Types Of Signaling Molecules Research Articles

Investigating mechanistic insights of curcumin in blocking the Interleukin-8 signaling pathway associated with Breast Cancer: An in-silico approach

Interleukin-8 (IL-8) is a chemokine, a type of signaling molecule that has a role in immunological responses and inflammation. In recent years, IL-8 is additionally related to cancer growth and recurrence. Breast cancer growth, progression, and metastatic developmentare all linked to IL-8. Breast cancer cells are known to develop faster when IL-8 stimulates their proliferation and survival. It can also cause angiogenesis, or the creation of new blood vessels, which is necessary for tumor nutrition and growth. IL-8 and curcumin have been subjects of interest in drug design, particularly in the context of inflammation-related disorders and cancer. This study aims to give an overview of the role of IL-8. Inhibitor-based treatment approaches were being used to target IL-8 with curcumin. Molecular docking method was employed to find a potential interaction to supress competitive inhibition of IL-8 with curcumin. PASS analysis and ADMET characteristics were also being carried out. In the end, IL-8 complexed with curcumin is chosen for MD simulations. Overall, our results showed that during the simulation, the complex stayed comparatively stable. It is also possible to investigate curcumin further as a possible treatment option. The combined results imply that IL-8 and their genetic alterations can be studied in precision cancer therapeutic treatments, utilizing target-driven therapy and early diagnosis.

Isolation and characterization of bacteria that produce quorum sensing molecules during the fermentation and deterioration of pickles

Pickles are typical traditional Chinese fermented vegetables. Complex microbiota interacts throughout the fermentation and deterioration process. Minimal studies are available involving quorum sensing (QS) signaling in pickles. This study investigated the changes in the general pickle properties and microbial diversity at 4 d, 31 d, and 79 d. The QS signaling activity of various strains isolated at these key time points was screened using biosensor strains, while the types of signal molecules were further identified using UHPLC/QTOF-MS/MS. At 4 d, Lactobacillus represented the dominant genus, while Lactobacillus plantarum was identified as the bacteria with AI-2-producing ability. At 31 d, the dominant genus was also Lactobacillus, while the relative abundance of Pediococcus displayed a distinct increase. At this time point, L. plantarum represented the AI-2-producing bacteria, followed by Lactobacillus brevis, Pediococcus sp., Enterobacter sp., and Bacillus megaterium. At 79 d, Lactobacillus was displaced by Enterobacter as the dominant microorganisms, while the AI-2-producing bacteria were identified as L. plantarum, Enterobacter sp., B. megaterium, Klebsiella sp., and Staphylococcus sp. Moreover, AHL activity was only present in isolates from the 79-d brine and was identified as C4-HSL and C6-HSL. In addition, the luxS gene was amplified via cDNA reversely transcription from the total RNA extracted from the brine at all three time points using the L. plantarum luxS primers. The AHL-related genes were only amplified in the RNA of 79-d brine samples using Klebsiella pneumoniae- and Bacillus cereus-related primers. This study presented theoretical references for QS during pickle fermentation and deterioration.

Microbiologically-Synthesized Nanoparticles and Their Role in Silencing the Biofilm Signaling Cascade.

The emergence of bacterial resistance to antibiotics has led to the search for alternate antimicrobial treatment strategies. Engineered nanoparticles (NPs) for efficient penetration into a living system have become more common in the world of health and hygiene. The use of microbial enzymes/proteins as a potential reducing agent for synthesizing NPs has increased rapidly in comparison to physical and chemical methods. It is a fast, environmentally safe, and cost-effective approach. Among the biogenic sources, fungi and bacteria are preferred not only for their ability to produce a higher titer of reductase enzyme to convert the ionic forms into their nano forms, but also for their convenience in cultivating and regulating the size and morphology of the synthesized NPs, which can effectively reduce the cost for large-scale manufacturing. Effective penetration through exopolysaccharides of a biofilm matrix enables the NPs to inhibit the bacterial growth. Biofilm is the consortia of sessile groups of microbial cells that are able to adhere to biotic and abiotic surfaces with the help extracellular polymeric substances and glycocalyx. These biofilms cause various chronic diseases and lead to biofouling on medical devices and implants. The NPs penetrate the biofilm and affect the quorum-sensing gene cascades and thereby hamper the cell-to-cell communication mechanism, which inhibits biofilm synthesis. This review focuses on the microbial nano-techniques that were used to produce various metallic and non-metallic nanoparticles and their “signal jamming effects” to inhibit biofilm formation. Detailed analysis and discussion is given to their interactions with various types of signal molecules and the genes responsible for the development of biofilm.

Flexibility and Adaptability of Quorum Sensing in Nature.

Quorum sensing (QS), a type of chemical communication, allows bacteria to sense and coordinate activities in natural biofilm communities using N-acyl homoserine lactones (AHLs) as one type of signaling molecule. For AHL-based communication to occur, bacteria must produce and recognize the same signals, which activate similar genes in different species. Our current understanding of AHL-QS suggests that signaling between species would arise randomly, which is not probable. We propose that AHL-QS signaling is a mutable and adaptable process, within limits. AHLs are highly-conserved signals, however, their corresponding receptor proteins (LuxR) are highly variable. We suggest that both flexibility and adaptation occur among receptor proteins, allowing for complex signaling networks to develop in biofilms over time.

Mode of Action of Farnesol, the "Noble Unknown" in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect.

Farnesol, the sesquiterpenoid precursor of insect juvenile hormones (JH) that itself has JH activity, existed already long before animals and their hormones came into being. Although it is omnipresent in all eukaryotes, this molecule remains a “noble unknown” in cell physiology. It is neither documented as a hormone nor as another type of signaling molecule. To date, its function as an intermediate in the synthesis of squalene-cholesterol-steroids in chordates/vertebrates, and of the insect/arthropod JHs, esters of farnesol, in the mevalonate biosynthetic pathway is assumed to be the only one. This assumption neglects that already two decades ago, farnesol has been shown to be a potent endogenous inhibitor of N-type voltage-gated Ca2+ channels in some mammalian cell types. The tandem mevalonate pathway and Ca2+ channels originated early in eukaryotic evolution, and has since been well conserved, “promoting” it as a ubiquitous player in Ca2+ homeostasis in all eukaryotes. This paper accentuates how this drastic change in thinking gained momentum after the discovery by Paroulek and Sláma that the huge amounts of JH I in male accessory glands of the Cecropia moth, are actually synthesized in these glands themselves and not in the corpora allata, the hitherto assumed unique synthesis site of such compounds. In addition, MAG-JHs have no hormonal- but an exocrine function. Here we hypothesize that MAG-JHs may function in protecting the spermatozoa against toxic Ca2+ concentrations, and in enabling their flagellum to undulate. They may do so by acting through membrane receptors. Our novel paradigm assigns to farnesol/JHs a function of flexible hydrophobic molecular valves for restricting untimely Ca2+-passage through some types of canonical Ca2+channels, using covalently bound farnesyl- or geranyl-geranyl group attachment as well as GPCRs-G proteins all containing a prenyl group. The high rotatable bond count, and their horseshoe-shape are instrumental to their valve function. In our paradigm, Met/Tai and Gce, to date generally thought to be the (only) functional (nuclear) receptors for JHs, are classified as probable Ca2+-sensitive transcription factors. Some theoretical and practical considerations for possible applications in a medical context will be discussed.

Influence of different mechanical stimuli in a multi-scale mechanobiological isotropic model for bone remodelling

This work represents a study of a mathematical model that describes the biological response to different mechanical stimuli in a cellular dynamics model for bone remodelling. The biological system discussed herein consists of three specialised cellular types, responsive osteoblasts, active osteoblasts and osteoclasts, three types of signalling molecules, transforming growth factor beta (TGF-β), receptor activator of nuclear factor kappa-b ligand (RANKL) and osteoprotegerin (OPG) and the parathyroid hormone (PTH). Three proposals for mechanical stimuli were tested: strain energy density (SED), hydrostatic and deviatoric parts of SED. The model was tested in a two-dimensional geometry of a standard human femur. The spatial discretization was performed by the finite element method while the temporal evolution of the variables was calculated by the 4th order Runge–Kutta method. The obtained results represent the temporal evolution of the apparent density distribution and the mean apparent density and thickness for the cortical bone after 600 days of remodelling simulation. The main contributions of this paper are the coupling of mechanical and biological models and the exploration of how the different mechanical stimuli affect the cellular activity in different types of physical activities. The results revealed that hydrostatic SED stimulus was able to form more cortical bone than deviatoric SED and total SED stimuli. The computational model confirms how different mechanical stimuli can impact in the balance of bone homeostasis.

A sustainable method for effective regulation of anaerobic granular sludge: Artificially increasing the concentration of signal molecules by cultivating a secreting strain

This study introduces sustainable quorum sensing (QS) granulation for anaerobic granular sludge (AnGS) and investigates the efficiency of three types of signal molecules on regulating AnGS granulation. The signal molecules of a secreting strain cultured in a QS regulating reactor increased their concentrations in an expanded granular sludge bed reactor throughout the granulating process. Increasing content of autoinducer-2 (AI-2) strengthened interspecific QS communication and gave a best performance with larger granular diameters, higher extracellular polymeric substance (EPS) production and relative hydrophobicity (RH). N-butyryl-homoserine lactone (C4-HSL) QS regulation was also favorable for granular growth, but its regulation was less than that of AI-2-QS. The AnGS granulated under these two types of QS regulations guided more filamentous bacteria to take part in granulation. Under diffusible signal factor (DSF)-QS regulation, the sludge had a lower granular level with a smaller granule diameter, lower EPS production (RH) when compared that of control medium.

Multiple signals modulate the activity of the complex sensor kinase TodS.

The reason for the existence of complex sensor kinases is little understood but thought to lie in the capacity to respond to multiple signals. The complex, seven-domain sensor kinase TodS controls in concert with the TodT response regulator the expression of the toluene dioxygenase pathway in Pseudomonas putida F1 and DOT-T1E. We have previously shown that some aromatic hydrocarbons stimulate TodS activity whereas others behave as antagonists. We show here that TodS responds in addition to the oxidative agent menadione. Menadione but no other oxidative agent tested inhibited TodS activity in vitro and reduced PtodX expression in vivo. The menadione signal is incorporated by a cysteine-dependent mechanism. The mutation of the sole conserved cysteine of TodS (C320) rendered the protein insensitive to menadione. We evaluated the mutual opposing effects of toluene and menadione on TodS autophosphorylation. In the presence of toluene, menadione reduced TodS activity whereas toluene did not stimulate activity in the presence of menadione. It was shown by others that menadione increases expression of glucose metabolism genes. The opposing effects of menadione on glucose and toluene metabolism may be partially responsible for the interwoven regulation of both catabolic pathways. This work provides mechanistic detail on how complex sensor kinases integrate different types of signal molecules.

Chemicals to induce plastid signals in Arabidopsis seedlings

Tetrapyrroles and abscisic acid (ABA) were considered as plastid signal molecules for plant cells. However, they attract hot controversies. High levels of sugars also trigger plastid signals to regulate nuclear gene expression. However, the effective concentrations of sugar are extremely high (100–10,000 times of tetrapyrroles). To resolve these controversies and inconsistencies, we investigated which chemicals at what concentrations may work as plastid signal molecules, and summarize their common chemical structures. We found that they can be classified into two categories: (1) tetrapyrroles or other carbon–nitrogen heterocyclic compounds with an adjacent three-membered ring (two of them may be incomplete), with a signaling impact order: Mg–protoporphyrin IX/ABA>Fe–protoporphyrin IX>Zn–protoporphyrin IX>protoporphyrin IX>tryptophan>histidine. The completeness of the rings with a chelated metal ion has a positive effect on the effectiveness of plastid signaling stimulation. (2) Sugar or other carbon–oxygen (sulfur) five- or six-membered ring compounds, such as cyclohexane and thiophene. The effective concentrations of the second category of signal molecules are very high (about 400 mM for the monosaccharide). The two types of signal molecules are possibly perceived by different receptors in the plastid.

Quorum-sensing regulates biofilm formation in Vibrio scophthalmi

BackgroundIn a previous study, we demonstrated that Vibrio scophthalmi, the most abundant Vibrio species among the marine aerobic or facultatively anaerobic bacteria inhabiting the intestinal tract of healthy cultured turbot (Scophthalmus maximus), contains at least two quorum-sensing circuits involving two types of signal molecules (a 3-hydroxy-dodecanoyl-homoserine lactone and the universal autoinducer 2 encoded by luxS). The purpose of this study was to investigate the functions regulated by these quorum sensing circuits in this vibrio by constructing mutants for the genes involved in these circuits.ResultsThe presence of a homologue to the Vibrio harveyi luxR gene encoding a main transcriptional regulator, whose expression is modulated by quorum–sensing signal molecules in other vibrios, was detected and sequenced. The V. scophthalmi LuxR protein displayed a maximum amino acid identity of 82% with SmcR, the LuxR homologue found in Vibrio vulnificus. luxR and luxS null mutants were constructed and their phenotype analysed. Both mutants displayed reduced biofilm formation in vitro as well as differences in membrane protein expression by mass-spectrometry analysis. Additionally, a recombinant strain of V. scophthalmi carrying the lactonase AiiA from Bacillus cereus, which causes hydrolysis of acyl homoserine lactones, was included in the study.ConclusionsV. scophthalmi shares two quorum sensing circuits, including the main transcriptional regulator luxR, with some pathogenic vibrios such as V. harveyi and V. anguillarum. However, contrary to these pathogenic vibrios no virulence factors (such as protease production) were found to be quorum sensing regulated in this bacterium. Noteworthy, biofilm formation was altered in luxS and luxR mutants. In these mutants a different expression profile of membrane proteins were observed with respect to the wild type strain suggesting that quorum sensing could play a role in the regulation of the adhesion mechanisms of this bacterium.

Can Bacteria Evolve Resistance to Quorum Sensing Disruption?

Traditional treatment of bacterial infections relies heavily on the use of antibacterial compounds that either kill bacteria (bactericidal) or inhibit their growth (bacteriostatic). Typically, the targets for the main conventional antibiotics are essential cellular processes such as bacterial cell wall biosynthesis, bacterial protein synthesis, and bacterial DNA replication and repair. However, resistance to these drugs arises and spreads very rapidly, even to such an extent that bacteria have been identified that are simultaneously resistant to all available antibiotics [1]. The increasing occurrence of resistant bacteria gradually renders antibiotics ineffective in treating infections and has enormous human and economic consequences worldwide. As a result, the identification of novel drug targets and the development of novel therapeutics constitute an important area of current scientific research. An alternative to killing or inhibiting growth of pathogenic bacteria is the specific attenuation of bacterial virulence, which can be attained by targeting key regulatory systems that mediate the expression of virulence factors. One of the target regulatory systems is quorum sensing (QS), or bacterial cell-to-cell communication. QS is a mechanism of gene regulation in which bacteria coordinate the expression of certain genes in response to the presence or absence of small signal molecules (Figure 1). Figure 1 General scheme of a quorum sensing system. Quorum Sensing: Bacterial Cell-to-Cell Communication QS was first discovered in the marine bacterium Vibrio fischeri and was thought to be restricted to only a limited series of species. Later on, similar systems were found to be present in many other Gram-negative bacteria. These Gram-negative bacteria use acylated homoserine lactones (AHLs) as signal molecules (for a review see [2]). AHLs are typically produced by a homolog of V. fischeri LuxI and detected by a homolog of V. fischeri LuxR. In addition to the AHL-mediated systems in Gram-negative bacteria, some Gram-positive bacteria also regulate a variety of processes by QS. The QS systems of Streptococcus pneumoniae, Bacillus subtilis, and Staphylococcus aureus, for instance, have been extensively studied (for a review see [3]). A different kind of QS system is found in vibrios. These bacteria use multichannel QS systems in which different types of signal molecules are produced. The signal molecules are detected at the cell surface by membrane-bound, two-component receptor proteins that feed a common phosphorylation/dephosphorylation signal transduction cascade (for a review on QS in vibrios, see [4]). One of the signals produced by vibrios is the so-called autoinducer 2 (AI-2), a furanosyl borate diester [5]. AI-2 activity has been detected in many different species (Gram-negative as well as Gram-positive), although its function as a signal is not generally accepted for all species (for a detailed discussion see [6]). The language of bacteria seems to be even more diversified as new QS systems, using different types of signal molecules, are still being discovered [7].

Cutting Off Communication

Biotechnology![Figure][1] CREDIT: N. KEVITIYAGALA/ SCIENCE Many bacteria communicate with one another through the secretion and uptake of small signaling molecules. If this process, known as quorum sensing, is disrupted, bacterial communities can no longer collectively respond to environmental stresses or cooperatively build complex structures such as biofilms. Yeon et al. have leveraged such a disruption to prevent biofouling—the clogging of membrane pores by accumulated particulate matter and bacteria—in wastewater treatment apparatus. The addition of a deactivating enzyme (acylase) quenched the quorum-sensing signal required for bacteria to form biofilms and thus increased the long-term performance of the filtration membrane. Furthermore, the use of a cell-sized magnetic carrier stabilized the acylase and facilitated its recovery and reuse over multiple operation cycles. Fortunately, the quenching process did not interfere with other beneficial bacterially driven processes in the bioreactor, such as the degradation of solid-phase organic matter. Although acylase is only specific to one type of signaling molecule, this procedure could eventually incorporate additional enzymes to quench the few other known quorum-sensing signals, effectively blocking all bacterial communication channels. Environ. Sci. Technol. 43 , 10.1021/es901323k (2009). [1]: pending:yes

Quorum-sensing in Gram-negative bacteria.

It has become increasingly and widely recognised that bacteria do not exist as solitary cells, but are colonial organisms that exploit elaborate systems of intercellular communication to facilitate their adaptation to changing environmental conditions. The languages by which bacteria communicate take the form of chemical signals, excreted from the cells, which can elicit profound physiological changes. Many types of signalling molecules, which regulate diverse phenotypes across distant genera, have been described. The most common signalling molecules found in Gram-negative bacteria are N-acyl derivatives of homoserine lactone (acyl HSLs). Modulation of the physiological processes controlled by acyl HSLs (and, indeed, many of the non-acyl HSL-mediated systems) occurs in a cell density- and growth phase-dependent manner. Therefore, the term 'quorum-sensing' has been coined to describe this ability of bacteria to monitor cell density before expressing a phenotype. In this paper, we review the current state of research concerning acyl HSL-mediated quorum-sensing. We also describe two non-acyl HSL-based systems utilised by the phytopathogens Ralstonia solanacearum and Xanthomonas campestris.

Novel type of signaling molecules: protein kinases covalently linked to ion channels

Recently we identified a new class of protein kinases with a novel type of catalytic domain structurally and evolutionarily unrelated to the conventional eukaryotic protein kinases. This new class, which we named alpha-kinases, is represented by eukaryotic elongation factor-2 kinase and the Dictyostelium myosin heavy chain kinases. Here we cloned, sequenced and analyzed the tissue distribution of five new putative mammalian alpha-kinases: melanoma alpha-kinase, kidney alpha-kinase, heart alpha-kinase, skeletal muscle alpha-kinase, and lymphocyte alpha-kinase. All five are large proteins of more than 1000 amino acids with an alpha-kinase catalytic domain located at the very carboxyl-terminus. We expressed the catalytic domain of melanoma alpha-kinase in Escherichia coli, and found that it autophosphorylates on threonine residues, demonstrating that it is a genuine protein kinase. Unexpectedly, we found that the long amino-terminal portions of melanoma and kidney alpha-kinases represent new members of the transient receptor potential (TRP) ion channel family, which are implicated in the mediation of capacitative Ca2+ entry in nonexcitable mammalian cells. This suggests that melanoma and kidney alpha-kinases, which represent a novel type of signaling molecule, are involved in the regulation of Ca2+ influx in mammalian cells.

Colocalization of amino acid signal molecules in neurons and endocrine cells.

During the last 20 to 30 years, numerous examples have been provided of neurons and endocrine cells that are able to produce, store, and in many cases release more than one type of signal molecule. Recent models propose that neurons often employ an amino acid, an amine, and one or more neuroactive peptides, and that endocrine cells may release more than one peptide hormone. In neurons, the different classes of transmitter convey fast, intermediate, and slow signalling respectively. However, a series of studies demonstrates that neurons may colocalize more than one neuroactive amino acid, and that endocrine cells may contain an amino acid along with their peptide hormone. These forms of colocalization seem to add new levels of complexity to the role of amino acids in cell signalling, suggesting that, in neurons, amino acids may interact at the receptor level, modifying the effect of each other, and that, in endocrine cells, amino acids may act together with or parallel to a peptide hormone in a paracrine or autocrine manner.

Retinoic acid causes an anteroposterior transformation in the developing central nervous system.

All-trans retinoic acid (RA) is well known as a biologically active form of vitamin A and a teratogen. The identification of nuclear receptors for this ligand suggests strongly that it is an endogenous signal molecule, and measurements of RA and teratogenic manipulations suggest further that RA is a morphogen specifying the anteroposterior axis during limb development. Besides the limb, RA and other retinoids affect development of other organs, including the central nervous system (CNS). None of these other effects has been investigated in detail. Our purpose here was to begin analysing the effects of RA on CNS development in Xenopus laevis. We find that RA acts on the developing CNS, transforming anterior neural tissue to a posterior neural specification. These and other findings raise the possibility that RA mediates an inductive interaction regulating anteroposterior differentiation within the CNS. Following recent reports implicating transforming growth factor-beta 2-like and fibroblast growth factor-like factors in mesoderm induction, this indicates that a different type of signal molecule (working through a nuclear receptor, not a plasma membrane receptor) might mediate inductive cell interactions during early embryonic development.