Plant polyphenols in cell-cell interaction and communication

Plant polyphenols including flavonoids and tannins are important constituent of our everyday diet and medical herbals. It is broadly accepted that polyphenols may protect us from toxins, carcinogens and pollutants though the mechanisms of the polyphenols action is still not clear. Here we discuss the ability of polyphenols and especially gallate rich compounds like tannins and catechin gallates to interact with proteins and lipids, establish binding between adjacent bilayer surfaces and initiate membrane aggregation. This phenomena discovered in model experiments could also influence lateral segregation and compartmentalization of cell surface compounds and assist the cell-cell interaction and signal transduction. The involvement of plant polyphenols in communication between cells could be an important factor responsible for anticarcinogenic, vascular and cardioprotective activity of these compounds and speculated to be implicated in the evolution of human brain and intelligence.Key words: human evolution, polyphenols, flavonoids, tannins, membranes, lipid rafts, bilayer structure, cell communicationPlant polyphenols including flavonoids and tannins are present on our daily diet. The opinion on their influence on the human health is contradictory and ranges widely from positive to skeptic and even to alarming.^1–3 Obviously the processes of their functioning in our body should be studied in more details.The polyphenols are know not only as patent antioxidants but also as cell metabolism regulators.⁴ The biological functioning of these compounds begins from their interaction with the cell surface and penetration through the plasma membrane into the cytoplasm. They can influence various physical properties of membrane lipids including diffusion, melting temperature, detergent solubility, osmotic stability, permeability to water soluble compounds^5–7 and general parameters of lipid packing and intrinsic bilayer curvature related to membrane interaction and fusion. Their penetration through the lipid bilayer inversive correlates with the number of hydroxyl groups and accordingly with the hydrophobicity of molecules.The background of polyphenols functioning is attributed to the ability of these compounds to interact with proteins, lipids and polynucleotides through electrostatic, hydrophobic, and even covalent binding.^6–9 The polyphenolic compounds are generally not very active chemically and only electrostatic and hydrophobic forces are responsible for their interaction within cells. However, after oxidation of catechol and gallate¹⁰ moieties to quinones (Fig. 1) in presence of peroxidases, polyphenol oxidases, alkaline pH, or transition metals they could be involved in reactions with free nucleophilic functional groups such as sulfhydryl, amine, amide, indole and imidazole substituents;¹¹ and result in covalent binding with different residues including lysine, methionine, cysteine and tryptophane.^8,12 We expect that terminal amino groups of phosphatidylethanolamines or sulfolipids of biological membranes can also participate in covalent binding with quinones. The consequence of chemical derivatization of proteins may lead to changes in a-helix and random coiled constituents and be accompanied by modulation of protein physical properties and functioning.⁸Open in a separate windowFigure 1A simplified scheme of catechol and gallate moieties oxidation to quinones and subsequent quinones reaction with terminal amino- and sulfa-groups of proteins and lipids (R₂ or R₃). The catechol and gallate moieties are attached to a larger molecule of polyphenol (R₁). For details see reviews.^8,12Among the polyphenolic compounds, tannins express the strongest influence on the lipid bilayer properties. The influence depends on the presence of numerous gallic moieties in the tannin molecule.¹³ Tannins are able to bind on the membrane surface, establish bridges between apposing bilayers and initiate their interaction and adhesion.¹⁴ The process is accompanied by reduction of the membrane dipole potential, lipid interdigitation and the decrease of interbilayer spacing from 15 Å to 5 Å. According to authors¹³ this happens because tannins (1) are amphipathic and partition into the bilayers interfacial region, (2) are long enough to span the interbilayer space, (3) contain several gallic acids distributed so that they can partition simultaneously into apposing bilayers, and (4) have sufficient gallic acid residues to interact with all lipid headgroups and cover the bilayer surface. The electrostatic interaction between the π electrons in the phenol ring and -N⁺(CH₃)₃ groups of phosphatidylcholines is also should be considered.It is necessary to mention that besides tannins the gallate moiety is present also in some antimalarial agents as rufigallol and exifone.¹⁵ The tea catechin gallate and a number of related compounds including gallocatechin gallate, epicatechin gallate, epigallocatechin gallate contain the gallic moiety and was found to influence the membrane fluidity.¹⁶ Some of the tea gallates reveal anticancer activity correlated with membrane rigidifying effect.¹⁷ Not long ago novel black tea pigments rich with gallate moieties and produced by oxidation of tea epagallocatechin-3-o-gallate were discovered (Fig. 2).¹⁸ The appearance of this kind of pigments in food is very typical example of enzymatic and thermal browning process accompanying various traditional preparation of beverages (tea, coffee, cacao, beer and so on) and meal (roasted or baked vegetables and meet).¹¹Open in a separate windowFigure 2Tannin (A) and a fragment of polymeric chain of gallate rich black tea pigment (B). The triplets of neighboring hydroxyl groups of gallic acid are emphasized by a larger font.According to our hypotheses (Fig. 3) the polyphenols rich with gallate moieties may attach to the cell surface, change physical properties of lipids, initiate lateral segregation and formation of lipid and protein clusters, and finally, initiate binding of neighbouring cells. The lateral segregation of the bilayer compounds is known as a physical background of membranes compartmentalization and lipid rafts formation.^19,20 This process is relevant for cell-cell communication, signalling and metabolism regulation; and, thus, responsible for numerous medically recognizable processes.²¹ It is known that lipid rafts are enriched with cholesterol and sphingolipids that serve as a platform for gathering of signalling and trafficking proteins.²² Tannins and other gallate rich molecules may specifically interact with -N⁺(CH₃)₃ groups of sphingomyelin present in the outer leaflet of plasma membrane. High reactivity of gallates towards nucleophilic moieties of proteins especially in presence of peroxidases may facilitate formation of covalent bridges between adjacent cells.Open in a separate windowFigure 3Polyphenols rich of gallate moieties can interact with the cell surface (A). Then gallates may initiate the phospholipid rigidifying process (physically modified lipids are emphasized by shape and color) (B) and lead to aggregation of some proteins and lipids in clusters (D). Polyphenol molecules could serve as bridges between surfaces of two neighbor cells and initiate cells binding and formation of similar clusters in the membrane of the opposite cell.Plant polyphenols as catechins of tea^23,24 are involved in cell-cell interactions responsible for their anticarcinogenic activity by upregulating the receptor and signaling cascades of communication between cells. Well known cardiovascular protective effect of plant polyphenols can also be explained by influence of these compounds on interaction between endothelial cells.²⁵The cell-cell communication and signal transduction is very important also for functioning of neural networks. In human evolution the plant polyphenol consumption would be considerable improved after invention of the fire cooking. It was supposed that the thermal treatment of meat and vegetables, mostly wild tubers of antic savanna, was an important factor of the brain evolution.²⁶ The increase of protein, lipid and carbohydrates availability contributes the most noticeable gain in human intellectual development.²⁷ The role of polyphenols in neuronal communication and brain evolution is still has to be uncovered. Flavonoids are known to protect the brain from oxidation stress and prevent the aging and numerous pathological processes including neuronal damage during Alzheimer''s disease, Parkinson''s disease, amyotrophic lateral sclerosis.^28,29 It seems the mechanism of polyphenols action on the brain functioning could not be restricted by prevention against oxidation stress because these compounds could also participate in the intracellular signal transduction cascades and modulation of brain functioning.³⁰ This may be explained by interactions of polyphenols with specific proteins and plasma membrane compartments responsible for signal transduction as well as for memory formation and storage.     

Exosomes: New players in cell-cell communication

Exosomes are small membrane vesicles of endosomal origin, which are secreted from a variety of cell types. During the 1980s exosomes were first described as organelles to remove cell debris and unwanted molecules. The discovery that exosomes contain proteins, messenger and microRNAs suggests a role as mediators in cell-to-cell communication. Exosomes can be transported between different cells and influence physiological pathways in the recipient cells. In the present review, we will summarize the biological function of exosomes and their involvement in physiological and pathological processes. Moreover, the potential clinical application of exosomes as biomarkers and therapeutic tools will be discussed.     

Direct cell-cell communication in the blood-forming system

In mammals, bone marrow is the principal tissue where blood is formed during adult life. Paracrine factors are generally considered to control this process but there is considerable evidence that gap junctions are present in haemopoietic tissues. Gap junctions have been implicated in developmental and patterning roles, and we set out to characterize the cells which are coupled, and to provide evidence for their role(s) in blood cell formation. Direct cell-cell communication, shown by dye-transfer, occurs between haemopoietic cells and certain stromal cells. In culture these stromal cells form a mat in which they retain their dye-coupling properties. Freeze-fracture electron microscopy confirms that this coupling is via gap junctions. When haemopoietic cells are cultured on top of these mats dye spreads upwards from the stromal cells into the haemopoietic cells above. Experiments in which haemopoietic cells were cultured alone, with stromal cell conditioned medium, or in direct contact with stromal cell underlays, were therefore carried out. The results of these experiments provide evidence that gap junctional communication may be playing a vital role in maintaining populations of precursor cells which would otherwise differentiate into end cells, leading to the ultimate demise of the system.     

Microfluidic modeling of cell-cell interactions in malaria pathogenesis

The clinical outcomes of human infections by Plasmodium falciparum remain highly unpredictable. A complete understanding of the complex interactions between host cells and the parasite will require in vitro experimental models that simultaneously capture diverse host-parasite interactions relevant to pathogenesis. Here we show that advanced microfluidic devices concurrently model (a) adhesion of infected red blood cells to host cell ligands, (b) rheological responses to changing dimensions of capillaries with shapes and sizes similar to small blood vessels, and (c) phagocytosis of infected erythrocytes by macrophages. All of this is accomplished under physiologically relevant flow conditions for up to 20 h. Using select examples, we demonstrate how this enabling technology can be applied in novel, integrated ways to dissect interactions between host cell ligands and parasitized erythrocytes in synthetic capillaries. The devices are cheap and portable and require small sample volumes; thus, they have the potential to be widely used in research laboratories and at field sites with access to fresh patient samples.     

MicroRNAs in viral replication and pathogenesis

MicroRNAs (miRNAs) are an important class of small, noncoding, regulatory RNAs found to be involved in regulating a wide variety of important cellular processes by the sequence-specific inhibition of gene expression. Viruses have evolved a number of mechanisms to take advantage of the regulatory potential of this highly conserved, ubiquitous pathway known as RNA interference (RNAi). This review will focus on the recent efforts to understand the complex relationship between vertebrate viruses and the RNAi pathway, as well as the role of silencing pathways in the inhibition of pathogenic genetic elements, including transposons and retrotransposons.     

Molecules mediating cell-ECM and cell-cell communication in human heart valves

The specific phenotype of different tissues depends on the interactions of cells with neighboring cells and the surrounding extracellular matrix, which is mediated by cell adhesion receptors including integrins, immunoglobulin family members, syndecans, and selectins. The aim of this study was to investigate the adhesion profile of native human valve interstitial cells (ICs) in situ and in vitro by analyzing these adhesion receptors. Flow cytometry and immunocytochemistry was used to quantify the expression of the specific receptors on ICs cultured from all human cardiac valves, and immunohistochemistry were used to profile their distribution pattern in valve tissue sections. The valve leaflets and cultured ICs from all valves expressed alpha1, alpha2, alpha3, alpha4, and alpha5 integrins to varying degrees and percentages with very little expression of alpha6 and alphaV. Valve leaflet ICs from all valves, expressed predominantly beta1 integrin but no beta3 or beta4 integrin. Syndecan-1 and Syndecan-4 were not detected. Intercellular adhesion molecule-1 was weakly detected, whereas vascular adhesion molecule-1 was barely detectable and E-selectin was not detected. This study has delineated the identity of some of the integrins synthesized and expressed by human valve ICs and the specificity of adhesion molecules with which the valve ICs interact with the extracellular matrix and mediate intercellular interactions. This pattern of expression of cell surface adhesion molecules may be considered as a basis for a fingerprint on which to base future cell alternatives and would provide useful information for valve tissue engineering.     

Autophagy in viral replication and pathogenesis

Autophagy is a catabolic process that is important for the removal of damaged organelles and long-lived proteins for the maintenance of cellular homeostasis. It can also serve as innate immunity to remove intracellular microbial pathogens. A growing list of viruses has been shown to affect this cellular pathway. Some viruses suppress this pathway for their survival, while others enhance or exploit this pathway to benefit their replication. The effect of viruses on autophagy may also sensitize cells to death or enhance cell survival and play a critical role in viral pathogenesis. In this article, we review the relationships between different viruses and autophagy and discuss how these relationships may affect viruses and their host cells.     

Cdon and Boc: Two transmembrane proteins implicated in cell-cell communication

Cdon and Boc, and their Drosophila homologues Ihog and Boi, are evolutionary conserved transmembrane glycoproteins belonging to a subgroup of the Immunoglobulin superfamily of cell adhesion molecules (CAMs). Initially isolated in vertebrates as CAMs that link cadherin function with MAPK signaling in myoblast differentiation, they have thereafter been shown to act as essential receptors for the Hedgehog (Hh) family of secreted proteins. They associate with both ligand and other Hh receptor components, including Ptch and Gas1, thus forming homo- and heteromeric complexes. In Drosophila, they are also involved in ligand processing and release from Hh producing cells. Cdon/Boc and Ihog/Boi can substitute one another and play redundant functions is some contexts. In addition, Boc, but not Cdon, mediates axon guidance information provided by Hh in specific neuronal populations, whereas mutations in the CDON cause holoprosencephaly, a human congenital anomaly defined by forebrain midline defects prominently associated with diminished Hh pathway activity.     

Cell behavior and cell-cell communication during fruiting body morphogenesis in Myxococcus xanthus

Formation of spatial patterns of cells from a mass of initially identical cells is a recurring theme in developmental biology. The dynamics that direct pattern formation in biological systems often involve morphogenetic cell movements. An example is fruiting body formation in the gliding bacterium Myxococcus xanthus in which an unstructured population of identical cells rearranges into an asymmetric, stable pattern of multicellular fruiting bodies in response to starvation. Fruiting body formation depends on changes in organized cell movements from swarming to aggregation. The aggregation process is induced and orchestrated by the cell-surface associated 17 kDa C-signal protein. C-signal transmission depends on direct contact between cells. Evidence suggests that C-signal transmission is geometrically constrained to cell ends and that productive C-signal transmission only occurs when cells engage in end-to-end contacts. Here, we review recent progress in the understanding of the pattern formation process that leads to fruiting body formation. Gliding motility in M. xanthus involves two polarly localized gliding machines, the S-machine depends on type IV pili and the A-machine seems to involve a slime extrusion mechanism. Using time-lapse video microscopy the gliding motility parameters controlled by the C-signal have been identified. The C-signal induces cells to move with increased gliding speeds, in longer gliding intervals and with decreased stop and reversal frequencies. The combined effect of the C-signal dependent changes in gliding motility behaviour is an increase in the net-distance travelled by a cell per minute. The identification of the motility parameters controlled by the C-signal in combination with the contact-dependent C-signal transmission mechanism have allowed the generation of a qualitative model for C-signal induced aggregation. In this model, the directive properties of the C-signal are a direct consequence of the contact-dependent signal-transmission mechanism, which is a local event involving direct contact between cells that results in a global organization of cells. This pattern formation process does not depend on a diffusible substance. Rather it depends on a cell-surface associated signal to direct the cells appropriately.     

Learning the language of cell-cell communication through connexin channels

A report on the Ninth International Gap Junction Conference, Honolulu, USA, 4-9 August 2001.     

Feline immunodeficiency virus decreases cell-cell communication and mitochondrial membrane potential.

The in vitro effects of viral replication on mitochondrial membrane potential (MMP) and gap junctional intercellular communication (GJIC) were evaluated as two parameters of potential cellular injury. Two distinct cell types were infected with the Petaluma strain of feline immunodeficiency virus (FIV). Primary astroglia supported acute FIV infection, resulting in syncytia within 3 days of infection, whereas immortalized Crandell feline kidney (CRFK) cells of epithelial origin supported persistent FIV infection in the absence of an obvious cytopathic effect. An examination of cells under conditions that included an infection rate of more than 90% for either population revealed that the astroglia produced about four times more virus than the CRFK cells. The mitochondrial uptake of the cationic fluorescent dye rhodamine 123 in infected astroglia was less than 45% of that of normal control cells, whereas the MMP of the CRFK cells, which produced about one-fourth as much virus, was 80.8% of that of the normal cells. Cell-cell communication between adjacent cells was determined by the recovery of fluorescence following photobleaching of a single cell. In spite of the lower level of innate cell-cell communication among cultured CRFK cells than among astroglia, viral replication resulted in a 30% decrease in the GJIC of both astroglia and CRFK cells. These studies indicate that cell injury, as defined by an inhibition of MMP and GJIC, can occur as a result of persistent and acute infection with the Petaluma strain of FIV.     

Working together for the common good: cell-cell communication in bacteria

The 4th ASM Conference on Cell-Cell Communication in Bacteria was held in Miami, FL, from 6 to 9 November 2011. This review highlights three key themes that emerged from the many exciting talks and poster presentations in the area of quorum sensing: sociomicrobiology, signal transduction mechanisms, and interspecies communication.     

Dengue viral infections; pathogenesis and epidemiology

Dengue viral infections affect up to 100 million individuals per year. Dengue haemorrhagic fever is a clinical form of disease characterised by intravascular fluid loss. There has been a marked increase in the incidence of this form of the disease over the last few decades, associated with significant mortality, particularly in the paediatric population. A number of theories relating to the pathogenesis of dengue haemorrhagic fever exist that have evolved from the analysis of the epidemiology of this disease. Virological and immunopathological factors are both important but the exact mechanisms for the disease are unknown.     

Modulation of cell-cell communication in the cause and chemoprevention/chemotherapy of cancer

Chemopreventive or chemotherapeutic agents have been those that either kill cancer cells to a differential degree over the non-cancer cells or those chemicals that either block the induction of tumors in carcinogen-treated animals or retard transplanted tumors in animals. Carcinogenesis is a multi-stage, multi-mechanism process, involving the irreversible alteration of a stem cell ("initiation"), followed by the clonal proliferation of the initiated cell ("promotion"). To develop a strategy for intervention with chemoprevention/chemotherapeutic chemicals, the basic mechanism(s) of carcinogenesis must be understood. Gap junction intercellular communication (GJIC) regulates cell growth, differentiation, apoptosis and adaptive functions of differentiated cells. Normal cells have functional GJIC while cancer cells do not. Tumor promoters and oncogenes inhibit GJIC, while anti-tumor promoter and anti-oncogene drugs can reverse the down-regulation of GJIC. Transfection of gap junction genes (connexins) has been shown to reverse the tumorigenic phenotype. If prevention/treatment of cancer is to occur, prevention of the chronic down regulation of GJIC by tumor promoters in non-tumorigenic but initiated cells or the up-regulation of GJIC in stably down-regulated GJIC in tumor cells must occur to prevent or to treat cancers.