Evidence for the Interaction between (−)-Epigallocatechin Gallate and Human Plasma Proteins Fibronectin,Fibrinogen, and Histidine-rich Glycoprotein

Human plasma proteins were subjected to affinity chromatography with (–)-epigallocatechin gallate (EGCg)-agarose, and the bound proteins were examined by sodium dodecylsulfate–polyacrylamide gel electrophoresis. A molecular weight evaluation of the protein bands suggested the presence of three proteins, fibronectin, fibrinogen, and a 75-kDa protein. When human serum was used, the 75-kDa protein dominated the bound fraction. The determination of the partial amino acid sequence of a peptide derived by endopeptidase digestion of this fraction suggested the 75-kDa protein to be histidine-rich glycoprotein (HRG). The presence of these proteins in the bound fraction was confirmed by the immunoblotting method. Affinity chromatography of the individual proteins indicated that fibrinogen and HRG had direct affinity for EGCg. Dot binding assays demonstrated the interaction of EGCg with these proteins. The method also showed that only gallate-containing catechins were bound by these proteins. These data suggest that when EGCg is absorbed in the body through the digestive system, it may interact with these proteins in blood plasma.     

Insights into the Interactions between Maleimide Derivates and GSK3β Combining Molecular Docking and QSAR

Many protein kinase (PK) inhibitors have been reported in recent years, but only a few have been approved for clinical use. The understanding of the available molecular information using computational tools is an alternative to contribute to this process. With this in mind, we studied the binding modes of 77 maleimide derivates inside the PK glycogen synthase kinase 3 beta (GSK3β) using docking experiments. We found that the orientations that these compounds adopt inside GSK3β binding site prioritize the formation of hydrogen bond (HB) interactions between the maleimide group and the residues at the hinge region (residues Val135 and Asp133), and adopt propeller-like conformations (where the maleimide is the propeller axis and the heterocyclic substituents are two slanted blades). In addition, quantitative structure–activity relationship (QSAR) models using CoMSIA methodology were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. We found a model to explain the structure–activity relationship of non-cyclic maleimide (NCM) derivatives (54 compounds). The best CoMSIA model (training set included 44 compounds) included steric, hydrophobic, and HB donor fields and had a good Q² value of 0.539. It also predicted adequately the most active compounds contained in the test set. Furthermore, the analysis of the plots of the steric CoMSIA field describes the elements involved in the differential potency of the inhibitors that can be considered for the selection of suitable inhibitors.     

Interaction between DNA Polymerase λ and Anticancer Nucleoside Analogs

The anticancer activity of cytarabine (AraC) and gemcitabine (dFdC) is thought to result from chain termination after incorporation into DNA. To investigate their incorporation into DNA at atomic level resolution, we present crystal structures of human DNA polymerase λ (Pol λ) bound to gapped DNA and containing either AraC or dFdC paired opposite template dG. These structures reveal that AraC and dFdC can bind within the nascent base pair binding pocket of Pol λ. Although the conformation of the ribose of AraCTP is similar to that of normal dCTP, the conformation of dFdCTP is significantly different. Consistent with these structures, Pol λ efficiently incorporates AraCTP but not dFdCTP. The data are consistent with the possibility that Pol λ could modulate the cytotoxic effect of AraC.     

Interactions between amyloid β peptide and lipid membranes

The presence of amyloid plaques in the brain is a typical characteristic of Alzheimer's disease (AD). Amyloid plaques are formed from the deposits of aggregated amyloid β peptide (Aβ). The toxicity induced by Aβ aggregates is correlated with Aβ-membrane interactions. The mutual influences between aggregation and membranes are complicated and unclear. In recent years advanced experiments and findings are emerging to give us more detailed information on Aβ-membrane interactions. In this review, we mainly focus on the Aβ-membrane interactions and membrane-induced Aβ structures. The mechanism of Aβ-membrane interactions is also summarized, which provides insights into the prevention and treatment of AD.     

Interactions between metals and alpha-synuclein--function or artefact?

alpha-synuclein is one of a family of proteins whose function remains unknown. This protein has become linked to a number of neurodegenerative disease although its potential causative role in these diseases remains mysterious. In diseases such as Parkinson's disease and Lewy body dementias, alpha-synuclein becomes deposited in aggregates termed Lewy bodies. Also, some inherited forms of Parkinson's diseases are linked to mutations in the gene for alpha-synuclein. Studies have mostly focussed on what causes the aggregation of the protein but, like many amyloidogenic proteins associated with a neurodegenerative disorder, this protein has now been suggested to bind copper. This finding is currently controversial. This review examines the evidence that alpha-synuclein is a copper binding protein and discusses whether this has any significance in determining the function of the protein or whether copper binding is at all necessary for aggregation.     

Interactions between malaria and HIV infection-an emerging public health problem?

Recent evidence demonstrates interactions between malaria and HIV infection. HIV-infected people are more likely to experience clinical malaria, and acute malaria can up-regulate HIV replication, leading to higher plasma viral loads. This is most serious in pregnant women, where HIV infection increases the risk of placental malaria, leading to increased infant morbidity and mortality.     

Anticooperative Nearest-Neighbor Interactions between Residues in Unfolded Peptides and Proteins

Growing evidence suggests that the conformational distributions of amino acid residues in unfolded peptides and proteins depend on the nature of the nearest neighbors. To explore whether the underlying interactions would lead to a breakdown of the isolated pair hypothesis of the classical random coil model, we further analyzed the conformational propensities that were recently obtained for the two guest residues (x,y) of GxyG tetrapeptides. We constructed a statistical thermodynamics model that allows for cooperative as well as for anticooperative interactions between adjacent residues adopting either a polyproline II or a β-strand conformation. Our analysis reveals that the nearest-neighbor interactions between most of the central residues in the investigated GxyG peptides are anticooperative. Interaction Gibbs energies are rather large at high temperatures (350 K), at which point many proteins undergo thermal unfolding. At room temperature, these interaction energies are less pronounced. We used the obtained interaction parameter in a Zimm-Bragg/Ising-type approach to calculate the temperature dependence of the ultraviolet circular dichroism (CD) of the MAX3 peptide, which is predominantly built by KV repeats. The agreement between simulation and experimental data was found to be satisfactory. Finally, we analyzed the temperature dependence of the CD and ³J(H^NH^α) parameters of the amyloid β_1–9 fragment. The results of this analysis and a more qualitative consideration of the temperature dependence of denatured proteins probed by CD spectroscopy further corroborate the dominance of anticooperative nearest-neighbor interactions. Generally, our results show that unfolded peptides—and most likely also proteins—exhibit some similarity with antiferromagnetic systems.     

Structural—Functional Relationships between Terminal Deoxynucleotidyltransferase and 5′-Triphosphates of Nucleoside Analogs

Substrate properties of nucleoside 5′-triphosphate (NTP) analogs, namely, 5′-triphosphates of L- and D-arabinonucleosides (D-FIAUTP, D-FMAUTP, and L-FMAUTP), D- and L-enantiomers of ddCTP analogs (D-ddCTP, L-ddCTP, D-FOddCTP, L-OddCTP, and L-SddCTP), and acyclic guanosine analogs (acyclovir and penciclovir) towards terminal deoxynucleotidyltransferase (TdT, EC 2.7.7.31) were studied. TdT can polymerize 5′-triphosphates of arabinonucleoside analogs (D-FIAUTP and D-FMAUTP). In contrast, L-FMAUTP is not recognized by TdT as a substrate. Kinetic parameters of D- and L-enantiomers of ddCTP analogs and 5′-triphosphates of acyclic nucleosides were evaluated. It is shown that stereospecificity of dNTP analogs and structure of the furanose residue play crucial roles in the interaction with TdT: L-enantiomers are much less potent as substrates compared to their D-counterparts. 5′-Triphosphates of acyclovir (ACVTP) and penciclovir (PCVTP) are about two orders of magnitude less effective as substrates than nucleosides bearing furanose residues, with PCVTP being a better substrate than ACVTP. It can be assumed that the hydroxyl group of PCVTP mimics the 3′-hydroxyl group of the ribose residue and plays an important role in the interaction with TdT.__________Translated from Biokhimiya, Vol. 70, No. 8, 2005, pp. 1078–1085.Original Russian Text Copyright © 2005 by Kukhanova, Ivanov, Jasko.     

Review – Interactions between diatoms and stainless steel: focus on biofouling and biocorrosion

There is a considerable body of information regarding bacterially enhanced corrosion, however, this review focuses on diatoms (unicellular algae) whose contribution to biocorrosion is less well studied. The reasons why diatoms have been neglected in studies of biocorrosion in natural waters are discussed and the question whether diatoms should be considered as inert with respect of electrochemical processes is considered. A particular focus is given to the case of stainless steels (SS), which are widely used in variety of applications in natural waters. Basic information on the cell biology of diatoms is included in the review, particularly with respect to their ability to ‘sense’ and adhere to surfaces. Investigations at the nanoscale are reviewed as these studies provide information about the behavior of cells at interfaces. Recent advances include the use of atomic force microscopy (AFM), although only a few studies have been applied to diatoms. Regarding the electrochemical behavior of SS, the mechanisms by which diatoms influence the potential ennoblement process is discussed. Such studies reveal the association of diatoms, in addition to bacteria, with biocorrosion processes.     

Molecular Modeling and Docking of Microbial Inulinases Towards Perceptive Enzyme–Substrate Interactions

Inulin is emerging as an extremely rare source of sugar, it is having more sweetening capacity than table sugar, has beneficial effect in diabetic patient. Inulinases mainly produced by the microorganism and it degrades inulin into fructose which is a digestible form. There are more than 58 strains of microorganisms which are involved in the production of inulinases. The present report investigates about the selectivity of inulin by inulinase and its action to produce fructose through molecular docking. We have investigated exo-inulinase and endo-inulinases from Penicillium sp. TN-88({"type":"entrez-protein","attrs":{"text":"BAC16218","term_id":"22852185","term_text":"BAC16218"}}BAC16218) and Penicillium sp. TN-88({"type":"entrez-protein","attrs":{"text":"BAA19132","term_id":"1841298","term_text":"BAA19132"}}BAA19132), respectively with different arrangement of amino acids in the active site which detect the substrate. The protein sequences described above were processed to homology modeling by Swiss model and further they were docked with 1-ketose and fructose-6-phosphate as substrate by DOCK6 software package (dock.compbio.ucsf.edu). The results of the present studies represented that fructose-6-phosphate ((2R,3R,4S) fructose-6-phosphate) was having better interaction with exo-inulinase showing grid score of −40.288094 and the conserved amino acid Asp-22, Asp 128, Asp 179 and Ser 84 of exo-inulinase are involved in the bonding. In addition to this it was also seen that 1-ketose ((3S,4R)-ketose 1-phosphate) did not shown any interaction with the conserved part of the endo-inulinase.     

Interactions between κ-carrageenan and chitosan in nanolayered coatings—Structural and transport properties

The interactions between κ-carrageenan and chitosan, two oppositely charged polysaccharides, have been investigated through microcalorimetric and quartz crystal microbalance measurements. Microcalorimetric measurements show that κ-carrageenan/chitosan interaction is an exothermic process and that the alternate deposition of κ-carrageenan and chitosan results in the formation of a nanolayered coating mainly due to the electrostatic interactions existing between the two polyelectrolytes (though other types of interactions may also be involved). Quartz crystal microbalance measurements confirmed that the alternating deposition of κ-carrageenan and chitosan resulted in the formation of a stable multilayer structure. The κ-carrageenan/chitosan nanolayered coating, assembled on a polyethylene terephthalate (PET) support, was characterized in terms of its surface (contact angle measurements) and gas barrier properties (water vapor and O₂ permeabilities) and analyzed by scanning electron microscopy (SEM). The water vapor permeability (WVP) and the oxygen permeability (O₂P) of the κ-carrageenan/chitosan nanolayers were found to be 0.020 ± 0.002 × 10⁻¹¹ and 0.043 ± 0.027 × 10⁻¹⁴ g m⁻¹ s⁻¹ Pa⁻¹, respectively. These results contribute to a better understanding of the type of interactions that play role during the construction of this type of nanostructures. This knowledge can be used in the establishment of an approach to produce edible, biodegradable multilayered nanostructures with improved mechanical and barrier properties for application in, e.g. food and biomedical industries.     

Interactions between naïve and infected macrophages reduce Mycobacterium tuberculosis viability

A high intracellular bacillary load of Mycobacterium tuberculosis in macrophages induces an atypical lysosomal cell death with early features of apoptosis that progress to necrosis within hours. Unlike classical apoptosis, this cell death mode does not appear to diminish M. tuberculosis viability. We previously reported that culturing heavily infected macrophages with na?ve macrophages produced an antimicrobial effect, but only if na?ve macrophages were added during the pre-necrotic phase of M. tuberculosis-induced cell death. In the present study we investigated the mechanism of antimicrobial activity in co-cultures, anticipating that efferocytosis of bacilli in apoptotic bodies would be required. Confocal microscopy revealed frustrated phagocytosis of M. tuberculosis-infected macrophages with no evidence that significant numbers of bacilli were transferred to the na?ve macrophages. The antimicrobial effect of na?ve macrophages was retained when they were separated from infected macrophages in transwells, and conditioned co-culture supernatants transferred antimicrobial activity to cultures of infected macrophages alone. Antimicrobial activity in macrophage co-cultures was abrogated when the na?ve population was deficient in IL-1 receptor or when the infected population was deficient in inducible nitric oxide synthase. The participation of nitric oxide suggested a conventional antimicrobial mechanism requiring delivery of bacilli to a late endosomal compartment. Using macrophages expressing GFP-LC3 we observed the induction of autophagy specifically by a high intracellular load of M. tuberculosis. Bacilli were identified in LC3-positive compartments and LC3-positive compartments were confirmed to be acidified and LAMP1 positive. Thus, the antimicrobial effect of na?ve macrophages acting on M. tuberculosis in heavily-infected macrophages is contact-independent. Interleukin-1 provides an afferent signal that induces an as yet unidentified small molecule which promotes nitric oxide-dependent antimicrobial activity against bacilli in autolysosomes of heavily infected macrophages. This cooperative, innate antimicrobial interaction may limit the maximal growth rate of M. tuberculosis prior to the expression of adaptive immunity in pulmonary tuberculosis.     

Molecular Insights into the Interaction between α-Synuclein and Docosahexaenoic Acid

α-Synuclein (α-syn) is a 140-residue protein of unknown function, involved in several neurodegenerative disorders, such as Parkinson's disease. Recently, the possible interaction between α-syn and polyunsaturated fatty acids has attracted a strong interest. Indeed, lipids are able to trigger the multimerization of the protein in vitro and in cultured cells. Docosahexaenoic acid (DHA) is one of the main fatty acids (FAs) in cerebral gray matter and is dynamically released following phospholipid hydrolysis. Moreover, it has been found in high levels in brain areas containing α-syn inclusions in patients affected by Parkinson's disease. Debated and unsolved questions regard the nature of the molecular interaction between α-syn and DHA and the effect exerted by the protein on the aggregated state of the FA. Here, we show that α-syn is able to strongly interact with DHA and that a mutual effect on the structure of the protein and on the physical state of the lipid derives from this interaction. α-Syn acquires an α-helical conformation in a simple two-state transition. The binding of the protein to the FA leads to a reduction of the size of the spontaneously formed aggregated species of DHA as well as of the critical aggregate concentration of the lipid. Specifically, biophysical methods and electron microscopy observations indicated that the FA forms oil droplets in the presence of α-syn. Limited proteolysis experiments showed that, when the protein is bound to the FA oil droplets, it is initially cleaved in the 89-102 region, suggesting that this chain segment is sufficiently flexible or unfolded to be protease-sensitive. Subsequent proteolytic events produce fragments corresponding to the first 70-80 residues that remain structured and show high affinity for the lipid. The fact that a region of the polypeptide chain remains accessible to proteases, when interacting with the lipid, suggests that this region could be involved in other interactions, justifying the ambivalent propensity of α-syn towards folding or aggregation in the presence of FAs.     

Physical Interactions between Mcm10, DNA, and DNA Polymerase ��

Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase α (pol α), with chromatin. We showed previously that the internal (ID) and C-terminal (CTD) domains of Mcm10 physically interact with both single-stranded (ss) DNA and the catalytic p180 subunit of pol α. However, the mechanism by which Mcm10 interacts with pol α on and off DNA is unclear. As a first step toward understanding the structural details for these critical intermolecular interactions, x-ray crystallography and NMR spectroscopy were used to map the binary interfaces between Mcm10-ID, ssDNA, and p180. The crystal structure of an Mcm10-ID·ssDNA complex confirmed and extended our previous evidence that ssDNA binds within the oligonucleotide/oligosaccharide binding-fold cleft of Mcm10-ID. We show using NMR chemical shift perturbation and fluorescence spectroscopy that p180 also binds to the OB-fold and that ssDNA and p180 compete for binding to this motif. In addition, we map a minimal Mcm10 binding site on p180 to a small region within the p180 N-terminal domain (residues 286–310). These findings, together with data for DNA and p180 binding to an Mcm10 construct that contains both the ID and CTD, provide the first mechanistic insight into how Mcm10 might use a handoff mechanism to load and stabilize pol α within the replication fork.To maintain their genomic integrity, cells must ensure complete and accurate DNA replication once per cell cycle. Consequently, DNA replication is a highly regulated and orchestrated series of molecular events. Multiprotein complexes assembled at origins of replication lead to assembly of additional proteins that unwind chromosomal DNA and synthesize nascent strands. The first event is the formation of a pre-replicative complex, which is composed of the origin recognition complex, Cdc6, Cdt1, and Mcm2–7 (for review, see Ref. 1). Initiation of replication at the onset of S-phase involves the activity of cyclin- and Dbf4-dependent kinases concurrent with recruitment of key factors to the origin. Among these, Mcm10 (2, 3) is recruited in early S-phase and is required for loading of Cdc45 (4). Mcm2–7, Cdc45, and the GINS complex form the replicative helicase (5–8). Origin unwinding is followed by loading of RPA,³ And-1/Ctf4, and pol α onto ssDNA (9–12). In addition, recruitment of Sld2, Sld3, and Dpb11/TopBP1 are essential for replication initiation (13, 14), and association of topoisomerase I, proliferating cellular nuclear antigen (PCNA), replication factor C, and the replicative DNA polymerases δ and ϵ completes the replisome (for review, see Ref. 15).Mcm10 is exclusive to eukaryotes and is essential to both initiation and elongation phases of chromosomal DNA replication (6, 8, 16). Mutations in Mcm10 in yeast result in stalled replication, cell cycle arrest, and cell death (2, 3, 17–19). These defects can be explained by the number of genetic and physical interactions between Mcm10 and many essential replication proteins, including origin recognition complex, Mcm2–7, and PCNA (3, 12, 20–24). In addition, Mcm10 has been shown to stimulate the phosphorylation of Mcm2–7 by Dbf4-dependent kinase in vitro (25). Thus, Mcm10 is an integral component of the replication machinery.Importantly, Mcm10 physically interacts with and stabilizes pol α and helps to maintain its association with chromatin (16, 26, 27). This is a critical interaction during replication because pol α is the only enzyme in eukaryotic cells that is capable of initiating DNA synthesis de novo. Indeed, Mcm10 stimulates the polymerase activity of pol α in vitro (28), and interestingly, the fission yeast Mcm10, but not Xenopus Mcm10, has been shown to exhibit primase activity (29, 30). Mcm10 is composed of three domains, the N-terminal (NTD), internal (ID), and C-terminal (CTD) domains (29). The NTD is presumably an oligomerization domain, whereas the ID and CTD both interact with DNA and pol α (29). The CTD is not found in yeast, whereas the ID is highly conserved among all eukaryotes. The crystal structure of Mcm10-ID showed that this domain is composed of an oligonucleotide/oligosaccharide binding (OB)-fold and a zinc finger motif, which form a unified DNA binding platform (31). An Hsp10-like motif important for the interaction with pol α has been identified in the sequence of Saccharomyces cerevisiae Mcm10-ID (16, 26).DNA pol α-primase is composed of four subunits: p180, p68, p58, and p48. The p180 subunit possesses the catalytic DNA polymerase activity, and disruption of this gene is lethal (32, 33). p58 and p48 form the DNA-dependent RNA polymerase (primase) activity (34, 35), whereas the p68 subunit has no known catalytic activity but serves a regulatory role (36, 37). Pol α plays an essential role in lagging strand synthesis by first creating short (7–12 nucleotide) RNA primers followed by DNA extension. At the critical length of ∼30 nucleotides, replication factor C binds to the nascent strand to displace pol α and loads PCNA with pols δ and ϵ (for review, see Ref. 38).The interaction between Mcm10 and pol α has led to the suggestion that Mcm10 may help recruit the polymerase to the emerging replisome. However, the molecular details of this interaction and the mechanism by which Mcm10 may recruit and stabilize the pol α complex on DNA has not been investigated. Presented here is the high resolution structure of the conserved Mcm10-ID bound to ssDNA together with NMR chemical shift perturbation competition data for pol α binding in the presence of ssDNA. Collectively, these data demonstrate a shared binding site for DNA and pol α in the OB-fold cleft of Mcm10-ID, with a preference for ssDNA over pol α. In addition, we have mapped the Mcm10-ID binding site on pol α to a 24-residue segment of the N-terminal domain of p180. Based on these results, we propose Mcm10 helps to recruit pol α to origins of replication by a molecular hand-off mechanism.     

Interactions between canthaxanthin and lipid membranes — possible mechanisms of canthaxanthin toxicity

Canthaxanthin (β, β-carotene 4, 4′ dione) is used widely as a drug or as a food and cosmetic colorant, but it may have some undesirable effects on human health, mainly caused by the formation of crystals in the macula lutea membranes of the retina. This condition is called canthaxanthin retinopathy. It has been shown that this type of dysfunction of the eye is strongly connected with damage to the blood vessels around the place of crystal deposition. This paper is a review of the experimental data supporting the hypothesis that the interactions of canthaxanthin with the lipid membranes and the aggregation of this pigment may be the factors enhancing canthaxanthin toxicity towards the macula vascular system. All the results of the experiments that have been done on model systems such as monolayers of pure canthaxanthin and mixtures of canthaxanthin and lipids, oriented bilayers or liposomes indicate a very strong effect of canthaxanthin on the physical properties of lipid membranes, which may explain its toxic action, which leads to the further development of canthaxanthin retinopathy.     

Interactions between Na?ve and Infected Macrophages Reduce Mycobacterium tuberculosis Viability

A high intracellular bacillary load of Mycobacterium tuberculosis in macrophages induces an atypical lysosomal cell death with early features of apoptosis that progress to necrosis within hours. Unlike classical apoptosis, this cell death mode does not appear to diminish M. tuberculosis viability. We previously reported that culturing heavily infected macrophages with naïve macrophages produced an antimicrobial effect, but only if naïve macrophages were added during the pre-necrotic phase of M. tuberculosis-induced cell death. In the present study we investigated the mechanism of antimicrobial activity in co-cultures, anticipating that efferocytosis of bacilli in apoptotic bodies would be required. Confocal microscopy revealed frustrated phagocytosis of M. tuberculosis-infected macrophages with no evidence that significant numbers of bacilli were transferred to the naïve macrophages. The antimicrobial effect of naïve macrophages was retained when they were separated from infected macrophages in transwells, and conditioned co-culture supernatants transferred antimicrobial activity to cultures of infected macrophages alone. Antimicrobial activity in macrophage co-cultures was abrogated when the naïve population was deficient in IL-1 receptor or when the infected population was deficient in inducible nitric oxide synthase. The participation of nitric oxide suggested a conventional antimicrobial mechanism requiring delivery of bacilli to a late endosomal compartment. Using macrophages expressing GFP-LC3 we observed the induction of autophagy specifically by a high intracellular load of M. tuberculosis. Bacilli were identified in LC3-positive compartments and LC3-positive compartments were confirmed to be acidified and LAMP1 positive. Thus, the antimicrobial effect of naïve macrophages acting on M. tuberculosis in heavily-infected macrophages is contact-independent. Interleukin-1 provides an afferent signal that induces an as yet unidentified small molecule which promotes nitric oxide-dependent antimicrobial activity against bacilli in autolysosomes of heavily infected macrophages. This cooperative, innate antimicrobial interaction may limit the maximal growth rate of M. tuberculosis prior to the expression of adaptive immunity in pulmonary tuberculosis.     

Interactions between Streptococcus pneumoniae and influenza virus: a mutually beneficial relationship?

Historically, most research on infectious diseases has focused on infections with single pathogens. However, infections with pathogens often occur in the context of pre-existing viral and bacterial infections. Clinically, this is of particular relevance for coinfections with Streptococcus pneumoniae and influenza virus, which together are an important cause of global morbidity and mortality. In recent years new evidence has emerged regarding the underlying mechanisms of influenza virus-induced susceptibility to secondary pneumococcal infections, in particular regarding the sustained suppression of innate recognition of S. pneumoniae. Conversely, it is also increasingly being recognized that there is not a unidirectional effect of the virus on S. pneumoniae, but that asymptomatic pneumococcal carriage may also affect subsequent influenza virus infection and the clinical outcome. Here, we will review both aspects of pneumococcal influenza virus infection, with a particular focus on the age-related differences in pneumococcal colonization rates and invasive pneumococcal disease.     

Interactions between α-tocopherol,polyunsaturated fatty acids,and lipoxygenases during embryogenesis

α-Tocopherol is a lipid-soluble antioxidant that is specifically required for reproduction and embryogenesis. However, since its discovery, α-tocopherol's specific biologic functions, other than as an antioxidant, and the mechanism(s) mediating its requirement for embryogenesis remain unknown. As an antioxidant, α-tocopherol protects polyunsaturated fatty acids (PUFAs) from lipid peroxidation. α-Tocopherol is probably required during embryonic development to protect PUFAs that are crucial to development, specifically arachidonic (ARA) and docosahexaenoic (DHA) acids. Additionally, ARA and DHA are metabolized to bioactive lipid mediators via lipoxygenase enzymes, and α-tocopherol may directly protect, or it may mediate the production and/or actions of, these lipid mediators. In this review, we discuss how α-tocopherol (1) prevents the nonspecific, radical-mediated peroxidation of PUFAs, (2) functions within a greater antioxidant network to modulate the production and/or function of lipid mediators derived from 12- and 12/15-lipoxygenases, and (3) modulates 5-lipoxygenase activity. The application and implication of such interactions are discussed in the context of α-tocopherol requirements during embryogenesis.