Intercellular Signaling System Research Articles

A Tiny Viral Protein, SARS-CoV-2-ORF7b: Functional Molecular Mechanisms.

This study presents the interaction with the human host metabolism of SARS-CoV-2 ORF7b protein (43 aa), using a protein-protein interaction network analysis. After pruning, we selected from BioGRID the 51 most significant proteins among 2753 proven interactions and 1708 interactors specific to ORF7b. We used these proteins as functional seeds, and we obtained a significant network of 551 nodes via STRING. We performed topological analysis and calculated topological distributions by Cytoscape. By following a hub-and-spoke network architectural model, we were able to identify seven proteins that ranked high as hubs and an additional seven as bottlenecks. Through this interaction model, we identified significant GO-processes (5057 terms in 15 categories) induced in human metabolism by ORF7b. We discovered high statistical significance processes of dysregulated molecular cell mechanisms caused by acting ORF7b. We detected disease-related human proteins and their involvement in metabolic roles, how they relate in a distorted way to signaling and/or functional systems, in particular intra- and inter-cellular signaling systems, and the molecular mechanisms that supervise programmed cell death, with mechanisms similar to that of cancer metastasis diffusion. A cluster analysis showed 10 compact and significant functional clusters, where two of them overlap in a Giant Connected Component core of 206 total nodes. These two clusters contain most of the high-rank nodes. ORF7b acts through these two clusters, inducing most of the metabolic dysregulation. We conducted a co-regulation and transcriptional analysis by hub and bottleneck proteins. This analysis allowed us to define the transcription factors and miRNAs that control the high-ranking proteins and the dysregulated processes within the limits of the poor knowledge that these sectors still impose.

A Mammalian-Based Synthetic Biology Toolbox to Engineer Membrane-Membrane Interfaces.

Intercellular membrane-membrane interfaces are compartments with specialized functions and unique biophysical properties that are essential in numerous cellular processes including cell signaling, development, and immunity. Using synthetic biology to engineer or to create novel cellular functions in the intercellular regions has led to an increasing need for a platform that allows generation of functionalized intercellular membrane-membrane interfaces. Here, we present a synthetic biology platform to engineer functional membrane-membrane interfaces using a pair of dimerizing proteins in both cell-free and cellular environments. We envisage this platform to be a helpful tool for synthetic biologists who wish to engineer novel intercellular signaling and communication systems.

Exploration of Chemical Diversity in Intercellular Quorum Sensing Signalling Systems in Prokaryotes.

Quorum sensing (QS) serves as a vital means of intercellular signalling in a variety of prokaryotes, which enables single cells to act in multicellular configurations. The potential to control community-wide responses has also sparked numerous recent biotechnological innovations. However, our capacity to utilize intercellular communication is hindered due to a scarcity of complementary signalling systems and a restricted comprehension of interconnections between these systems caused by variations in their dynamic range. In this study, we utilize uniform manifold approximation and projection and extended-connectivity fingerprints to explore the available chemical space of QS signalling molecules. We investigate and experimentally characterize a set of closely related QS signalling ligands, consisting of N-acyl homoserine lactones and the aryl homoserine lactone p-coumaroyl, as well as a set of more widely diverging QS ligands, consisting of photopyrones, dialkylresorcinols, 3,5-dimethylpyrazin-2-ol and autoinducer-2, and define their performance. We report on a set of six signal- and promoter-orthogonal intercellular QS signalling systems, significantly expanding the toolkit for engineering community-wide behaviour. Furthermore, we demonstrate that ligand diversity can serve as a statistically significant tool to predict much more complicated ligand-receptor interactions. This approach highlights the potential of dimensionality reduction to explore chemical diversity in microbial dynamics.

Exploration of Chemical Diversity in Intercellular Quorum Sensing Signalling Systems in Prokaryotes

AbstractQuorum sensing (QS) serves as a vital means of intercellular signalling in a variety of prokaryotes, which enables single cells to act in multicellular configurations. The potential to control community‐wide responses has also sparked numerous recent biotechnological innovations. However, our capacity to utilize intercellular communication is hindered due to a scarcity of complementary signalling systems and a restricted comprehension of interconnections between these systems caused by variations in their dynamic range. In this study, we utilize uniform manifold approximation and projection and extended‐connectivity fingerprints to explore the available chemical space of QS signalling molecules. We investigate and experimentally characterize a set of closely related QS signalling ligands, consisting of N‐acyl homoserine lactones and the aryl homoserine lactone p‐coumaroyl, as well as a set of more widely diverging QS ligands, consisting of photopyrones, dialkylresorcinols, 3,5‐dimethylpyrazin‐2‐ol and autoinducer‐2, and define their performance. We report on a set of six signal‐ and promoter‐orthogonal intercellular QS signalling systems, significantly expanding the toolkit for engineering community‐wide behaviour. Furthermore, we demonstrate that ligand diversity can serve as a statistically significant tool to predict much more complicated ligand‐receptor interactions. This approach highlights the potential of dimensionality reduction to explore chemical diversity in microbial dynamics.

New synthetic monophenolic antioxidant TS-13 penetrates the blood-brain barrier

TS-13 (sodium 3-(3’-tert-butyl-4’-hydroxyphenyl)propylthiosulfonate) is a synthetic antioxidant that has demonstrated biological effectiveness in numerous studies in modeling pathological conditions in vivo, in particular, in the model of Parkinson’s disease. In order to establish whether these effects are mediated or associated, among other things, with the direct effect of TS-13 on the organs and tissues of animals, in this work, the concentration of TS-13 in rat blood plasma and brain after intragastric administration was determined. Material and methods. After a single intragastric administration of a solution of TS-13 at a dose of 100 mg/kg, biomaterial (blood, brain) was taken for 24 h in male Sprague Dawley stock rats (n = 57). To measure the concentration of a substance in samples, a bioanalytical method was developed and validated using high-performance liquid chromatography with UV detection. Results and discussion. The method of quantitative determination was developed by us for the first time and validated before the study. It has been established that the calculated values of the calibration samples meet the acceptance criteria (have the required accuracy and precision) in the concentration range from 0.05 to 6 µg/ml, R=0.9998. The results of determining TS-13 concentration in rat blood plasma and brain showed that after a single administration per os, the compound enters the blood, where it is detected for 15 h (mean retention time 7.94 h, half-life 7.59 h, elimination constant 0.13 h-1, total clearance 40.1 l/(kg × h)), and also penetrates the blood-brain barrier, quickly entering the brain (maximum concentration is reached after 1 h). The compound has a low affinity for brain tissue (tissue availability 0.32), and therefore its concentration does not reach high values, however, a slow excretion of the substance is observed - the average retention time is 6.56 h, the half-life is 6.43 h, the elimination constant 0.11 h-1. Conclusions. After a single intragastric administration to rats, TS-13 enters the blood, where at least part of it is detected unchanged after 30 minutes, reaching maximum values after 1 hour. Similar kinetics of the substance is characteristic of the brain, where it is found in smaller amounts. Thus, as a result of the study, it was shown that TS-13 penetrates the blood-brain barrier and is able to directly affect brain structures, which, however, does not negate the possibility of an indirect effect mediated by the ability to change the activity of intra- and intercellular signaling systems.

Synthetic intercellular signaling system for robust maintenance and differentiation of stem-state cells

Synthetic intercellular signaling system for robust maintenance and differentiation of stem-state cells

The Antibacterial Effect of Cannabigerol toward Streptococcus mutans Is Influenced by the Autoinducers 21-CSP and AI-2

Bacteria can communicate through an intercellular signaling system referred to as quorum sensing (QS). The QS system involves the production of autoinducers that interact with their respective receptors, leading to the induction of specific signal transduction pathways. The QS systems of the oral cariogenic Streptococcus mutans regulate the maturation of biofilms and affect its virulent properties. We have previously shown that the non-psychoactive compound cannabigerol (CBG) of the Cannabis sativa L. plant has anti-bacterial and anti-biofilm activities towards S. mutans. Here we were interested in investigating the effect of the two QS systems ComCDE and LuxS on the susceptibility of S. mutans to CBG and the anti-QS activities of CBG. This was assessed by using various comCDE and luxS mutant strains and complementation with the respective autoinducers, competence stimulating peptide (CSP) and (S)-4,5-dihydroxy-2,3-pentandione (DPD, pre-AI-2). We found that S. mutans comCDE knockout strains were more sensitive to the anti-bacterial actions of CBG compared to the WT strain. Exogenously added 21-CSP prevented the anti-bacterial actions caused by CBG on the ΔcomC, ΔcomE and ΔluxS mutants, while having no effect on the susceptibility of the WT and ΔcomCDE strains to CBG. Exogenously added DPD increased the susceptibility of WT and ΔluxS to CBG. Vice versa, CBG significantly reduced the 21-CSP-induced expression of comCDE genes and ComE-regulated genes and suppressed the expression of luxS with concomitant reduction in AI-2 production. DPD induced the expression of comCDE genes and ComE-regulated genes, and this induction was repressed by CBG. 21-CSP alone had no significant effect on luxS gene expression, while ΔcomCDE strains showed reduced AI-2 production. In conclusion, our study shows that the susceptibility of S. mutans to CBG is affected by the ComCDE and LuxS QS pathways, and CBG is a potential anti-QS compound for S. mutans. Additionally, we provide evidence for crosstalk between the ComCDE and LuxS QS systems.

The Role of luxS in Campylobacter jejuni Beyond Intercellular Signaling.

The full role of the luxS gene in the biological processes, such as essential amino acid synthesis, nitrogen and pyruvate metabolism, and flagellar assembly, of Campylobacter jejuni has not been clearly described to date. Therefore, in this study, we used a comprehensive approach at the cellular and molecular levels, including transcriptomics and proteomics, to investigate the key role of the luxS gene and compared C. jejuni 11168ΔluxS (luxS mutant) and C. jejuni NCTC 11168 (wild type) strains. Transcriptomic analysis of the luxS mutant grown under optimal conditions revealed upregulation of luxS mutant metabolic pathways when normalized to wild type, including oxidative phosphorylation, carbon metabolism, citrate cycle, biosynthesis of secondary metabolites, and biosynthesis of various essential amino acids. Interestingly, induction of these metabolic pathways was also confirmed by proteomic analysis, indicating their important role in energy production and the growth of C. jejuni. In addition, genes important for the stress response of C. jejuni, including nutrient starvation and oxidative stress, were upregulated. This was also evident in the better survival of the luxS mutant under starvation conditions than the wild type. At the molecular level, we confirmed that metabolic pathways were upregulated under optimal conditions in the luxS mutant, including those important for the biosynthesis of several essential amino acids. This also modulated the utilization of various carbon and nitrogen sources, as determined by Biolog phenotype microarray analysis. In summary, transcriptomic and proteomic analysis revealed key biological differences in tricarboxylic acid (TCA) cycle, pyruvate, nitrogen, and thiamine metabolism as well as lipopolysaccharide biosynthesis in the luxS mutant. IMPORTANCE Campylobacter jejuni is the world's leading foodborne bacterial pathogen of gastrointestinal disease in humans. C. jejuni is a fastidious but widespread organism and the most frequently reported zoonotic pathogen in the European Union since 2005. This led us to believe that C. jejuni, which is highly sensitive to stress factors (starvation and oxygen concentration) and has a low growth rate, benefits significantly from the luxS gene. The role of this gene in the life cycle of C. jejuni is well known, and the expression of luxS regulates many phenotypes, including motility, biofilm formation, host colonization, virulence, autoagglutination, cellular adherence and invasion, oxidative stress, and chemotaxis. Surprisingly, this study confirmed for the first time that the deletion of the luxS gene strongly affects the central metabolic pathway of C. jejuni, which improves its survival, showing its role beyond the intercellular signaling system.

The association between Vitamin D levels and postpartum depression: a review

According to WHO, Postpartum Depression (PPD) occurs in 10–15% of women after giving birth. Several studies assumed that vitamin D deficiency might worsen PPD symptoms. However, the association between vitamin D levels and PPD is still conflicting. This article summarizes the association between vitamin D levels and PPD. A literature search about Vitamin D levels and PPD from Scopus and PubMed databases was performed in June 2022. Eleven studies were obtained out of 30 studies. Nine out of 11 studies showed that vitamin D levels were significantly associated with PPD. However, the two others showed no significant association. The difference in the blood sample taken and how to assess depression contributes to a different result. The association is related to the role of vitamin D in mood regulation, synthesis of neurotransmitters, stimulating brain receptors, and intercellular neuronal signaling systems.

Secondary Messengers – A Role in The Regulation of Cell Function

Secondary intermediaries, or secondary messengers, are intracellular signaling molecules released in response to stimulation of receptors. They are the initiating elements in many intracellular signaling cascades and cause the activation of primary effector messenger proteins. This triggers a cascade of physiological changes that are important for the growth, development, differentiation of cells, gene transcription, protein biosynthesis, secretion of hormones, neurotransmitters or cytokines, changes in bioelectric activity and cell migration, and apoptosis induction. Several universal secondary signaling systems exist in the cell, which are mediated by the main three types of mediators: hydrophobic molecules: water-insoluble molecules (diacylglycerol, phosphatidylinositol) that bind to cell membranes and diffuse across intermembrane spaces to organelle membranes, reaching and acting with membrane-bound secondary effector proteins; hydrophilic molecules: water-soluble molecules (cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositol triphosphate, calcium), which are distributed in the aqueous medium of the cytoplasm; gases: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S), which pass through the cell membrane and diffuse into the cytoplasm. The purpose of this review is to generalize and systematize literature data on the mechanisms for the implementation of the functions of secondary messengers in the intercellular signaling system. The study of their functioning and regulation can serve as a fundamental basis for the study of normal brain and experimental pathology, creating the basis for subsequent clinical studies. Keywords: Secondary Mediators; Intercellular Signaling; Effector Proteins; Receptors; Ligands; Brain.

Noncanonical Notch signals have opposing roles during cardiac development

The Notch pathway is an ancient intercellular signaling system with crucial roles in numerous cell-fate decision processes across species. While the canonical pathway is activated by ligand-induced cleavage and nuclear localization of membrane-bound Notch, Notch can also exert its activity in a ligand/transcription-independent fashion, which is conserved in Drosophila, Xenopus, and mammals. However, the noncanonical role remains poorly understood in in vivo processes. Here we show that increased levels of the Notch intracellular domain (NICD) in the early mesoderm inhibit heart development, potentially through impaired induction of the second heart field (SHF), independently of the transcriptional effector RBP-J. Similarly, inhibiting Notch cleavage, shown to increase noncanonical Notch activity, suppressed SHF induction in embryonic stem cell (ESC)-derived mesodermal cells. In contrast, NICD overexpression in late cardiac progenitor cells lacking RBP-J resulted in an increase in heart size. Our study suggests that noncanonical Notch signaling has stage-specific roles during cardiac development.

Dietary Control of Inflammation and Resolution.

The healing of any injury requires a dynamic balance of initiation and resolution of inflammation. This hypothesis-generating review presents an overview of the various nutrients that can act as signaling agents to modify the metabolic responses essential for the optimal healing of injury-induced inflammation. In this hypothesis-generating review, we describe a defined nutritional program consisting of an integrated interaction of a calorie-restricted anti-inflammatory diet coupled with adequate levels of omega-3 fatty acids and sufficient levels of dietary polyphenols that can be used in clinical trials to treat conditions associated with insulin resistance. Each dietary intervention works in an orchestrated systems-based approach to reduce, resolve, and repair the tissue damage caused by any inflammation-inducing injury. The orchestration of these specific nutrients and their signaling metabolites to facilitate healing is termed the Resolution Response. The final stage of the Resolution Response is the activation of intracellular 5' adenosine monophosphate-activated protein kinase (AMPK), which is necessary to repair tissue damaged by the initial injury-induced inflammation. The dietary optimization of the Resolution Response can be personalized to the individual by using standard blood markers. Once each of those markers is in their appropriate ranges, activation of intracellular AMPK will be facilitated. Finally, we outline how the resulting activation of AMPK will affect a diverse number of other intercellular signaling systems leading to an extended healthspan.

The architecture of a mixed fungal-bacterial biofilm is modulated by quorum-sensing signals.

Interkingdom communication is of particular relevance in polymicrobial biofilms. In this work, the ability of the fungus Ophiostoma piceae to form biofilms individually and in consortium with the bacterium Pseudomonas putida, as well as the effect of fungal and bacterial signal molecules on the architecture of the biofilms was evaluated. Pseudomonas putida KT2440 is able to form biofilms through the secretion of exopolysaccharides and two large extracellular adhesion proteins, LapA and LapF. It has two intercellular signalling systems, one mediated by dodecanoic acid and an orphan LuxR receptor that could participate in the response to AHL-type quorum sensing molecules (QSMs). Furthermore, the dimorphic fungus O. piceae uses farnesol as QSM to control its yeast to hyphae morphological transition. Results show for the first time the ability of this fungus to form biofilms alone and in mixed cultures with the bacterium. Biofilms were induced by bacterial and fungal QSMs. The essential role of LapA-LapF proteins in the architecture of biofilms was corroborated, LapA was induced by farnesol and dodecanol, while LapF by 3-oxo-C6-HSL and 3-oxo-C12-HSL. Our results indicate that fungal signals can induce a transient rise in the levels of the secondary messenger c-di-GMP, which control biofilm formation and architecture.

Microbial Biofilms in the Food Industry-A Comprehensive Review.

Biofilms, present as microorganisms and surviving on surfaces, can increase food cross-contamination, leading to changes in the food industry’s cleaning and disinfection dynamics. Biofilm is an association of microorganisms that is irreversibly linked with a surface, contained in an extracellular polymeric substance matrix, which poses a formidable challenge for food industries. To avoid biofilms from forming, and to eliminate them from reversible attachment and irreversible stages, where attached microorganisms improve surface adhesion, a strong disinfectant is required to eliminate bacterial attachments. This review paper tackles biofilm problems from all perspectives, including biofilm-forming pathogens in the food industry, disinfectant resistance of biofilm, and identification methods. As biofilms are largely responsible for food spoilage and outbreaks, they are also considered responsible for damage to food processing equipment. Hence the need to gain good knowledge about all of the factors favouring their development or growth, such as the attachment surface, food matrix components, environmental conditions, the bacterial cells involved, and electrostatic charging of surfaces. Overall, this review study shows the real threat of biofilms in the food industry due to the resistance of disinfectants and the mechanisms developed for their survival, including the intercellular signalling system, the cyclic nucleotide second messenger, and biofilm-associated proteins.

Histone Acetylation Modification H4K16ac Involved in Notch1 Signaling in Breast Cancer

The Notch signaling pathway is a fundamental intercellular signaling system that regulates cell fate decisions in terms of proliferation and differentiation in multiple tissues. Abnormal activation of Notch1 signaling pathway leads to a variety of diseases, including the malignant tumors. Dysregulated Notch receptor activity has been implicated in breast cancer but the epigenetic mechanisms remains not clear. Compared to adjacent tissues, high expression of NIC1 and low expression of H4K16ac were found in cancer tissues. Notch1 knocked down in the breast cancer cell line MCF-7 resulted in increased H4K16ac expression and a parallel reduction in their proliferation and migration capacity. Our study prompting H4K16ac to participate in the signal transduction of Notch1 in breast cancer cells. These results confirm Notch1 as a signal triggering epigenetic mechanisms in breast cancer cells, which may have implications in tumor dissemination, metastasis and proliferation. The identification of specific factors interacting with NOTCH signaling could thus be relevant to fully understanding the role of NOTCH in breast neoplasia.

ROLE OF SIRTUIN 1 IN REGULATION OF MELANOMA CELL PROLIFERATION

Melanoma remains one of the most dangerous skin cancers among fair-skinned population. the search for new effective treatments, including therapy based on the selection of molecular targets, is one of the main and difficult tasks in the study of melanoma. One of the trends in experimental oncology is the study of microRNa’s role in carcinogenesis. MicroRNas are involved in many physiological and pathological processes, including cell proliferation, differentiation, migration, invasion, and carcinogenesis. It has been previously revealed that miR-204-5p levels are reduced in malignant tumors, in particular, in skin melanoma. the aim of this study was to determine the functional role of sIRt1 as a direct target of miR-204-5p in the pathogenesis of skin melanoma. Bioinformatics analysis allowed identification of micrRNa target genes that affected apoptosis, proliferation and cell viability. the level of proliferation of melanoma cells under the influence of small interfering RNa was estimated using the Mtt test and fluorescence microscopy. Luciferase Reporter assay was performed to evaluate whether sIRt1 was a target of miR-204-5p. Relative luciferase activity was calculated 48 hours after transfection with miR-204-5p mimic. the Mtt test showed that the proliferative activity of melanoma cells decreased 72 hours after siRNa sIRt1 knockdown. Fluorescent microscope revealed the same tendency in sIRt1 siRNa transfected cells. Mechanistic studies revealed that miR-204-5p repressed the expression of sIRt1 through binding to its 3`utR. therefore, miR-204-5p can regulate melanoma cell proliferation by targeting sIRt1 which can affect intercellular signaling systems related to cell cycle.

FEATURES OFT THE PERIODONTAL TISSUES ULTRASTRUCTURE UNDER CHRONIC PSYCHOEMOTIONAL STRESS

With the help of electron microscopic and morphometric methods, the features of changes in the ultrastructure of periodontal tissues in persons with psychoemotional stresses were studied.It was shown that chronic psychoemotional stress is accompanied in the gum tissue by the development of endothelial and mitochondrial dysfunction with signs of edema and destruction of the capillary endothelium and a violation of the ultrastructure of about 50 % of the mitochondria in the cells.Structural changes were also observed in bone tissue. They testified about the development of destructive processes with the violation of intercellular signaling system and signs of necrotic cells. Such changes in the gum and bone tissues can promote the development of periodontitis in the case of chronic psychoemotional stress and lead to tooth loss.

Designed Small-Molecule Inhibitors of the Anthranilyl-CoA Synthetase PqsA Block Quinolone Biosynthesis in Pseudomonas aeruginosa.

The Gram-negative bacterial pathogen Pseudomonas aeruginosa uses three interconnected intercellular signaling systems regulated by the transcription factors LasR, RhlR, and MvfR (PqsR), which mediate bacterial cell–cell communication via small-molecule natural products and control the production of a variety of virulence factors. The MvfR system is activated by and controls the biosynthesis of the quinolone quorum sensing factors HHQ and PQS. A key step in the biosynthesis of these quinolones is catalyzed by the anthranilyl-CoA synthetase PqsA. To develop inhibitors of PqsA as novel potential antivirulence antibiotics, we report herein the design and synthesis of sulfonyladeonsine-based mimics of the anthranilyl-AMP reaction intermediate that is bound tightly by PqsA. Biochemical, microbiological, and pharmacological studies identified two potent PqsA inhibitors, anthranilyl-AMS (1) and anthranilyl-AMSN (2), that decreased HHQ and PQS production in P. aeruginosa strain PA14. However, these compounds did n...

Epigenetic regulation of intercellular communication in the heart.

The myocardium is a highly structured tissue consisting of different cell types including cardiomyocytes, endothelial cells, fibroblasts, smooth muscle cells, inflammatory cells, and stem cells. Microvascular endothelial cells are the most abundant cell type in the myocardium and play crucial roles during cardiac development, in normal adult myocardium, and during myocardial diseases such as heart failure. In the last decade, epigenetic changes have been described regulating cellular function in almost every cell type in the organism. Here, we review recent evidence on different epigenetic changes that regulate intercellular communication in normal myocardium and during myocardial diseases, including cardiac remodeling. Epigenetic changes influence many intercellular communication signaling systems, including the nitric oxide, angiotensin, and endothelin signaling systems. In this review, we go beyond discussing classic endothelial function (for instance nitric oxide secretion) and will discuss epigenetic regulation of intercellular communication.

Gene expression in patients with abdominal aortic aneurysm - more than immunological mechanisms involved.

Abdominal aortic aneurysm (AAA) is a serious condition of unclear pathogenesis and progression. Two samples were collected from 48 patients during AAA surgery. One sample was collected from the aneurysm, the other from the aneurysm proximal neck where the tissue did not exhibit any aneurysmal changes. Subsequently, gene expression profiles using microarrays (Illumina) were compared in RNA extracted from the samples. Overall, 2,185 genes were found to be upregulated and 2,100 downregulated; from which 158 genes had a different expression with FDR<0.05 (False Discovery Rate) and FC>/=2 (Fold Change). Of this number, 115 genes were over-expressed and 43 under-expressed. The analysis of the gene list based on their biological pathways revealed that the regulation of inflammation was mediated by chemokine and cytokine signaling pathways, the integrin signaling pathway, and T and B cell activation. Moreover, a change was identified in the expression of genes involved in both intercellular and intracellular signaling systems.