Chemical Signaling Systems Research Articles

Bactericidal effect of Iberin combined with photodynamic antimicrobial chemotherapy against Pseudomonas aeruginosa biofilm cultured on ex vivo wound model

Wounds infected by Pseudomonas aeruginosa (P. aeruginosa) biofilms are characterized by poor healing and by being long lasting. Pyocyanin and pyoverdine are exotoxins that contribute to P. aeruginosa pathogenicity in wound infections and are known as virulence factors. Despite the usefulness of antimicrobial photodynamic therapy (PDT) in the management of wound infections, biofilms are hurdle for microbial photoinactivation. Quorum sensing (QS) is a cell density-dependent chemical signaling system P. aeruginosa uses to regulate biofilm formation and virulence factors production. In the current study, QS attenuation was used in combination with PDT against P. aeruginosa biofilm cultured on skin explant. Iberin is a QS inhibitor that attenuates P. aeruginosa virulence and affects biofilm integrity. The antibiofilm and QS inhibitory activities of iberin in combination with either riboflavin or 5,10,15,20-Tetrakis(1-methyl-4-pyridinio) porphyrin tetra p-toluenesulfonate (TMP) mediated PDT were investigated using viable count method and pyocyanin and pyoverdine assays, respectively.No bactericidal activity was reported when iberin was added to a mature biofilm (24 h) followed by PDT. When added to a growing biofilm at multiple time points (0 h, 24 h and 48 h), iberin inhibited P. aeruginosa biofilm QS signaling system. This inhibitory effect resulted in an observable decrease in the levels of the QS-regulated virulence factors, pyocyanin and pyoverdine, without any effect on the growth of the biofilm cultures. These changes in biofilm virulence were associated with a decrease in biofilm resistance to PDT and caused bactericidal effect upon photosensitizers treatment and irradiation. Iberin-treated-riboflavin-mediated PDT resulted in a significant 1.3 log reduction in biofilm population. Similarly, iberin-treated-TMP-mediated PDT caused a significant 1.8 log reduction in biofilm population. The combination of QS inhibitor with PDT is a promising alternative antimicrobial therapy for the management of biofilms.

A Novel and Efficient Platform for Discovering Noncanonical Quorum-Quenching Proteins.

Quorum sensing (QS) is a well-known chemical signaling system responsible for intercellular communication that is widespread in bacteria. Acyl-homoserine lactone (AHL) is the most-studied QS signal. Previously, bacterially encoded AHL-degrading enzymes were considered to be canonical quorum-quenching proteins that have been widely used to control pathogenic infections. Here, we report a novel platform that enabled the efficient discovery of noncanonical AHL quorum-quenching proteins. This platform initially asked bacteriologists to carry out comparative genomic analyses between phylogenetically related AHL-producing and non-AHL-producing members to identify genes that are conservatively shared by non-AHL-producing members but absent in AHL-producing species. These candidate genes were then introduced into recombinant AHL-producing E. coli to screen for target proteins with the ability to block AHL production. Via this platform, we found that non-AHL-producing Lysobacter containing numerous environmentally ubiquitous members encoded a conserved glycosyltransferase-like protein Le4759, which was experimentally shown to be a noncanonical AHL-quenching protein. Le4759 could not directly degrade exogenous AHL but rather recognized and altered the activities of multiple AHL synthases through protein-protein interactions. This versatile capability enabled Le4759 to block specific AHL synthase such as CarI from Pectobacterium carotovorum to reduce its protein abundance to suppress AHL synthesis, thereby impairing bacterial infection. Thus, this study provided bacteriologists with a unique platform to discover noncanonical quorum-quenching proteins that could be developed as promising next-generation drug candidates to overcome emerging bacterial antibiotic resistance. IMPORTANCE Targeting and blocking bacterial quorum sensing (QS), the process known as quorum quenching (QQ) is an effective mean to control bacterial infection and overcome the emerging antibiotic resistance. Previously, diverse QS signal-degradation enzymes are identified as canonical QQ proteins. Here, we provided a novel and universal platform that enabled to discover previously unidentified noncanonical QQ proteins that were unable to degrade acyl-homoserine lactone (AHL) but could block AHL generation by recognizing multiple AHL synthases via direct protein-protein interactions. Our findings are believed to trigger broad interest for bacteriologists to identify potentially widely distributed noncanonical QQ proteins that have great potential for developing next-generation anti-infectious drugs.

Evidence-based Potential Therapeutic Applications of Cannabinoids in Wound Management.

Although wound management is a major component of all domains of healthcare, conventional therapeutics have numerous limitations. The endocannabinoid system of the skin, one of the major endogenous systems, has recently been connected to wound healing. Cannabinoids and their interactions with the endogenous chemical signaling system may be a promising therapeutic option because they address some of the fundamental pathways for physiologic derangement that underpin chronic integumentary wounds. The therapeutic applications of cannabinoids are increasing because of their legalization and resulting market expansion. Recently, their immunosuppressive and anti-inflammatory properties have been explored for the treatment of wounds that are not effectively managed by conventional medicines. Failure to manage wounds effectively is associated with reduced quality of life, disability, mortality, and increased healthcare expenditures. Therapeutic options that can manage wounds effectively and efficiently are needed. In this review, the authors summarize recent advances on the use of cannabinoids to treat skin disorders with an emphasis on wound management. Effective wound management requires medicines with good therapeutic outcomes and minimal adverse effects. Despite the promising results of cannabinoids in wound management, further controlled clinical studies are required to establish the definitive role of these compounds in the pathophysiology of wounds and their usefulness in the clinical setting.

Escherichia coli small molecule metabolism at the host-microorganism interface.

Escherichia coli are a common component of the human microbiota, and isolates exhibit probiotic, commensal and pathogenic roles in the host. E. coli members often use diverse small molecule chemistry to regulate intrabacterial, intermicrobial and host-bacterial interactions. While E. coli are considered to be a well-studied model organism in biology, much of their chemical arsenal has only more recently been defined, and much remains to be explored. Here we describe chemical signaling systems in E. coli in the context of the broader field of metabolism at the host-bacteria interface and the role of this signaling in disease modulation.

Evolutionary history of mental glands in turtles reveals a single origin in an aquatic ancestor and recurrent losses independent of macrohabitat

Despite the relevance of chemical communication in vertebrates, comparative examinations of macroevolutionary trends in chemical signaling systems are scarce. Many turtle and tortoise species are reliant on chemical signals to communicate in aquatic and terrestrial macrohabitats, and many of these species possess specialized integumentary organs, termed mental glands (MGs), involved in the production of chemosignals. We inferred the evolutionary history of MGs and tested the impact of macrohabitat on their evolution. Inference of ancestral states along a time-calibrated phylogeny revealed a single origin in the ancestor of the subclade Testudinoidea. Thus, MGs represent homologous structures in all descending lineages. We also inferred multiple independent losses of MGs in both terrestrial and aquatic clades. Although MGs first appeared in an aquatic turtle (the testudinoid ancestor), macrohabitat seems to have had little effect on MG presence or absence in descendants. Instead, we find clade-specific evolutionary trends, with some clades showing increased gland size and morphological complexity, whereas others exhibiting reduction or MG loss. In sister clades inhabiting similar ecological niches, contrasting patterns (loss vs. maintenance) may occur. We conclude that the multiple losses of MGs in turtle clades have not been influenced by macrohabitat and that other factors have affected MG evolution.

Cannabis and Cannabinoids in Reproduction and Fertility: Where We Stand

Although cannabis use is increasing in general population, their prevalence among young adults is remarkably high. In recent years, their medical use gained a renewed interest. However, it can underline the reputation of cannabis being a harmless drug. Between cannabinoids, uniquely found on the cannabis plant, Δ9-tetrahydrocannabinol (THC) is the well-studied compound. It is responsible for the psychoactive effects via central cannabinoid receptors. Nevertheless, cannabinoids interact with other chemical signalling systems such as the hypothalamic-pituitary-gonadal axis. THC indirectly decreases gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus. The consequences are diverse, and several key hormones are affected. THC disturbs important reproductive events like folliculogenesis, ovulation and sperm maturation and function. Although generally accepted that cannabinoid consumption impacts male and female fertility, prevailing evidence remains largely on pre-clinical studies. Here, we introduce cannabinoids and the endocannabinoid system, and we review the most prominent clinical evidence about cannabis consumption in reproductive potential and teratogenicity.

Coupled Active Systems Encode an Emergent Hunting Behavior in the Unicellular Predator Lacrymaria olor.

Many single-celled protists use rapid morphology changes to perform fast animal-like behaviors. To understand how such behaviors are encoded, we analyzed the hunting dynamics of the predatory ciliate Lacrymaria olor, which locates and captures prey using the tip of a slender "neck" that can rapidly extend more than seven times its body length (500μm from its body) and retract in seconds. By tracking single cells in real-time over hours and analyzing millions of sub-cellular postures, we find that these fast extension-contraction cycles underlie an emergent hunting behavior that comprehensively samples a broad area within the cell's reach. Although this behavior appears complex, we show that it arises naturally as alternating sub-cellular ciliary and contractile activities rearrange the cell's underlying helical cytoskeleton to extend or retract the neck. At short timescales, a retracting neck behaves like an elastic filament under load, such that compression activates a series of buckling modes that reorient the head and scramble its extensile trajectory. At longer timescales, the fundamental length of this filament can change, altering the location in space where these transitions occur. Coupling these fast and slow dynamics together, we present a simple model for how Lacrymaria samples the range of geometries and orientations needed to ensure dense stochastic sampling of the immediate environment when hunting to locate and strike at prey. More generally, coupling active mechanical and chemical signaling systems across different timescales may provide a general strategy by which mechanically encoded emergent cell behaviors can be understood or engineered.

Synthesis and Biological Evaluation of a Photoswitchable Quorum Sensing Molecule

Quorum sensing is the ability of bacteria to communicate with one another via chemical signals. This ignites a response within the collective group of bacteria to produce a single response that ultimately benefits the bacteria, an example being biofilm formation. If this natural process could be controlled or coopted, the biotecnical applications arising from this natural ability of bacteria could be limitless. Photoswitching molecules are able to respond to a light stimiulus. Azostilbenes in particular isomerize from trans to the cis conformation in response to the appropriate wavelengths of light. If one of the available conformations is bioactive, while the other is not, this photoisomerization has the effect of activating or inactivating the molecule in response to light. The power of light responsive chemical signaling systems comes from their ability to achieve exquisite spatial and temporal control, which is of tremendous utility for numerous bioindustrial applications. To this end, we have designed a series of photoswitching molecules based upon N‐acyl homoserine lactones (AHLs), which are known to be prominent chemical messengers in numerous bacterial species, by integrating the azo‐stilbenoid motif into the parent molecule scaffold. These molecules are made by Mills coupling between the appropriate aniline and aryl‐nitroso species. Their photokinetic properties are measured by UV/Vis spectroscopy and their bioactivity measured in the presence and absence of isomerizing light. We herein describe the synthesis, photokinetic studies, and bioactivity of this class of photoswitchable molecule. We also describe potential industrial applications of this technology.Support or Funding InformationAlbion College Foundation for Undergraduate Research, Scholarship, and Creative ActivityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Desiccation Resistance and Micro-Climate Adaptation: Cuticular Hydrocarbon Signatures of Different Argentine Ant Supercolonies Across California

Cuticular hydrocarbons (CHCs), the dominant fraction of the insects' epicuticle and the primary barrier to desiccation, form the basis for a wide range of chemical signaling systems. In eusocial insects, CHCs are key mediators of nestmate recognition, and colony identity appears to be maintained through a uniform CHC profile. In the unicolonial Argentine ant Linepithema humile, an unparalleled invasive expansion has led to vast supercolonies whose nestmates can still recognize each other across thousands of miles. CHC profiles are expected to display considerable variation as they adapt to fundamentally differing environmental conditions across the Argentine ant's expanded range, yet this variation would largely conflict with the vastlyextended nestmate recognition based on CHC uniformity. To shed light on these seemingly contradictory selective pressures, we attempt to decipher which CHC classes enable adaptation to such a wide array of environmental conditions and contrast them with the overall CHC profile uniformity postulated to maintain nestmate recognition. n-Alkanes and n-alkenes showed the largest adaptability to environmental conditions most closely associated with desiccation, pointing at their function for water-proofing. Trimethyl alkanes, on the other hand, were reduced in environments associated with higher desiccation stress. However, CHC patterns correlated with environmental conditions were largely overriden when taking overall CHC variation across the expanded range of L. humile into account, resulting in conserved colony-specific CHC signatures. This delivers intriguing insights into the hierarchy of CHC functionality integrating both adaptation to a wide array of different climatic conditions and the maintenance of a universally accepted chemical profile.

Host shift induces changes in mate choice of the seed predator Acanthoscelides obtectus via altered chemical signalling.

The mechanisms of host shift in phytophagous insects are poorly understood. Among the many proposed processes involved, sexual selection via semiochemicals has recently been suggested. This hypothesizes that sexual communication using pheromones is modified as a result of development on a new host, and such plant-induced phenotypic divergence in mate recognition cues can lead to reproductive isolation between host lines. We tested this hypothesis on Acanthoscelides obtectus, an oligophagous bruchid of Phaseolus vulgaris beans worldwide, which also develops in acceptable non-hosts, such as chickpea (Cicer arietinum L.). Male sex pheromone blends of the bean, chickpea and chickpea/bean host lines during artificially induced host shifts showed different composition. Bean-reared females did not distinguish between blends, whereas chickpea and chickpea/bean females preferred the chickpea male pheromone. However, electrophysiological (EAG) responses to male odour of antennae of the three female host lines were similar, all preferring bean-reared males. Egg-laying choice tests revealed a uniform preference for bean seeds across female host lines, even after multiple generations, whereas larvae did not distinguish between bean and chickpea seeds. We conclude that the development of divergent chemical signalling systems during host shifts does not facilitate the evolution of host races in A. obtectus, because oviposition preferences remain unaffected.

Tracking traumatic head injuries with the chemical senses.

Chemosensory disorders, primarily olfactory, have diagnostic significance for prevalent human illnesses, but the multitude of smells makes measuring function appear daunting. The olfactory system operates under dynamic natural sensing conditions in which many individual odor chemicals are waxing and waning. Yet, in experimentally controlled simulations, mixture-component selective adaptation shows individual or shared prominent characteristic odors are detected but molecular stimulus features are not. As in other biological chemical signaling systems, including taste, odors activate dedicated receptors (OR). Given rapid OR adaptation with the passage of time, individual odor recognition is momentary. Receptive dendrites of the nearly 400 genetically variable human-OR in the olfactory epithelium critically project axons to the olfactory bulb through perforations in the cribriform plate of the skull. Analytic chemical-quality codes detect single odor-mixture components. However, identities of no more than 3 or 4 most salient odors are perceived due to central mixture-suppression, the mutual inhibition among diverse olfactory-bulb or cortical neurons. The componental codes allow olfaction to readily discern odor quality and valence of a wide range of unrelated chemicals, a few at a time. Head trauma may result in a partial or complete loss of smell and facial trauma a loss of taste-nerve function. Testing smell could plot the course of recovery from chronic traumatic encephalopathies that prevail in contact sports. Measuring brain function with olfaction would provide simpler and more direct monitoring of prognosis than biochemical sensors.

Neurodegenerative diseases are a function of matrix breakdown: how to rebuild extracellular matrix and intracellular matrix.

Neurodegenerative diseases are a function of matrix breakdown: how to rebuild extracellular matrix and intracellular matrix.

Emotional Modulation of Learning and Memory: Pharmacological Implications.

Memory consolidation involves the process by which newly acquired information becomes stored in a long-lasting fashion. Evidence acquired over the past several decades, especially from studies using post-training drug administration, indicates that emotional arousal during the consolidation period influences and enhances the strength of the memory and that multiple different chemical signaling systems participate in this process. The mechanisms underlying the emotional influences on memory involve the release of stress hormones and activation of the basolateral amygdala, which work together to modulate memory consolidation. Moreover, work suggests that this amygdala-based memory modulation occurs with numerous types of learning and involves interactions with many different brain regions to alter consolidation. Additionally, studies suggest that emotional arousal and amygdala activity in particular influence synaptic plasticity and associated proteins in downstream brain regions. This review considers the historical understanding for memory modulation and cellular consolidation processes and examines several research areas currently using this foundational knowledge to develop therapeutic treatments.

Sensitivity and Robustness in an Axon Guidance Signaling System

Correct functioning of the brain requires the orderly wiring of billions of cells during development. A major mechanism that mediates this is the guidance of axons to their targets by extracellular chemical gradients. Although well studied, the computational rules by which even simple guidance decisions are made are not yet understood at a biophysical level. The task of a growing axon to estimate a direction signal is immense, as unavoidable biological noise corrupts the measurement at all levels of processing. Here, we show how the modulation of growth by a balance of positive and negative feedback can explain the remarkable chemotactic sensitivity observed in vitro. We perform a detailed analysis of the experimental data of ref. [1] which characterizes the neurite growth of ∼2500 rat dorsal root ganglia explants in very shallow gradients of nerve growth factor. Constrained by these data, we construct a model chemical signaling system for growth and guidance in the developing brain. In the model, amplification of the gradient signal occurs via paracrine signalling between cell bodies within the ganglion, while robustness is conferred by the dynamics of receptor trafficking. The model gives a unified and quantitative account of experimentally observed behavior, and yields testable predictions with implications for understanding brain development and repair after injury.[1] Mortimer, D. et al (2009) A Bayesian model predicts the response of axons to molecular gradients. Proc. Natl. Acad. Sci. U.S.A, 106(25), 10296-10301.

The Epinephrine/Norepinephrine/Autoinducer-3 Interkingdom Signaling System in Escherichia coli O157:H7.

Epinephrine/norepinephrine/AI-3 signaling is used as an interkingdom chemical signaling system between microbes and their hosts. This system is also exploited by pathogens to regulate virulence traits. In enterohemorrhagic E. coli (EHEC) O157:H7, it is essential for pathogenesis and flagella motility. These three signals activate expression of a pathogenicity island named locus of enterocyte effacement (LEE), Shiga toxin, and the flagella regulon. These signals are sensed by the two-component system QseBC, whereas the bacterial membrane receptor QseC autophosphorylates and phosphorylates the QseB response regulator initiating a complex phosphorelay signaling cascade that activates the expression of a second two-component system, QseEF. The QseEF two-component system is also involved in the expression of the virulence genes, and it senses epinephrine, phosphate, and sulfate. This complex signaling cascade still needs to be completely elucidated.

Smart plants: Memory and communication without brains

The immobility of plants is consistent with their principal function: collecting light to provide photosynthetic substrate for the biological system. Their immobility does impose limitations on some basic requirements, such as the need for pollination, for seed dispersal, and for protection against herbivores. Meeting these 3 needs will logically necessitate some ability for plant communication – at least a capability for beneficial adaptive behavior. Three types of plant behavior provide evidence of memory and communication abilities: a capability for memory, a capability for measuring time, and extensive evidence of chemical signaling systems. These may provide benefits for genetic outcrossing, seed dispersal and protection – beneficial adaptive behaviors. The chemical signaling system constitutes a wireless communication network that draws mobile animals into assisting plant functions that require mobility. Plants share their chemical signaling systems most frequently with insects and birds. These beneficial adaptable behaviors may be interpreted as some type of consciousness.

Microbiota, the immune system, black moods and the brain—melancholia updated

There is now abundant evidence that the immune system and the brain have close functional interactions in both directions. This review focuses on the influence of the microbiota (the bacteria resident in the gut) on brain function in major depressive disorder (MDD) and related syndromes. The gut and the central nervous system communicate partly through the autonomic nervous system (ANS), consisting of the sympathetic (i.e., the splanchnic nerves) and the parasympathetic (i.e., the vagus nerve and the sacral parasympathetic pelvic nerves) nervous system. The brain integrates inputs from the digestive tract by a central autonomic network that includes the hypothalamus, limbic system and cerebral cortex with output to the ANS and hypothalamic-pituitary-adrenal gland (HPA) stress axis (Bonaz, 2013). There are also extensive chemical signaling systems via the blood.

Mechanical control of the endothelial barrier

The integrity of the endothelial barrier is controlled by the combined action of chemical and mechanical signaling systems. Permeability-regulating factors signal through small GTPases to regulate the architecture of the cytoskeleton and this has a strong impact on the morphology and stability of VE-cadherin-based cell-cell junctions. The details of how structural and mechanical properties of the actin cytoskeleton influence cell-cell adhesion and how this impacts the dynamic regulation of the endothelial barrier, are beginning to be elucidated. In this review, we discuss the physical and regulatory interactions between the VE-cadherin complex and the actomysoin cytoskeleton, as they are the main determinants of cell-cell adhesion and the mechanical architecture of the cytoskeleton. We discuss, based on recent in vitro data, how a balance between Linear Adherens Junctions, paralleled by cortical actin bundles and Focal Adherens Junctions, connected to radial action bundles, determines endothelial barrier function. We discuss how small GTPases control this balance by regulating the spatial organization and mechanics of actomyosin. We propose a hypothetical model of how biochemical and mechanical signals cooperate locally, at the actomyosin-adhesion interface to open and re-seal the barrier in a rapid and controlled manner.

EFFECTS OF PERFUSION OF TESTICULAR FRACTIONS ON BRAIN CATECHOLAMINES IN THE FEMALE CATFISH HETEROPNEUSTES FOSSILIS

Fish have highly developed chemosensory and chemical signaling systems as they inhabit aquatic environment devoid of light but rich in dissolved compounds. Four major classes of chemicals have been identified as specific olfactory stimuli namely amino acids, sex steroids, bile acids or salts and prostaglandins. Pheromones are defined as substances which are secreted to the outside by an individual, in which they release specific reaction; for eg; a definite behavior or a developmental process in conspecifics[1]. In many teleost species, pheromones play an important role in various events of reproductionand spawning [7,4]. The gonads of teleosts secrete pheromonally active substances, most likely steroidal glucuronides, which can activate the neuroendocrine axis to release gonadotropin–II. In the African catfish, strong olfactory sensitivity to steroid conjugate fraction has been attributed to glucuronides synthesized by the seminal vesicle [3,2]. It was reported that the testicular homogenate or its, glucuronide fraction [6] and the seminal vesicle fluid or its glucuronide fraction [2] induced either ovulation or behavior effects in zebrafish and African catfish, respectively. The testis of the

Quantum: May be a new-found messenger in biological systems

Current studies on biological communications mainly focus on chemical signals. Since organisms are extremely complex, different kinds of signals may exist in the process of cell communication. The most probable candidate for alternative forms of organism communications is electromagnetic radiation, as many experiments have confirmed that electromagnetic radiation widely exists in cells, tissues, organisms and even between organisms and their surroundings. The well-known connection between electromagnetic radiation and quantization of the energy transfer makes us to suggest a bold, but fresh view that quantum can serve as a biological messenger. This view also coincides with the medium of Qi in the human body according to traditional Chinese medicine (TCM). Relating Qi with quantum may further explain a number of phenomena that cannot be explained solely by conventional chemical signaling systems.