Pro) (CHP) is obtained from the action of pyroglutamate aminopeptidase on the thyrotropin-releasing hormone (TRH, pGlu-His-Pro) . The resulting dipeptide is then nonenzymatically cyclized to CHP. The proline induces constraints that promote the cisconformation of the peptide bond between the histidine and the proline, thereby facilitating cyclization, which generates the CDP scaffold.

As for the enzymatic pathways of CDP formation, two unrelated biosynthetic enzyme families catalyze the formation of CDPs: NRPSs and CDPSs. It has been shown that CDP scaffolds can be synthesized by one or more specialized NRPSs, either via specific biosynthetic pathways or via the premature release of dipeptidyl intermediates during the chain elongation process. The NRPS genes for certain peptides are usually organized in one operon in prokaryotes, and in a gene cluster in eukaryotes (Schwarzer et al., 2003) . NRPSs are large modular enzymes, which simultaneously act as a template and as biosynthetic machinery. Each module is responsible for the incorporation of one amino acid into the final peptide, and can be further subdivided into the catalytic domains responsible for specific synthetic steps during peptide synthesis (Felnagle et al., 2008) . In each module, NRPSs consist of three necessary domains: an adenylation (A) domain; a thiolation (T) domain, posttranslationally modified with a 4 0 -phosphopantetheinyl (4 0 -Ppant) arm, also termed the peptidyl carrier protein (PCP) domain; and a condensation (C) domain, separated by short spacer regions of approximately 15 amino acids. The A domain selects, activates, and loads the monomer onto the PCP domain. Here, the thiol group of the 4 0 -Ppantarm of the T domain mediates the nucleophilic attack of the adenylated amino acid. Subsequent peptide bond formation between two adjacent T-bound aminoacyl intermediates is catalyzed by the C domains (Belin et al., 2012) . Another essential NRPS catalytic unit is the thioesterase (TE) domain, which is located in the C-terminus and catalyzes peptide release by either hydrolysis or macrocyclization. In addition, modification domains can be integrated into NRPS modules at different locations to modify the incorporated amino acids. Epimerization and N-methyltransferase domains catalyze the generation of D-and methylated amino acids, respectively (Koglin and Walsh, 2009; Strieker et al., 2010) . NRPSs rely not only on the 20 canonical amino acids, but also use several different building blocks, including nonproteinogenic amino acids, and this contributes to the structural diversity of nonribosomal peptides and their differential biological activities (Koglin and Walsh, 2009) . CDPs, once synthesized by NRPSs, can be further modified by tailoring enzymes, usually encoded by genes clustered with the NRPS genes. The majority of known NRPS-derived CDPs are produced by fungi, whereas few bacteria are recognized as NRPS-derived CDP producers. Many CDPs can be formed by dedicated NRPS pathways, such as brevianamide F, erythrochelin, ergotamine, roquefortine C, acetylaszonalenin, thaxtomin A, gliotoxin, and sirodesmin PL (Balibar and Walsh, 2006; Correia et al., 2003; García-Estrada et al., 2011; Gardiner et al., 2004; Healy et al., 2002; Maiya et al., 2006; Lazos et al., 2010; Yin et al., 2009) . In a few cases, CDPs can be formed by NRPSs during the synthesis of longer peptides, as truncated side products, as in the biosynthesis of cyclo(D-Phe-L-Pro) and cyclomarazine A (Gruenewald et al., 2004; Schultz et al., 2008) . Biosynthesis of CDPs can also be CDPS-mediated: CDPS are a family of tRNA-dependent peptide bond-forming enzymes that do not require amino acid charging. CDPSs share a common architecture reminiscent of the catalytic domain of class-Ic amino acid tRNA synthetases (aaRSs), such as TyrRS and TrpRS (Sauguet et al., 2011) . Both CDPSs and class-Ic aaRSs comprise well conserved Rossmann-fold domains, structural features associated with binding of nucleotides such as flavin adenine dinucleotide, nicotinamide adenine dinucleotide (NAD + ), and nicotinamide adenine dinucleotide phosphate (NADP + ), along with a helical connective polypeptide 1 (CP1) subdomain. However, class-IcaaRSs possess signature motifs involved in ATP binding (HIGH and KMSKS sequences) that are not present in CDPSs. In addition, CDPSs do not possess a distinct tRNA-binding domain, but rather contain a large patch of positively charged residues located in helix α4, which are important for the binding of aminoacyl-tRNA substrates. All these observed differences between CDPSs and their ancestral aaRSs result in unique enzymes for CDP biosynthesis. CDPSs use amino acid tRNAs as substrates to catalyze the formation of CDP peptide bonds (Belin et al., 2012; Giessen and Marahiel, 2012; Giessen et al., 2013; Gondry et al., 2009) , diverting two aminoacyl-tRNAs from their essential role in ribosomal protein synthesis for use as substrates and catalyzing the formation of the two peptide bonds required for CDP formation (Lahoud and Hou, 2010) . The synthesis process is initiated by the binding of the first aminoacyl substrate, likely involving ionic interactions between the negatively-charged ribose-phosphate tRNA backbone and the positive charges in helix α4 (Bonnefond et al., 2011; Sauguet et al., 2011) . Hence, by using aminoacyl-tRNAs as substrates, CDPSs represent a direct link between primary and secondary metabolism. The catalytic mechanism of CDPSs can be described using a ping-pong model. All CDPSs possess two surface-accessible pockets that contain active site residues important for substrate selection and catalysis. The different aminoacyl binding sites for the two aa-tRNA substrates are termed pocket 1 (P1) and pocket 2 (P2). Upon specific recognition of the first substrate, the first aminoacyl group is transferred to the conserved serine residue of P1. Here, interaction between the tRNA moiety and basic residues in the α4 helix generates an aminoacyl-enzyme intermediate (Moutiez et al., 2014) . At the same time, the aminoacyl moiety of the second aa-tRNA interacts with P2 through the α6-α7 loop. Finally, the aminoacyl-enzyme intermediate reacts with the second aa-tRNA to generate a dipeptidyl-enzyme intermediate, which undergoes intramolecular cyclization through the involvement of a conserved tyrosine, leading to the CDP scaffold as the final product. These CDPs can be modified by closely associated tailoring enzymes. There are approximately 163 putative CDPS genes identified so far, and of these, 150 are reported in bacteria, distributed among six phyla (Actinobacteria, Bacteroidetes, Chlamydiae, Cyanobacteria, Firmicutes, and Proteobacteria). Most known CDPSs are found in Actinobacteria, with 77 CDPSs reported to date. Twelve CDPSs are distributed among four eukaryotic phyla (Ascomycota, Annelida, Ciliophora, and Cnidaria), and one archaeon (Haloterrigena hispanica) CDPS has also been reported (Belin et al., 2012; Giessen and Marahiel, 2014; Tommonaro et al., 2012) . Some bacterial CDPSs have been fully characterized, such as albonoursin in Streptomyces noursei, pulcherrimin in Bacillus subtilis, and mycocyclosin in Mycobacterium tuberculosis (Belin et al., 2012; Giessen et al., 2013) .

The biosynthetic enzymes are usually physically and, as alluded to previously, transcriptionally associated with tailoring enzymes that specifically modify CDP-containing natural products. Putative tailoring enzymes that modify the initially assembled CDP scaffold can be found in almost all NRPS and CDPS gene clusters, and are responsible for introducing functional groups crucial for the biological activities of CDPs. In CDPS-dependent pathways, a large variety of different modification enzymes are found in close association with the respective CDPS genes (Belin et al., 2012; Giessen and Marahiel, 2014) , including different types of oxidoreductases, hydrolases, transferases, and ligases. The most prevalent putative tailoring enzymes in CDPS clusters are cyclic dipeptide oxidases (CDOs). CDOs are composed of two distinct small subunits that assemble into an apparent megadalton protein complex. Depending on the substrate, the CDO can sequentially perform one or two dehydrogenation reactions. The precise reaction mechanism for this has not been elucidated, although three different scenarios have been proposed: direct dehydrogenation, α-hydroxylation followed by loss of water, and imine formation with subsequent rearrangement of the enamine (Gondry et al., 2001) . Known CDOs include at least seven distinct P450 enzymes, five different types of α-ketoglutarate/FeIIdependent oxygenases, and three distinct flavin-containing mono-oxygenases. In addition to oxidoreductases, a large number of different C-, N-, and O-methyltransferases, α/β-hydrolases, peptide ligases, and acyl-CoA transferases have been found in CDPS gene clusters in which different transcription factors belonging to the LuxR and MarR families, among others, are observed. They are usually involved in regulating various processes in response to environmental stimuli like toxic chemicals and antibiotics, which may hint at the biological functions of CDPS-dependent modified CDPs (Ellison and Miller, 2006) . Regarding NRPS-dependent pathways, a similar variety of modification enzymes has been reported, and again, enzymes that modulate the oxidation of the CDP scaffold and side chains are the most numerous (Belin et al., 2012) . One distinguishing feature of fungal NRPS gene clusters is the prevalence of different prenyltransferases, which perform prenylations and reverse prenylations at various positions of tryptophan-containing CDP scaffolds (Yu et al., 2012) . Judging by the diverse set of putative modification enzymes found within NRPS and CDPS gene clusters, it is assumed that highly modified CDPs represent a diverse family of microbial natural products with varied functions.

Moreover, it is worth noting that the CDP core, besides rendering these molecules resistant to proteolysis, also enables the crossing of the intestinal barrier and blood-brain barrier (BBB; Beck et al., 2012; Teixidó et al., 2009) . Thus the combination of flexibility and stability provides the CDP molecules with biological properties and a wide array of therapeutic possibilities (Bellezza et al., 2014a,b) . The ability to inhibit plasminogen activator inhibitor-1 (PAI-1), enabling intervention in cardiovascular disease and blood clotting functions (Einholm et al., 2003) , was the first discovered biological action of CDPs, later followed by the discovery of antibacterial (Rhee, 2004) , antitumor (Nicholson et al., 2006) , antifungal, and antiviral activities (Kwak et al., 2013; Kwak et al., 2014; Mishra et al., 2017) . Korean fermented vegetable kimchi is a rich source of Pro-based CDPs that have activities against multidrug resistant bacteria (Liu et al., 2017) , and cyclo(L-Val-L-Pro) and cyclo(L-Phe-L-Pro), produced by vegetables fermented with Lactobacillus plantarum LBP-K10, can inhibit the growth of Candida albicans (Kwak et al., 2014) . Cyclo(D-Tyr-D-Phe), extracted from fermented modified nutrient broth of Bacillus sp. N strain associated with the rhabditid entomopathogenic nematode, shows significant antitumor activity against A549 cells without cytotoxicity for normal fibroblast cells (Kumar et al., 2013) . The pleiotropic actions of CDPs are reflected in their ability to bind an array of targets: by binding with high affinity to oxytocin receptors, thus acting as antagonists, CDPs can inhibit ejaculation Cl ement et al., 2013) . CDPs released by the coldwater marine sponge Geodia barretti synergistically exert chemical defense (Sj€ ogren et al., 2011) . Moreover, CHP, a catabolic product of TRH (thyrotropin releasing hormone), can control blood glucose levels Jung et al., 2011 Jung et al., , 2016 Koo et al., 2011; Lee et al., , 2013 Park et al., 2012) and, associated to zinc, has already been patented in the United States as an antidiabetic drug with no side effects in humans (Uyemura et al., 2010) .

CDPs have been isolated from marine sponges (Schmitz et al., 1983) , Gram negative ( Jayatilake et al., 1996) and Gram positive marine bacteria (Stierle et al., 1988) . Therefore, marine bacteria are a promising source for this class of bioactive compounds. It is known that marine sponges are an abundant source of novel microorganisms that produce compounds with potential pharmacologic activity . Marine sponges with their surfaces and internal spaces provide a highly specialized environmental niche containing high numbers of bacteria. They exceed the bacteria contained in seawater by two or three orders of magnitude (Engel et al., 2002; Friedrich et al., 2001) . Sponge-bacteria associations are widely distributed and evolutionarily ancient, with a direct relationship between the size and density of sponges and the content of bacterial associates. Several data suggest an advantageous coexistence of microorganisms and sponges (Proksch et al., 2002) . Autotrophy of cyanobacteria can provide host sponges with additional carbon sources and fixed nitrogen, specific associations with heterotrophic bacteria facilitate the metabolism of a wide range of organic compounds, and associated bacterial and cyanobacterial communities produce secondary metabolites that enhance the chemical defense of the host (Abbamondi et al., 2014; De Rosa et al., 2003) . There is experimental evidence that sponge-associated microflora are species-specific (Friedrich et al., 2001; Schmidt et al., 2000; and represent a stable population (Friedrich et al., 2001; capable of communicating with the sponge itself. Marine sponge-associated bacteria secrete QS signals such as N-acyl homoserine lactones (AHLs; Taylor et al., 2004) and CDPs (Tommonaro et al., 2012) . Holden et al. (1999) reported that several Gram negative bacteria produced and secreted CDPs which, in turn, can activate and/or antagonize other LuxR-based QS systems. Pseudomonas putida WCS358 can produce and secrete four CDPs, some capable of interacting with the QS LuxI and LuxR homologues (Degrassi et al., 2002) . A set of CDPs was isolated from a range of Gram negative bacteria and reported to modulate LuxR, TraR, or LasR activity in sensitive AHL biosensor strains previously considered specific for AHLs (Degrassi et al., 2002; Holden et al., 1999; Park et al., 2006) . Therefore, the capacity of QS signals generated in one organism has been demonstrated to regulate the behavior of a second organism. Thus CDPs, isolated either individually or as mixtures from culture supernatants of Pseudomonas aeruginosa, Pseudomonas fluorescens, P. putida, Pseudomonas alcaligenes, Proteus mirabilis, Enterobacter agglomerans, Vibrio vulnificus, and Citrobacter freundii, represent interspecies and cross-kingdom signals (Campbell et al., 2009) . Cyclo(D-Ala-L-Val) and cyclo(L-Pro-L-Tyr) inhibit the activity of regulatory LuxR-type proteins that are involved in AHL-dependent QS regulation (Campbell et al., 2009; Galloway et al., 2011) . In addition, the lasI-dependent QS system represses the CDP biosynthesis, and this is a determinant factor in the underlying interaction with Arabidopsis thaliana plants, since cyclo(L-Pro-L-Tyr), cyclo(L-Pro-L-Val), and cyclo(L-Pro-L-Phe) appear to mimic the biological role of auxin, a natural phytohormone (Ortiz-Castro et al., 2011) .

In the case of specific sponge-bacteria associations, associated bacteria may prosper or at least survive with sponge material. A ribosomal RNA study of axenic cell cultures of Suberites domuncula showed a 16S rRNA band specific for bacteria (Thakur et al., 2003) . The presence of D-amino acids and unusual amino acids in sponge peptides supports the microbial origin of sponge peptides (Fusetani and Matsunaga, 1993) . CDPs attributed to the sponge Tedania ignis (Schmitz et al., 1983) were produced by the associated bacterium Micrococcus sp. (Stierle et al., 1988) , and theopalauamide, a cyclic glycopeptide isolated from the sponge Theonella swinhoei, is included in uncultivable symbiont "Candidatus Entotheonella palauensis" (Schmidt et al., 2000) . In addition, several CDPs that regulate bacterial-sponge interactions have been isolated from a proteobacterium of the genus Ruegeria associated with the marine sponge S. domuncula, from strains of the genera Staphylococcus and Bacillus associated with Ircinia variabilis, and from the marine bacteria Vibrio sp. associated with the marine sponge Dysidea avara (De Rosa et al., 2003; Mitova et al., 2004) .

It is known that bacteria establish pathogenic or symbiotic relationships with their eukaryotic hosts, as in the case of P. aeruginosa, a well-known human and plant pathogen that proliferates in the rhizosphere, a narrow zone of soil influenced by root exudates. To overcome host defenses, P. aeruginosa produces toxins, adhesins, pyocyanin, and other virulence factors (Battle et al., 2008; de Abreu et al., 2014 ) by a QS mechanism in which CDPs play a pivotal role . P. aeruginosa QS is rather complex: the las and rhl systems are dependent on N-(3-oxododecanoyl)-L-homoserine lactone and N-butanoyl-L-homoserine lactone, respectively. These compounds are synthesized by the acyl-L-homoserine lactone synthases, encoded by the lasI and rhlI genes (de Kievit and Iglewski, 2000; Fuqua and Greenberg, 2002; Lee and Zhang, 2015) . A third QS system involves the 2-heptyl-3-hydroxy-4-(1H)-quinolone and 2-heptyl-4-hydroxyquinolone, encoded by the pqs gene cluster (Gallagher et al., 2002; Lee and Zhang, 2015) . All these systems connect signal transduction to transcription factors of the LysR-type, namely LasR, RhlR, and PqsR, which specifically respond to the cognate signal molecules and drive expression of hundreds of genes (Lee and Zhang, 2015) . Signaling hierarchy, upstream of the pqs and rhl systems, is further defined by the signaling molecule, 2-(2-hydroxyphenyl)-thiazole-4-carbaldehyde (IQS, also called aeruginaldehyde), which is synthesized by the ambBCDE gene cluster and plays an important role in pathogenesis via the production of pyochelin siderophores (Dandekar and Greenberg, 2013; Lee et al., 2013; Lee and Zhang, 2015) . The ambBCDE cluster encodes enzymes for L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) biosynthesis, which occurs via a nonribosomal peptide synthase (NRPS) pathway and shows toxic effects to prokaryotes and eukaryotes (Rojas Murcia et al., 2015) . By employing bioinformatics and functional approaches, González and co-workers (2017) recently identified NRPS from P. aeruginosa PAO1 wild-type (WT) strain and studied the role of CDPs in bacterial physiology and their interaction with plants. The authors showed that in mutants defective in putative MM-NRPS, the production of CDPs was altered and that these changes, although ineffective on virulence, interfered, at very high concentrations, with the QS systems by interacting with the binding site of the cognate AHL. By using a bacteria-plant interaction system (i.e., P. aeruginosa-A. thaliana co-cultivation), they observed that either the repression of root growth or the promotion of root branching exerted by selected WT and NRPS mutants was related to AHLdependent QS status and was modified by CDP levels in vivo. CDPs are also responsible for food spoilage since QS systems govern bacterial behavior in food spoilage ecosystems (Gu et al., 2013; Skandamis and Nychas, 2012) . Large yellow croaker (Pseudosciaena crocea), one of the most commercially important marine fish species in China, is highly susceptible to spoilage as a result of digestive enzymes and microbial activity within a short period of time postmortem even under refrigerated conditions. Microbial growth and its metabolism byproducts leads to the production of trimethylamines, organic acids, alcohols, sulfides, biogenic amines, aldehydes, and ketones with unpleasant and unacceptable offflavors (Gram and Dalgaard, 2002) . The microbial spoilage of chilled fish is chiefly connected with the presence of Gram negative proteolytic psychrotrophic bacteria, mainly Shewanella spp., Pseudomonas spp., and genera of the Enterobacteriaceae family (Gram and Dalgaard, 2002; Skandamis and Nychas, 2012) , each species regulating the cell-cell communication by producing, secreting, and responding to small diffusible molecules to activate or repress a specific target gene expression. Various signaling compounds, including AHLs and AI-2, have been reported in spoiled milk, meat, vegetables, and aquatic product (Blana and Nychas, 2014; Liu et al., 2006; Rash et al., 2005) . Several authors (Gu et al., 2013; Zhu et al., 2016) studied the specific spoilage organism (SSO) of P. crocea by investigating the role of QS system of SSO isolated from spoiled fish. They found that Shewanella, mainly Shewanella baltica and Shewanella putrefaciens, was the predominant genera at the end of shelf-life of P. crocea. In cell-free S. baltica culture, AI-2 and two CDPs, cyclo-(L-Pro-L-Leu) and cyclo-(L-Pro-L-Phe), were detected. The production of biofilm, trimethylamines, and putrescine in these spoilers significantly increased in the presence of cyclo-(L-Pro-L-Leu), rather than cyclo-(L-Pro-L-Phe) and 4,5-dihydroxy-2,3-pentanedione (the AI-2 precursor). Exposure to exogenous cyclo-(L-Pro-L-Leu) upregulated the transcription levels of luxR, torA, and ODC. In the fish homogenate, under refrigerated storage, exogenous cyclo-(L-Pro-L-Leu) enhanced the growth rate of the dominant bacteria, H 2 S-producing bacteria, while the exogenous AI-2 precursor retarded the growth of competing bacteria, such as Enterobacteriaceae. Cyclo-(L-Pro-L-Leu) stimulated the accumulation of metabolites on the spoilage process of homogenate, thus confirming that the spoilage potential of S. baltica in P. crocea is regulated by QS mediated by CDPs. Finally, because of the growing importance of bacterial microbiome/bacteriome, fungal microbiome/mycobiome, the role of CDPs as mediators between oral bacteria and fungal genus has been also investigated (Brown et al., 2015) . Oral candidiasis is a major complication of HIV infection (Shiboski et al., 2001; Shiboski, 2002; Thompson et al., 2010) . A study by Brown et al. (2015) focused on the interaction of Candida with other taxa in the oral metabiome. Oral metabolites are products of the host, the oral bacterial microbiome (bacteriome), and the oral fungal microbiome (mycobiome). Functional shifts in the bacteriome and mycobiome contribute to the difference in a healthy oral environment versus oral candidiasis, and a significant shift in correlations between disease and control samples indicates an underlying metabolic change in the ecosystem. By profiling the entire oral metabiome and by using correlation difference probability network analysis, the authors proved the significant role of cyclic mono and dipeptides as QS mediators between oral bacteria and fungal genus, and hypothesized a possible contribution of CDPs to the etiology of oral candidiasis. Marchesan et al. (2015) , by analyzing microbial community composition in periodontitis affected subjects, discovered the presence of several periodontal pathogens of the phylum Synergistetes. The authors demonstrated that Synergistetes phylum was strongly associated with two novel metabolites-cyclo(Leu-Pro) and cyclo(Phe-Pro)-which, by acting as QS molecules, can cause periodontal dysbiosis and periodontal disease.

Endogenous or probiotic strains have been shown to attenuate the production of virulence factor by bacterial pathogens. Indeed, Li et al. (2011) demonstrated that vaginal resident Lactobacillus reuteri RC-14 produces the CDPs cyclo(L-Phe-L-Pro) and cyclo(L-Tyr-L-Pro) that interfere with the staphylococcal QS system agr, a key regulator of virulence genes. This leads to the repression of the expression of toxic shock syndrome toxin-1 by the prototypical menstrual Staphylococcus aureus strain responsible for the menstruation-associated toxic shock syndrome .

Thyrotropin-releasing hormone is a tripeptide formed by pGlu-His-Pro-NH 2 , which is generated in the hypothalamus following the action of the pyroglutamyl-peptidase enzyme before being transformed into a linear dipeptide (His-Pro-NH 2 ), then cyclized by a nonenzymatic process at 37°C to produce CHP, also known as histidylproline diketopiperazine (Minelli et al., 2008; Prasad and Peterkofsky, 1976) . In the 1970s, distribution studies showed that CHP is ubiquitous in the central nervous system-a finding that prompted significant research effort to define the biological roles of the CDP. The administration of exogenous CHP to animals is followed by a variety of biological activities, such as attenuation of ketamine anesthesia, extension of pentobarbital-induced sleep, and alleviation of some pharmacological effects of alcohol (Prasad, 2001) . Moreover, it plays a significant role in modulating food intake and body core temperature, pain awareness, and by acting as an endocrine effector, inhibits prolactin secretion (Morley et al., 1981; Prasad, 1995 Prasad, , 2001 . All these effects seem to share common dopaminergic mechanisms. Faden et al. (1981) reported that TRH and TRH-like compounds improve neurological recovery after spinal trauma and enhance cognitive function, although presenting potent endocrine, analeptic, and autonomic actions that hinder the therapeutic use of TRH. However, strikingly, the same authors also showed that CHP, the metabolic product of TRH, retains all pharmacological activities without known side effects (Faden et al., 2004 (Faden et al., , 2005 . Further support for the involvement of CHP in brain function and potential implications for neurological diseases arose in 2007 when Taubert et al. (2007) showed that the CDP is a specific substrate for Organic Cation Transporter 2, a sodium-dependent transporter highly expressed in the dopaminergic brain structures classically targeted in Parkinson disease, particularly the substantia nigra pars compacta (Taubert et al., 2007) . Not only was CHP found to co-localize in these regions; it was further shown to protect neurons from cytotoxicity induced by salsolinol, a metabolite of L-DOPA linked to Parkinson.

For more than a decade, Minelli and coworkers have been actively involved in defining the effects of CHP in the brain. Indeed, the first clues of the potential application of this molecule in treating neurological disorders came in late 2006, when they discovered that CHP protects dopaminergic PC12 cells from apoptosis only in the presence of experimental conditions that cause cellular stress. Moreover, it has been shown that the treatment with CDPs activates two heat-shock proteins (Hsp), hsp27 and alpha-B-crystallin (Minelli et al., 2006) , proteins implicated in the correct protein folding. Moreover, Hsps by mitigating apoptosis induced by protein misfolding are deeply involved in neurodegenerative diseases. This effect had been practically unnoticed at the time, while today it looks likely to acquire considerable significance by linking the cell-protective antiapoptotic effect of the compound to enhanced capacity to manage metabolic stresses such as the protein misfolding response. CHP attenuates the production of reactive oxygen species (ROS), and prevents glutathione (GSH) depletion caused by stressors such as glutamate, rotenone, paraquat, and beta-amyloid treatment, by triggering the nuclear accumulation of NF-E2-related factor-2 (Nrf2), a transcription factor that upregulates antioxidant-/electrophile-responsive element (ARE-EpRE)-related genes (see later for details). Based on these findings, it was reasoned that CHP, acting as a selective activator of the brain modulable Nrf2 pathway, may be a promising candidate as a neuroprotective agent acting through the induction of phase II genes (Minelli et al. 2009a,b) . Oxidative stress is a condition in which the production of ROS exceeds the cellular buffering capacity. ROS are extremely reactive species that can cause irreparable damage to macromolecules, such as proteins, nucleic acids, and lipids, thus leading to cell death/genetic mutations. Neurons are terminally differentiated cells and thus extremely susceptible to oxidative stress. Indeed, they largely depend on surrounding glial cells for GSH availability (Hsu et al., 2005; Reynolds et al., 2007) . GSH is an unconventional tripeptide that undergoing redox reactions can buffer increased ROS levels and repair oxidized cellular macromolecules. Several enzymes are involved in GSH action, and the majority are under the transcriptional control of Nrf2 (see later; Brigelius-Floh e and Floh e, 2011; Minelli et al., 2009a,b) . Moreover, glial cells, by acting as the immune system of the central nervous system, respond to neuroinflammatory stimuli by increasing the production of reactive nitrogen species (RNS) such as nitric oxide (NO), a very diffusible molecule that can react with ROS, in particular with superoxide anion, to produce the highly reactive and toxic peroxynitrite. This condition has been recognized as nitrosative stress. The brain is therefore very sensitive to changes in redox status, and maintaining redox homeostasis is critical for preventing oxidative damage. When glial cells are overpowered by very high levels of ROS, brain cells experience oxidative stress and nitrosative stress, which act synergistically to disrupt normal neuronal processes. In fact, markers of oxidative stress and nitrosative stress are a defining feature of all neurodegenerative diseases and strongly corroborate a causal link between ROS/RNS and neurodegeneration (Gupta et al., 2014; Leszek et al., 2016; Tsang and Chung, 2009; Valko et al., 2007) . Under conditions of oxidative stress, mitochondria and the process of energy generation by oxidative phosphorylation become dysfunctional, thus generating greater levels of ROS and decreasing ATP synthesis. It worth pointing out that mitochondrial dysfunction is strongly associated with neurodegenerative diseases. Indeed, in the presence of failing mitochondria, NADPH oxidase produces superoxide anions, which combined with NO, produced mainly by inducible nitric oxide synthase, generate the highly RNS peroxynitrite (Contestabile et al., 2003; Dasuri et al., 2013; Grottelli et al., 2016; Valko et al., 2007) . Since mismanaged oxidative stress signals lead to apoptosis and apoptotic cells are themselves known to release ROS, one can imagine a self-perpetuating cycle of ROS-induced apoptosis driving the apoptotic release of further ROS, leading to additional apoptosis.

In mammals, oxidative stress damage is controlled mainly by the NF-E2-related factor 2 (Nrf2) Kelch-like ECH-associated protein 1 (Keap1) system, inherited from ancestors as an antistress response, aimed at preserving cellular homeostasis. Under basal conditions, Nrf2 is sequestered by cytoplasmic Keap1 and targeted for proteasomal degradation (Bellezza et al., 2010; Brigelius-Floh e and Floh e, 2011; Itoh et al., 1999) . Under conditions of oxidative stress, the Nrf2-Keap1 interaction is dissolved in a dose-dependent manner, allowing Nrf2 to translocate to the nucleus where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the antioxidant response elements (AREs) that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription (Suzuki et al., 2013; Suzuki and Yamamoto, 2015) . Nrf2 affects the expression of nearly 500 genes that encode proteins acting as redox balancing factors, detoxifying enzymes, stress response proteins, and metabolic enzymes (Fuse and Kobayashi, 2017; Hahn et al., 2015; Yang et al., 2016) , thus Nrf2 can be regarded as master regulators of the oxidative stress response. It follows that CHP, with its ability to activate the Nrf2 system, can conceivably be regarded as an antioxidant compound. It was reasoned that this capacity to induce a protective antioxidation response might make the CDP a valuable treatment for neurological disease based on oxidative damage. However, since neurological disorders are multifactorial pathologies in which crucial roles are also played by endoplasmic reticulum (ER) stress, calcium loading, excitotoxicity, and inflammation, it can be hypothesized that the beneficial effects of the dipeptide could not be solely ascribed to the activation of Nrf2.

Indeed, stressful conditions lead to the activation of several pathways, including the unfolded protein response (UPR) that is induced by misfolded proteins accumulating in the lumen of the ER, a condition recognized as ER stress. ER stress leads to the activation of three stress sensor proteins located in the ER membrane PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase), ATF6 (activating transcription factor 6), and IRE1 (inositol-requiring enzyme 1), via the dissociation of the molecular chaperone GRP78/Bip (binding immunoglobulin protein/78 kDa glucose-regulated protein). This results in the general inhibition of protein translation, through PERK-mediated eif2α phosphorylation, in order to alleviate ER protein load. Furthermore, through ATF6 and IRE1α branches molecular chaperones expression is upregulated to increase the folding capacity of the cell. When the stressful stimuli overcome cellular mending capacity, homeostatic conditions cannot be restored and the cell undergoes apoptosis. Indeed, a persistent stress condition causes the induction of the transcription factor CHOP (C/EBP homologous protein), which induces the cellular machinery to initiate the apoptotic program.

A role for CHP in the regulation of UPR Has been demonstrated by finding that the CDP counteracts ER stress induced by tunicamycin in microglial cells (Bellezza et al., 2014a,b) . Indeed, CHP induces a protective UPR by activating eif2α and GRP78/Bip, and protects cells from apoptosis by reducing the expression of the proapoptotic protein CHOP. These molecular events significantly reduce the tunicamycin-induced decrease in cell viability (Bellezza et al., 2014a,b) . It is noteworthy that the PERK arm of UPR activates Nrf2 that, in turn, by reducing oxidative stress, can then lessen the amount of oxidized and thus misfolded proteins.

Various studies have proposed that Nrf2 plays a critical role in counteracting the NF-κBdriven inflammatory response in a variety of experimental models (Bellezza et al., 2010 (Bellezza et al., , 2014a Brigelius-Floh e and Floh e, 2011; Sandberg et al., 2014) . The term NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) refers to a family of transcription factors that controls inflammatory responses. The most studied NF-κB family member is the p50-p65 heterodimer which, upon inflammatory stimuli, induces the expression of proinflammatory mediators. NF-κB is maintained in an inactive state in the cytoplasm through the binding to its inhibitor, inhibitor of κB (IκBα). Canonical NF-κB activation pathway relies on the activation of IKK (IκB kinase) protein kinases that phosphorylate IκBα which, in turn, is degraded by the proteasome. This event leads to NF-κB activation and nuclear translocation with the consequent upregulation of NF-κB target genes (Bellezza et al., 2010) .

At the transcriptional level, NF-κB competes with transcription coactivator CREB binding protein, thus repressing Nrf2 signaling. In addition, by recruiting histone deacetylase 3 (HDAC3) and causing a local hypoacetylation, NF-κB reduces Nrf2 signaling . In the presence of concurrent nuclear increases in these two transcription factors, NF-κB antagonizes Nrf2-induced gene transcription, whereas all the compounds that reduce the inflammatory response by suppressing NF-κB signaling activate the Nrf2 pathway (Grottelli et al., 2016; Kim et al., 2013; Li et al., 2008; Minelli et al., 2012) . This link, first suggested by studies showing that Nrf2-deficient mice exhibit a neurodegenerative phenotype (Burton et al., 2006) , was substantiated by the fact that the lack of Nrf2 is associated with an increase in cytokine production (Pan et al., 2012) . In the Nrf2 proximal promoter, there are several κB sites (i.e., genomic sequences recognized and bound by NF-κB); therefore in the presence of a proinflammatory stimulus such as tumor necrosis factor α (TNFα), some cells respond by upregulating Nrf2, leading to feedback suppression of cytokine gene expression (Rushworth et al., 2012) . In addition, NF-κB activation can modulate Nrf2 activity as a protective anti-inflammatory mechanism via the small GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1). Once activated by LPS (lipopolysaccharide), RAC1, through Nrf2 activation, upregulates HO-1 (heme-oxygenase 1) expression, which shifts the cells to a more reducing environment, essential for terminating the NF-κB activation (Cuadrado et al., 2014) . The molecular mechanism of CHP action on the NF-κB system was investigated by using a mouse ear inflammation model. It was observed that CHP reduces 12-otetradecanoylphorbol-13-acetate-induced edema. Moreover, CHP interferes with the crosstalk between the antioxidant Nrf2/HO-1 and the proinflammatory NF-κB pathways in murine immortalized microglial BV2 cells challenged with the proinflammatory molecule LPS. Indeed, cyclooxygenase-2 and matrix metalloproteinase 3, two gene products governed by NF-κB, were downregulated by CHP and upregulated in heme oxygenase-1 (HO-1) knock-down cells. On the basis of these data, showing that CHP suppresses the proinflammatory NF-κB signaling via Nrf2-mediated HO-1 activation, the use of CHP as an in vivo antiinflammatory compound has been proposed (Minelli et al., 2012) . It is becoming increasingly clear that neuroinflammation is one of the features shared by all neurodegenerative diseases (Bellezza et al., 2014a,b; Dinkova-Kostova et al., 2018; González-Reyes et al., 2017) . Usually triggered by peripheral inflammation, the term describes a wide range of immune responses by the central nervous system cells, such as microglia, astrocytes, and blood brain barrier, each linked by a dynamic crosstalk. In the presence of prolonged and sustained inflammation, the neuroinflammatory response results in synaptic impairment, neuronal death, and eventually neurodegeneration (Boulamery and Desplat-J ego, 2017; Lyman et al., 2014; Rustenhoven et al., 2017) . As described previously, the effects of CHP could counteract this pathogenic state in two ways: by activating Nrf2 and inducing HO-1 activity, the compound might simultaneously drive a protective antioxidant response, mitigating oxidative stress damage, while inhibiting NF-κB signaling, reducing damage associated with inflammation (Minelli et al., 2012) . Based on these considerations, the inhibition of glial inflammation by the CDP was hypothesized. Systemic administration of CHP exerts antiinflammatory effects in the central nervous system by downregulating systemic (hepatic) and local (cerebral) TNFα expression, thereby counteracting LPS-induced gliosis (Bellezza et al., 2014a,b) . These effects are known to decrease the detrimental effect of inflammatory neurotoxins on neurons (Catorce and Gevorkian, 2016) . These data suggested a beneficial effect of CHP in a neuroinflammatory setting and its potential therapeutic utility in neuroinflammatory diseases, and we suggested that the CDP might be used also to treat other neuropathological conditions. To test this possibility more directly, Minelli and coworkers tested the effects of CHP in the microglial cells of hSOD1G93A mice. These transgenic mice, expressing the human gene encoding for (superoxide dismutase 1) SOD1 mutated in Gly93-Ala (SOD1G93A), recapitulate several aspects of amyotrophic lateral sclerosis (ALS) and provide a powerful model system to identify pathophysiological mechanisms of the disease and to screen potential therapeutic compounds (Grottelli et al., 2015 (Grottelli et al., , 2016 . In this setting, CHP acts as an antioxidant agent even in a SOD1G93A environment, and more importantly, its effects even offered the prospect of going beyond protection toward neuronal regrowth by strongly upregulating mRNA levels of the neuronal growth factor brain-derived neurotrophic factor, a molecule linked to the preservation of existing neuronal function but also the growth and differentiation of new neurons. Thus CHP may both inhibit the neuronal damage associated with oxidative stress and microglial inflammatory responses caused by SOD1 mutations, and act directly on neurons themselves to preserve and perhaps restore their function, suggesting its possible utility as a therapeutic agent to prevent or delay disease progression in ALS (Fig. 2) .

Neurodegenerative diseases are multifactorial pathologies, although each disease is characterized by distinct etiopathogenetic causes. However, common pathogenic mechanisms, such as neuroinflammation, oxidative stress, and ER stress, underpin neurodegeneration. It has been shown that CHP can counteract each of these pathogenic pathways in several neurotoxinexposed cellular models. So far, only the mutant SOD1 cells, the golden model for ALS, have been employed. It remains to be tested whether CHP is effective on other neurodegenerative disease-specific cellular and animal models.

Quite recently, it has been suggested that any unbalance of the gut microbiome leads to pathological signaling to the brain that might result in proinflammatory reactions, oxidative stress, and a general increase in cellular degeneration, thus contributing to multiple neurodegenerative diseases (Noble et al., 2017) . The human gastrointestinal tract harbors a number of bacterial cells that outnumber by a factor of 10 the host's cells and encodes a number of genes that outnumber by a factor of 100 the host's genes. These human digestive-tractassociated microbes are now known as the gut microbiome/microbiota. Assessments of the number of bacterial species present in the human gut vary widely among studies, but it is generally accepted that individuals harbor more than 1000 microbial, species-level phylotypes (Lozupone et al., 2012) that can communicate via a QS mechanism (Bivar Xavier, 2018). The role of the human gut microbiome in health and disease has been the topic of broad research, and a role for the bacterial commensals in various neurological conditions is well accepted (Byrd et al., 2018; Caballero-Villarraso et al., 2017; Cox and Weiner, 2018; Friedland and Chapman, 2017; Ho et al., 2018; Kitai and Tang, 2018; Marietta et al., 2018; Perez-Pardo et al., 2017; Roszyk and Puszczewicz, 2017; Sherwin et al., 2018; Thion et al., 2018; Yang and Duan, 2018) . Indeed, the gastrointestinal tract is deeply connected with the central nervous system through the gut-brain axis, an interconnected and bidirectional network of neuroendocrine signals and immunological factors. It has been demonstrated that the gut microbiota is capable of communicating information derived from the ingested foods to the central nervous system to obtain a systemic response (Noble et al., 2017) . In 1995, the presence of CHP in the gastrointestinal tract was connected to a role as a gut peptide of the entero-insular axis (Prasad, 1995) . Currently, because of the highlighted role of CHP as a QS signal, capable of controlling behavior and functions of bacterial population-level responses, we propose a novel role of CHP as a modulator of the gut microbiota. Therefore, CHP, by acting directly on central nervous system cells and potentially on gut microbiota, can be considered a potential new drug for neurodegenerative diseases.

No information is currently available on the latter proposed role, since they might be validated only by preclinical trials. In this context, we hope to stimulate interest in the scientific community to test this hypothesis to produce novel therapeutic modalities for the plethora of diseases linked to gut-microbiome dysfunction.

It has been demonstrated that CHP is an endogenous CDP that can reduce oxidative and ER stress as well as inflammation, the main culprits of several neurological disorders. Thus we propose that this CDP, even orally administered, can cross the blood brain barrier and exert its beneficial effects on glial cells, whose uncontrolled response is currently recognized as one of the several causes of neuronal death. Moreover, because CHP can act as QS signal, it is plausible to suggest that this dipeptide can modulate the gut microbiome for clinical benefit in the diverse pathologies in which microbiome dysregulation is implicated.

Thus by acting directly to cease several causes of neurodegeneration and by acting indirectly on the gut microbiome linked to neurological diseases, we can potentially relieve many of the diverse contributors to neurodegenerative disease pathogenesis.

Amyotrophic lateral sclerosis (ALS) A neurodegenerative disease characterized by muscle spasticity, rapidly progressive weakness due to muscle atrophy, and difficulty in speaking (dysarthria), swallowing (dysphagia), and breathing (dyspnea) due to degeneration of the upper and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to control all voluntary movement, although bladder and bowel function and the muscles responsible for eye movement are usually spared until the final stages of the disease. Cognitive function is generally spared for most patients. Biofilms A structured community of bacterial cells enclosed in a self-produced protective polymeric matrix and adherent to an inert or living surface. Blood-brain barrier (BBB) A highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the CNS. Formed by endothelial cells that are connected by tight junctions, it allows the passage of molecules crucial to neural function and prevents the entry of potential neurotoxins. Cyclic dipeptides (CDPs), or 2,5-diketopiperazines Relatively simple compounds resulting from nonenzymatic cyclization of dipeptides and their amides. They are the most common peptide derivatives found in nature and are synthesized by proteobacterial species as well as by humans. CDPs are characterized by stability to proteolysis and promotion of interactions with biological targets. Cyclic scaffold A six-membered ring that, due to its stable structural characteristics, represents a significant pharmacophore in medicinal chemistry. Human microbiome The human body comprises around 10 trillion cells but harbors 100 trillion bacteria, for example, on the skin and in the gut. This is the human "microbiome" and has a huge impact on human health. Nevertheless, humans, in turn, can affect their microbiome by influencing the species of bacteria that take up residence in and on their bodies. Inflammation A response of the innate immune system to harmful stimuli such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. Classical signs are pain, heat, redness, swelling, and loss of function. Lipopolysaccharide (LPS) A glycolipid of Gram negative bacteria of the outer membrane. It is recognized by toll-like receptor 4 (TLR4) in immune cells, where it induces the activation of a proinflammatory response. Microglia A type of nonneural cell that constitutes the resident macrophages of the brain and spinal cord and acts as the first and main form of active immune defense in the CNS. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) A family of transcription factors that controls inflammatory responses. The most studied NF-κB family member is the p50-p65 heterodimer, which upon inflammatory stimuli induces the expression of proinflammatory mediators. Quorum sensing (QS) A mechanism of cell-cell communication via secreted signaling molecules. Secreted autoinducers regulate the expression of a particular set of genes once the cell population density is sufficient to produce a threshold accumulation of the secreted autoinducer. Reactive oxygen species (ROS) A number of reactive molecules and free radicals derived from molecular oxygen, such as singlet oxygen, superoxides, peroxides, the hydroxyl radical, and hypochlorous acid.

Thyrotropin-releasing hormone (TRH) A tripeptide hormone produced by the hypothalamus that stimulates the release of the thyroid-stimulating hormone and prolactin from the anterior pituitary. Unfolded-protein response (UPR) An evolutionarily conserved response related to the ER stress response. The initial intent of the UPR is to adapt to the changing environment and reestablish normal ER function. When adaptation fails, ER-initiated pathways signal alarm by inducing the expression of genes encoding mediators of host defense. Excessive and prolonged ER stress triggers cell suicide, usually in the form of apoptosis, representing a last resort of multicellular organisms to dispense with dysfunctional cells. Virulence factors Molecules expressed and secreted by pathogens (bacteria, viruses, fungi, and protozoa) that enable them to replicate and disseminate within a host in part by subverting or eluding host defenses. 

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Bioactive cyclic dipeptides

Role of endogenous cyclo(His-Pro) in voluntary alcohol consumption by alcohol-preferring C57Bl mice

Demonstration of pyroglutamyl peptidase and amidase activities toward thyrotropin-releasing hormone in hamster hypothalamic extracts

Drugs from the seas-current status and microbiological implications

Involvement of bacterial quorum-sensing signals in spoilage of bean sprouts

Oxidative stress and the pathogenesis of neurodegenerative disorders

Cyclic dipeptides exhibit synergistic, broad spectrum antimicrobial effects and have antimutagenic properties

The RNPP family of quorum-sensing proteins in Gram-positive bacteria

The Pseudomonas aeruginosa antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) is made from glutamate and two alanine residues via a thiotemplate-linked tripeptide precursor. Front. Microbiol. 6, 170. Rosier, A

Role of human microbiome and selected bacterial infections in the pathogenesis of rheumatoid arthritis

The high Nrf2 expression in human acute myeloid leukemia is driven by NF-kappaB and underlies its chemo-resistance

Brain pericytes as mediators of neuroinflammation

The DSF family of cell-cell signals: an expanding class of bacterial virulence regulators

NRF2-regulation in brain health and disease: implication of cerebral inflammation

Cyclodipeptide synthases, a family of class-I aminoacyl-tRNA synthetase-like enzymes involved in non-ribosomal peptide synthesis

The evolution of quorum sensing as a mechanism to infer kinship

Identification of the antifungal peptide-containing symbiont of the marine sponge Theonella swinhoei as a novel δ-proteobacterium

Metabolites from the marine sponge Tedania ignis. A new atisanediol and several known diketopiperazines

Biosynthesis and structures of cyclomarins and cyclomarazines, prenylated cyclic peptides of marine actinobacterial origin

Nonribosomal peptides: from genes to products

Recent developments in understanding the role of the gut microbiota in brain health and disease

HIV-related oral disease epidemiology among women: year 2000 update

Adolescent Medicine HIV/AIDS Research Network, 2001. HIV-related oral manifestations among adolescents in a multicenter cohort study

Two brominated cyclic dipeptides released by the coldwater marine sponge Geodia barretti act in synergy as chemical defense

Quorum sensing in the context of food microbiology

Eukaryotes learn to count: quorum sensing by yeast

A marine Micrococcus produces metabolites ascribed to the sponge Tedania ignis

Nonribosomal peptide synthetases: structures and dynamics

Molecular basis of the Keap1-Nrf2 system. Free Radic

Toward clinical application of the Keap1-Nrf2 pathway

Cyclic peptides on a merry-go-round; towards drug design

Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons

Evidence for acyl homoserine lactone signal production in bacteria associated with marine sponges

A novel family of diketopiperazines as a tool for the study of transport across the blood-brain barrier (BBB) and their potential use as BBB-shuttles

Antibacterial activity of the sponge Suberites domuncula and its primmorphs: potential basis for epibacterial chemical defense

Microbiome influences prenatal and adult microglia in a sex-specific manner

Oropharyngeal candidiasis in the era of antiretroviral therapy. Oral Surg

Diketopiperazines produced by the halophilic archaeon, Haloterrigena hispanica, activate AHL bioreporters

Oxidative and nitrosative stress in Parkinson's disease

Metabolism and toxicity of high doses of cyclo(His-Pro) plus zinc in healthy human subjects

Free radicals and antioxidants in normal physiological functions and human disease

Stapled peptides for intracellular drug targets

Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage. Free Radic

The culturable microbial community of the great barrier reef sponge Rhopaloeides odorabile is dominated by an α-proteobacterium

Phylogenetic diversity of bacteria associated with the marine sponge Rhopaloeides odorabile

Collective decision making in bacterial viruses

Exploring the chemical space of quorum sensing peptides

The local defender and functional mediator: Gut microbiome

Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane

Acetylaszonalenin biosynthesis in Neosartorya fischeri: identification of the biosynthetic gene cluster by genomic mining and functional proof of the genes by biochemical investigation

Biochemical characterization of indole prenyltransferases: filling the last gap of prenylation positions by a 5-dimethylallyltryptophan synthase from Aspergillus clavatus

Quorum sensing signals affect spoilage of refrigerated large yellow croaker (Pseudosciaena crocea) by Shewanella baltica

Peptide-binding dependent conformational changes regulate the transcriptional activity of the quorum-sensor NprR

Further Reading

The effects of diketopiperazines from Callyspongia sp. on release of cytokines and chemokines in cultured J774A.1 macrophages

Hypoglycemic dipeptide cyclo(His-Pro) significantly altered plasma proteome in streptozocin-induced diabetic rats and genetically-diabetic (ob/ob) mice

A tRNA-dependent two-enzyme pathway for the generation of singly and doubly methylated ditryptophan 2,5-diketopiperazines

Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration

Structural biology of nonribosomal peptide synthetases

Synthetic cycle of the initiation module of a formylating nonribosomal peptide synthetase

New diterpenes from the gorgonian Solenopodium excavatum

Nonribosomal peptide synthesis in animals: the cyclodipeptide synthase of Nematostella