Showing papers in "Advances in Experimental Medicine and Biology in 2011"
TL;DR: Quercetin has a higher reduction potential compared with curcumin at three different pH settings and is comparable to Trolox at pH 7-9.5, providing a physico-chemical basis for comparing antioxidants, with potential benefits individually or in combination.
Abstract: Quercetin, a plant-derived aglycone form of flavonoid glycosides, has been used as a nutritional supplement and may be beneficial against a variety of diseases, including cancer. We examined the antioxidant properties of quercetin. The reduction potential of quercetin was measured at various pH values using voltammetric methods, and its total antioxidant capacity (TAC) was measured using the phosphomolybdenum method. The effect of quercetin on production of reactive oxygen species (ROS) and nitric oxide (NO) in LPS-stimulated human THP-1 acute monocytic leukemia cells was determined by flow cytometry using CM-H2DCFDA dye. The results were compared with curcumin, a natural product exhibiting a similar range of reported health benefits. Results: 1) Quercetin has a higher reduction potential compared with curcumin at three different pH settings and is comparable to Trolox at pH 7-9.5; 2) its TAC is 3.5 fold higher than curcumin; 3) it reduced LPS-induced ROS to near normal levels; 4) it reduced LPS-induced NO production. These data provide a physico-chemical basis for comparing antioxidants, with potential benefits individually or in combination.
209 citations
TL;DR: Staphylococcal adherence to an either biotic or abiotic surface is the critical first event in the establishment of an infection with these serious pathogens.
Abstract: Staphylococcal adherence to an either biotic or abiotic surface is the critical first event in the establishment of an infection with these serious pathogens. Especially Staphylococcus aureus harbours a variety of proteinaceous and non-proteinaceous adhesins that mediate attachment to a multitude of host factors, such as extracellular matrix and plasma proteins and human host cells, or intercellular adhesion, which is essential for biofilm accumulation. Proteinaceous adhesins may be classified in covalently surface-anchored proteins of the MSCRAMM (microbial surface components recognizing adhesive matrix molecules) family or in proteins that are surface-associated by different means, such as ionic or hydrophobic interactions. Non-covalently surface-associated proteins include the autolysin/adhesins, proteins of the SERAM (secretable expanded repertoire adhesive molecules) family, or membrane-spanning proteins. Non-proteinaceous adhesins comprise the polysaccharide PIA (polysaccharide intercellular adhesin) and wall teichoic and lipoteichoic acids. The features and functions of surface and surface-associated protein adhesins as well as of non-proteinaceous adhesins are discussed.
194 citations
TL;DR: Overall, mast cell proteases have a variety of roles, inflammatory and anti-inflammatory, protective and deleterious, in keeping with the increasingly well-appreciated contributions of mast cells in allergy, tissue homeostasis and innate immunity.
Abstract: Proteases are the most abundant class of proteins produced by mast cells. Many of these are stored in membrane-enclosed intracellular granules until liberated by degranulating stimuli, which include cross-linking of high affinity IgE receptor FceRI by IgE bound to multivalent allergen. Understanding and separating the functions of the proteases is important because expression differs among mast cells in different tissue locations. Differences between laboratory animals and humans in protease expression also influence the degree of confidence with which results obtained in animal models of mast cell function can be extrapolated to humans. The inflammatory potential of mast cell proteases was the first aspect of their biology to be explored and has received the most attention, in part because some of them, notably tryptases and chymases, are biomarkers of local and systemic mast cell degranulation and anaphylaxis. Although some of the proteases indeed augment allergic inflammation and are potential targets for inhibition to treat asthma and related allergic disorders, they are protective and even anti-inflammatory in some settings. For example, mast cell tryptases may protect from serious bacterial lung infections and may limit the “rubor” component of inflammation caused by vasodilating neuropeptides in the skin. Chymases help to maintain intestinal barrier function and to expel parasitic worms and may support blood pressure during anaphylaxis by generating angiotensin II. In other life-or-death examples, carboxypeptidase A3 and other mast cell peptidases limit systemic toxicity of endogenous peptideslike endothelin and neurotensin during septic peritonitis and inactivate venom-associated peptides. On the other hand, mast cell peptidase-mediated destruction of protective cytokines, like IL-6, can enhance mortality from sepsis. Peptidases released from mast cells also influence nonmast cell proteases, such as by activating matrix metalloproteinase cascades, which are important in responses to infection and resolution of tissue injury. Overall, mast cell proteases have a variety of roles, inflammatory and anti-inflammatory, protective and deleterious, in keeping with the increasingly well-appreciated contributions of mast cells in allergy, tissue homeostasis and innate immunity.
150 citations
TL;DR: This work has pursued the discoveries of human macrophage fusion factors with emphasis on foreign body giant cells, and identified adhesion receptors and signaling intermediates, as well as an adhesion protein substrate (vitronectin) that supports macrophages' fusion.
Abstract: Macrophages undergo fusion with other macrophages to form the hallmark multinucleated giant cells of chronic inflammation. However, neither the existence of distinct morphological types of giant cells, the signaling pathways that induce their formation, the molecular mechanism(s) of macrophage fusion, nor the significance of macrophage multinucleation at chronic inflammatory sites are well understood. Our efforts have been focused on these unknowns, particularly as they relate to the foreign body-type giant cells that form on implanted biomaterials and biomedical devices. We have pursued the discoveries of human macrophage fusion factors (interleukin-4, interleukin-13, α-tocopherol) with emphasis on foreign body giant cells, and identified adhesion receptors and signaling intermediates, as well as an adhesion protein substrate (vitronectin) that supports macrophage fusion. Studies on the molecular mechanism of macrophage fusion have revealed it to be a mannose receptor-mediated phagocytic process with participation of the endoplasmic reticulum. Further phenotypic and functional investigations will foster new perspectives on these remarkable multinucleated cells and their physiological significances in multiple inflammatory processes.
149 citations
TL;DR: This chapter briefly review decision tree and related ensemble algorithms and shows the successful applications of such approaches on solving biological problems, and aims to provide a platform to bridge the gap between biologists and computer scientists.
Abstract: Machine learning approaches have wide applications in bioinformatics, and decision tree is one of the successful approaches applied in this field. In this chapter, we briefly review decision tree and related ensemble algorithms and show the successful applications of such approaches on solving biological problems. We hope that by learning the algorithms of decision trees and ensemble classifiers, biologists can get the basic ideas of how machine learning algorithms work. On the other hand, by being exposed to the applications of decision trees and ensemble algorithms in bioinformatics, computer scientists can get better ideas of which bioinformatics topics they may work on in their future research directions. We aim to provide a platform to bridge the gap between biologists and computer scientists.
147 citations
TL;DR: G protein is the only class III fusion protein for which structures of both pre- and post-fusion states have been determined, shedding light on the mechanism involved in the conformational change and membrane fusion.
Abstract: Members of class III of viral fusion proteins share common structural features and molecular architecture, although they belong to evolutionary distant viruses and carry no sequence homology. Based of the experimentally determined three-dimensional structures of their ectodomains, glycoprotein B (gB) of herpesviruses, G protein of rhabdoviruses and glycoprotein 64 (gp64) of baculoviruses have been identified as class III fusion proteins. The structures are proposed to represent post-fusion conformations, and they reveal trimeric, elongated, rod-like molecules, with each protomer being composed of five domains. Sequences which interact with target membranes and form the fusion peptides are located in two loops found at one end of the molecule. Class III fusion proteins are embedded in viral envelope with the principal function of catalyzing fusion of viral and cellular membranes, an event that is essential for infection to occur. In addition, they have been implicated in processes such as attachment to target cells and viral maturation. G protein is the only class III fusion protein for which structures of both pre- and post-fusion states have been determined, shedding light on the mechanism involved in the conformational change and membrane fusion. Whether similar structural organization of class III fusion proteins translates into a common mechanism involved in carrying out membrane fusion remains to be investigated.
133 citations
TL;DR: Cysteine proteases of malaria parasites have demonstrated potent antimalarial effects and the optimization and testing of falcipain inhibitor antimalarials is underway, andGene disruption studies suggested that SERA-5 andSERA-6 are essential.
Abstract: A number of cysteine proteases of malaria parasites have been described and many more are suggested by analysis of the Plasmodium falciparum genome sequence. The best characterized of these proteases are the falcipains, a family of four papain-family enzymes. Falcipain-2 and falcipain-3 act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. Disruption of the falcipain-2 gene led to a transient block in hemoglobin hydrolysis and parasites with increased sensitivity to protease inhibitors. Disruption of the falcipain-3 gene was not possible, strongly suggesting that this protease is essential for erythrocytic parasites. Disruption of the falcipain-1 gene did not alter development in erythrocytes, but led to decreased production of oocysts in mosquitoes. other papain-family proteases predicted by the genome sequence include dipeptidyl peptidases, a calpain homolog and serine-repeat antigens (SERAs). Dipeptidyl aminopeptidase 1 appears to be essential and localized to the food vacuole, suggesting a role in hemoglobin hydrolysis. Dipeptidyl aminopeptidase 3 appears to play a role in the rupture of erythrocytes by mature parasites. the P. falciparum calpain homolog gene could not be disrupted, suggesting that the protein is essential and a role in the parasite cell cycle has been suggested. Nine P. falciparum SERAs have cysteine protease motifs, but in some the active site cys is replaced by a Ser. Gene disruption studies suggested that SERA-5 and SERA-6 are essential. activation of SERA-5 by a serine protease seems to be required for merozoite egress from the erythrocyte. New drugs for malaria are greatly needed and cysteine proteases represent potential drug targets. cysteine protease inhibitors have demonstrated potent antimalarial effects and the optimization and testing of falcipain inhibitor antimalarials is underway.
129 citations
TL;DR: The molecular characteristics of Salmonella adhesins are described and link these features to their multiple functions in infection biology and how they act in concert with other virulence determinants are linked.
Abstract: Salmonella enterica is an invasive, facultative intracellular pathogen of animal and man with the ability to colonize various niches in diverse host organisms. The pathogenesis of infections by S. enterica requires adhesion to various host cell surfaces, and a large number of adhesive structures can be found. Depending on the serotype of S. enterica, gene clusters for more than 10 different fimbrial adhesins were identified, with type I fimbriae such as Fim, Lpf (long polar fimbriae), Tafi (thin aggregative fimbriae) or the type IV pili of serotype Typhi. In addition, autotransporter adhesins such as ShdA, MisL and SadA and the type I secreted large repetitive adhesins SiiE and BapA have been identified. Although the functions of many of the various adhesins are not well understood, recent studies show the specific structural and functional properties of Salmonella adhesins and how they act in concert with other virulence determinants. In this chapter, we describe the molecular characteristics of Salmonella adhesins and link these features to their multiple functions in infection biology.
128 citations
TL;DR: Biosurfactants have been reported as a promising strategy as they effectively inhibit bacterial adhesion and retard biofilm formation, and are thus potentially useful as a new generation of anti-adhesive and antimicrobial coatings for medical devices.
Abstract: Microbial infections resulting from bacterial adhesion to biomaterial surfaces have been observed on almost all medical devices. Biofilm infections pose a number of clinical challenges due to their resistance to immune defence mechanisms and antimicrobials, and, regardless of the sophistication of the implant, all medical devices are susceptible to microbial colonisation and infection. Research efforts are currently directed towards eliminating or reducing infection of medical devices. Strategies to prevent biofilm formation include physiochemical modification of the biomaterial surface to create anti-adhesive surfaces, incorporation of antimicrobial agents into medical device polymers, mechanical design alternatives, and release of antibiotics. Nevertheless, the success of these alternatives has been modest, mainly due to the various environments into which devices are placed and the diversity of ways in which organisms can colonise surfaces. Biosurfactants have been reported as a promising strategy as they effectively inhibit bacterial adhesion and retard biofilm formation, and are thus potentially useful as a new generation of anti-adhesive and antimicrobial coatings for medical devices.
127 citations
TL;DR: This introductory chapter outlines and highlights the various topics of mast cell biology that will be discussed in further detail in subsequent chapters.
Abstract: In recent years, the field of mast cell biology has expanded well beyond the boundaries of atopic disorders and anaphy laxis, on which it has been historically focused. The biochemical and signaling events responsible for the development and regulation of mast cells has been increasingly studied, aided in large part by novel breakthroughs in laboratory techniques used to study these cells. The result of these studies has been a more comprehensive definition of mast cells that includes added insights to their overall biology as well as the various disease states that can now be traced to defects in mast cells. This introductory chapter outlines and highlights the various topics of mast cell biology that will be discussed in further detail in subsequent chapters.
127 citations
TL;DR: In this paper, the authors describe mouse models used for analyzing mast-cell function in vivo and illustrate how such models have been used to identify positive or negative immunomodulatory roles for mast cells during specific innate or adaptive immune responses.
Abstract: Mast cells often represent one of the first cells of the immune system to interact with environmental antigens, invading pathogens or environmentally-derived toxins. Mast cells also can undergo alterations in phenotype, anatomic distribution and numbers during innate or adaptive immune responses. In addition to their well-known roles as effector cells during IgE- and antigen-induced allergic reactions, mast cells can be activated by many other signals, including some that are derived directly from pathogens or which are generated during innate or adaptive immune responses. Mast cells also express many costimulatory molecules with immunoregulatory activities and can secrete many products that can positively or negatively regulate immune responses. In this chapter, we describe mouse models used for analyzing mast-cell function in vivo and illustrate how such models have been used to identify positive or negative immunomodulatory roles for mast cells during specific innate or adaptive immune responses. We also briefly describe some of the mast-cell functions, products and surface receptors that have the potential to permit mast cells to promote or suppress immune responses that can either enhance host defense or contribute to disease.
TL;DR: Bacteria-mediated environmental restoration and bioleaching have been attracting much attention owing to their potential to remediate environmental effluents produced by the mining and metallurgy industries.
Abstract: Extracellular polysaccharides are as structurally and functionally diverse as the bacteria that synthesise them. They can be present in many forms, including cell-bound capsular polysaccharides, unbound "slime", and as O-antigen component of lipopolysaccharide, with an equally wide range of biological functions. These include resistance to desiccation, protection against nonspecific and specific host immunity, and adherence. Unsurprisingly then, much effort has been made to catalogue the enormous structural complexity of the extracellular polysaccharides made possible by the wide assortment of available monosaccharide combinations, non-carbohydrate residues, and linkage types, and to elucidate their biosynthesis and export. In addition, the work is driven by the commercial potential of these microbial substances in food, pharmaceutics and biomedical industries. Most recently, bacteria-mediated environmental restoration and bioleaching have been attracting much attention owing to their potential to remediate environmental effluents produced by the mining and metallurgy industries. In spite of technological advances in chemistry, molecular biology and imaging techniques that allowed for considerable expansion of knowledge pertaining to the bacterial surface polysaccharides, current understanding of the mechanisms of synthesis and regulation of extracellular polysaccharides is yet to fully explain their structural intricacy and functional variability.
TL;DR: Therapeutic approaches to modulate activation of specific TRP channels are likely to have an important impact in reducing tissue damage in a number of diseases resulting from oxidant stress including ischemia/reperfusion injury and diabetes.
Abstract: The transient receptor potential (TRP) protein superfamily is a diverse group of cation-permeable channels expressed in mammalian cells, which is divided into six subfamilies based on sequence identity. Three subfamilies have members with roles in oxidative stress: the TRPC subfamily characterized by receptor operated calcium entry channels; the TRPM subfamily with a number of members involved in cell proliferation and death; and the TRPV subfamily which is activated by chemical, mechanical, and physical stimuli. The TRPC members TRPC3 and TRPC4 can serve as subunits of a redox-sensitive ion channel in native aortic endothelial cells. The TRPM family member TRPM2 has a number of physiologic isoforms expressed in many cell types and responds to stimuli including oxidative stress, TNFα, and β-amyloid peptide. The important role of TRPM2 isoforms in cell proliferation and oxidant-induced cell death has been well established using divergent cell systems and techniques including overexpression, channel depletion or inhibition, and calcium chelation. TRPM7 has been shown to be involved in Ca2+ influx and anoxic cell death in cortical neurons. In these cells and in B cells, precise expression of TRPM7 is necessary for cell survival. TRPV1 is involved in oxidant stress-induced pain and in neuronal injury, contributing to diabetic sensory neuropathy. Future studies will likely identify additional channels involved in oxidant injury, as well as better define mechanisms through which these channels are regulated and mediate their effects. Therapeutic approaches to modulate activation of specific TRP channels are likely to have an important impact in reducing tissue damage in a number of diseases resulting from oxidant stress including ischemia/reperfusion injury and diabetes.
TL;DR: This chapter provides an economic perspective on vaccination programs, detailing in particular a new line of inquiry that makes a case for the importance of vaccination to achieving national economic aims.
Abstract: Vaccination is most often studied from a scientific, clinical, or epidemiological perspective, and rightly so, for vaccines are meant to improve health outcomes. But these are not the only lenses through which the effects of vaccination programs can be understood. This chapter provides an economic perspective on vaccination programs, detailing in particular a new line of inquiry that makes a case for the importance of vaccination to achieving national economic aims. Research has shown that national spending on childhood vaccination programs does more than just reduce morbidity and mortality in a country: it also promotes national economic growth and poverty reduction. The chapter begins with a look at recent research that demonstrates powerful links that run from population health to economic well-being. Second, it discusses how knowledge of the economic benefits of health fundamentally transforms how we understand the value of vaccination. And third, it provides evidence for the scale of the returns that countries receive when they invest in immunization programs - returns that have not been fully captured by traditional economic analyses.
TL;DR: expression of macrophage antigens in breast- and colorectal-cancers may have a prognostic relevance in clinical praxis and resemblance with macrophages may indicate a more invasive phenotype due to genetic exchange between the primary tumor cells and associated Macrophages.
Abstract: Macrophages are a heterogeneous cell population of the myeloid linage derived from monocytes. These cells show two different polarization states, M1 and M2 macrophages in response to different micro environmental signals. Tumor associated macrophages (TAM) represent the M2 type and promote tumor progression. These cells express antigens that more or less are specific for macrophages like: CD14, CD68, MAC387, CD163, and DAP12. In a series of recent studies it is shown that cancer cells may express these antigens and CD163, MAC387 and DAP12 may be expressed by e.g. breast cancer cells. Thus, 48% of the breast cancers expressed CD163 that is a scavenger receptor normally expressed by macrophages alone. The corresponding figure for rectal cancer is 31%. The expression of CD163 is correlated to early distant recurrence in breast cancer and local recurrence in rectal cancer and reduced survival time in both conditions. Expression of macrophage antigens in breast- and colorectal-cancers may have a prognostic relevance in clinical praxis. One explanation to these findings is that resemblance with macrophages may indicate a more invasive phenotype due to genetic exchange between the primary tumor cells and associated macrophages. This is further supported by the finding that expression of DAP12, a macrophage fusion receptor, in breast cancer is associated with an advanced tumor grade and higher rates of skeletal and liver metastases and overall shorter distant recurrence free survival. Another explanation to the changed phenotype is a genetic exchange between the cells by exosome-mediated transfer.
TL;DR: This chapter provides an overview of the recent developments in the understanding of this class of RNAs from diverse perspectives including biogenesis, mechanism of their function, evolution of their clusters, and discuss the approaches currently available for the construction of post-transcriptional networks governed by them.
Abstract: Gene expression is a highly controlled process which is known to occur at several levels in eukaryotic organisms. Although RNAs have been traditionally viewed as passive molecules in the pathway from transcription to translation, there is increasing evidence that their metabolism is controlled by a class of small noncoding RNAs called MicroRNAs (miRNAs). MicroRNAs (miRNAs) control essential gene regulatory pathways in both plants and animals however our understanding about their function, evolution and interplay with other cellular components is only beginning to be elucidated. In this chapter, we provide an overview of the recent developments in our understanding of this class of RNAs from diverse perspectives including biogenesis, mechanism of their function, evolution of their clusters, and discuss the approaches currently available for the construction of post-transcriptional networks governed by them. We also present our current understanding on these post-transcriptional networks in the context other cellular networks. We finally argue that such developments would not only allow us to gain a deeper understanding of regulation at a level that has been under-appreciated over the past decades, but would also allow us to use the newly developed high-throughput approaches to interrogate the prevalence of these phenomena in different states, and thereby exploit the functions of these RNA molecules for therapeutic advantage in higher eukaryotes.
TL;DR: Structural studies on TRP channels, while limited, are poised for a quickened pace and rapid expansion, and technical advances in structural approaches promise a bright outlook for TRP channel structural biology.
Abstract: Structural studies on TRP channels, while limited, are poised for a quickened pace and rapid expansion. As of yet, no high-resolution structure of a full length TRP channel exists, but low-resolution electron cryomicroscopy structures have been obtained for 4 TRP channels, and high-resolution NMR and X-ray crystal structures have been obtained for the cytoplasmic domains, including an atypical protein kinase domain, ankyrin repeats, coiled coil domains and a Ca2+-binding domain, of 6 TRP channels. These structures enhance our understanding of TRP channel assembly and regulation. Continued technical advances in structural approaches promise a bright outlook for TRP channel structural biology.
TL;DR: The recent finding in animal models that pharmacological reduction of glycosphingolipid biosynthesis ameliorates insulin resistance and prevents some manifestations of metabolic syndrome, supports the view that somehow glycospittingolipids act as critical regulators and since reductions in glycospheric biosynthesis have been found to be well tolerated, such approaches may have a therapeutic potential.
Abstract: Glycosphingolipids are structural membrane components, residing largely in the plasma membrane with their sugar-moieties exposed at the cell's surface. In recent times a crucial role for glycosphingolipids in insulin resistance has been proposed. A chronic state of insulin resistance is a rapidly increasing disease condition in Western and developing countries. It is considered to be the major underlying cause of the metabolic syndrome, a combination of metabolic abnormalities that increases the risk for an individual to develop Type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and nonalcoholic fatty liver disease. As discussed in this chapter, the evidence for a direct regulatory interaction of glycosphingolipids with insulin signaling is still largely indirect. However, the recent finding in animal models that pharmacological reduction of glycosphingolipid biosynthesis ameliorates insulin resistance and prevents some manifestations of metabolic syndrome, supports the view that somehow glycosphingolipids act as critical regulators, Importantly, since reductions in glycosphingolipid biosynthesis have been found to be well tolerated, such approaches may have a therapeutic potential.
TL;DR: The path from the initial identification of this proteases activity and its validation as a bone fide drug target to the arduous task of the discovery of an inhibitor targeting this protease and finally the path towards the clinic is charted.
Abstract: Cruzain is the major papain-like cysteine protease of Trypanosoma cruzi, the etiological agent causing Chagas' disease in humans in South America. Cruzain is indispensable for the survival and propagation of this protozoan parasite and therefore, it has attracted considerable interest as a potential drug target. This chapter charts the path from the initial identification of this proteases activity and its validation as a bone fide drug target to the arduous task of the discovery of an inhibitor targeting this protease and finally the path towards the clinic.
TL;DR: In this article, the role of Orai1 and TRPC1 in store-operated Ca2+ entry (SOCE) is discussed and the potential mechanisms involved in the regulation of TRPC channels by store depletion are discussed.
Abstract: Store-operated Ca2+ entry (SOCE) is activated in response to depletion of the ER-Ca2+ stores by the ER Ca2+ sensor protein, STIM1 which oligomerizes and moves to ER/PM junctional domains where it interacts with and activates channels involved in SOCE. Two types of channel activities have been described. ICRAC, via Ca2+ release-activated Ca2+ (CRAC) channel, which displays high Ca2+ selectivity and accounts for the SOCE and cell function in T lymphocytes, mast cells, platelets, and some types of smooth muscle and endothelial cells. Orai1 has been established as the pore-forming component of CRAC channels and interaction of Orai1 with STIM1 is sufficient for generation of the CRAC channel. Store depletion also leads to activation of relatively non-selective cation currents (referred to as ISOC) that contribute to SOCE in several other cell types. TRPC channels, including TRPC1, TRPC3, and TRPC4, have been proposed as possible candidate channels for this Ca2+ influx. TRPC1 is the best characterized channel in this regard and reported to contribute to endogenous SOCE in many cells types. TRPC1-mediated Ca2+ entry and cation current in cells stimulated with agonist or thapsigargin are inhibited by low [Gd3+] and 10–20 μM 2APB (conditions that block SOCE). Importantly, STIM1 also associates with and gates TRPC1 via electrostatic interaction between STIM1 (684KK685) and TRPC1 (639DD640). Further, store depletion induces dynamic recruitment of a TRPC1/STIM1/Orai1 complex and knockdown of Orai1 completely abrogates TRPC1 function. Despite these findings, there has been much debate regarding the activation of TRPC1 by store depletion as well as the role of Orai1 and STIM1 in SOC channel function. This chapter summarizes recent studies and concepts regarding the contributions of Orai1 and TRPC1 to SOCE. Major unresolved questions regarding functional interaction between Orai1 and TRPC1 as well as possible mechanisms involved in the regulation of TRPC channels by store depletion will be discussed.
TL;DR: This chapter will highlight the enormous progress in understanding the role of TRP channels in nociception, and mainly focus on twoTRP channels that have been particularly implicated in transducing signals associated with pain sensation.
Abstract: It is crucial for a living organism to recognize and discern potentially harmful noxious stimuli from innocuous stimuli to avoid hazards in the environment However, unnecessary or exaggerated nociception is at best unpleasant and often compromises the quality of life In order to lessen the intensity of nociception or eliminate the pathological pain, it is important to understand the nature of nociception and the mechanisms of hyperalgesia or allodynia Transient receptor potential (TRP) channels play central roles in nociception under physiological and pathological conditions including inflammation and neuropathy In this chapter, we will highlight the enormous progress in understanding the role of TRP channels in nociception We will mainly focus on two TRP channels (TRPV1 and TRPA1) that have been particularly implicated in transducing signals associated with pain sensation, and briefly discuss the role of TRPM8, TRPV3 and TRPV4 We will stress debatable issues that needed to be resolved and provide perspectives for the future studies
TL;DR: The ubiquitously expressed TRPM4 channel has been implicated in insulin secretion, the immune response, constriction of cerebral arteries, the activity of inspiratory neurons and cardiac dysfunction, whereas TRPM5 whose expression is more restricted, has until now been mainly implicated in taste transduction.
Abstract: Transient Receptor Potential (TRP) proteins are non-selective cationic channels with a consistent Ca2+-permeability, except for TRPM4 and TRPM5 that are not permeable to this ion. However, Ca2+ is a major regulator of their activity since both channels are activated by a rise in internal Ca2+. Thus TRPM4 and TRPM5 are responsible for most of the Ca2+-activated non-selective cationic currents (NSCCa) recorded in a large variety of tissues. Their activation induces cell-membrane depolarization that modifies the driving force for ions as well as activity of voltage gated channels and thereby strongly impacts cell physiology. In the last few years, the ubiquitously expressed TRPM4 channel has been implicated in insulin secretion, the immune response, constriction of cerebral arteries, the activity of inspiratory neurons and cardiac dysfunction. Conversely, TRPM5 whose expression is more restricted, has until now been mainly implicated in taste transduction.
TL;DR: Studies in mast cells revealed much about the mechanisms described but little about allergic and autoimmune diseases although studies in other types of cells have exposed genetic defects that lead to aberrant calcium signaling in immune diseases.
Abstract: A calcium signal is essential for degranulation, generation of eicosanoids and optimal production of cytokines in mast cells in response to antigen and other stimulants. The signal is initiated by phospholipase C-mediated production of inositol1,4,5-trisphosphate resulting in release of stored Ca2+ from the endoplasmic reticulum (ER) and Golgi. Depletion of these stores activates influx of extracellular Ca2+, usually referred to as store-operated calcium entry (SOCE), through the interaction of the Ca2+-sensor, stromal interacting molecule-1 (STIM1 ), in ER with Orai1(CRACM1) and transient receptor potential canonical (TRPC) channel proteins in the plasma membrane (PM). This interaction is enabled by microtubular-directed reorganization of ER to form ER/PM contact points or “punctae” in which STIM1 and channel proteins colocalize. The ensuing influx of Ca2+ replenishes Ca2+ stores and sustains elevated levels of cytosolic Ca2+ ions-the obligatory signal for mast-cell activation. In addition, the signal can acquire spatial and dynamic characteristics (e.g., calcium puffs, waves, oscillations) that encode signals for specific functional outputs. This is achieved by coordinated regulation of Ca2+ fluxes through ATP-dependent Ca2+-pumps and ion exchangers in mitochondria, ER and PM. As discussed in this chapter, studies in mast cells revealed much about the mechanisms described above but little about allergic and autoimmune diseases although studies in other types of cells have exposed genetic defects that lead to aberrant calcium signaling in immune diseases. Pharmacologic agents that inhibit or activate the regulatory components of calcium signaling in mast cells are also discussed along with the prospects for development of novel SOCE inhibitors that may prove beneficial in the treatment inflammatory mast-cell related diseases.
TL;DR: The present review summarizes the current knowledge concerning the association of TRp proteins with Orai and STIM proteins and how this affects the participation of TRP proteins in store-operated or receptor-operated Ca(2+) entry.
Abstract: Transient receptor potential (TRP) proteins are involved in a large number of non-selective cation channels that are permeable to both monovalent and divalent cations. Two general classes of receptor-mediated Ca2+ entry has been proposed: one of then is conduced by receptor-operated Ca2+ channels (ROC), the second is mediated by channels activated by the emptying of intracellular Ca2+ stores (store-operated channels or SOC). TRP channels have been presented as subunits of both ROC and SOC, although the precise mechanism that regulates the participation of TRP proteins in these Ca2+ entry mechanisms remains unclear. Recently, TRPC proteins have been shown to associate with Orai1 and STIM1 in a dynamic ternary complex regulated by the occupation of membrane receptors in several cell models, which might play an important role in the function of TRPC proteins. The present review summarizes the current knowledge concerning the association of TRP proteins with Orai and STIM proteins and how this affects the participation of TRP proteins in store-operated or receptor-operated Ca2+ entry.
TL;DR: Information to be presented will suggest that MCs may serve as a novel therapeutic target for cancer treatment with particular emphasis on the capacity of these cells to stimulate tumor growth by promoting angiogenesis and lymphangiogenesis.
Abstract: Mast cells (MCs) were first described by Paul Ehrlich 1 in his doctoral thesis. MCs have long been implicated in the pathogenesis of allergic reactions and certain protective responses to parasites. As most tumors contain inflammatory cell infiltrates, which often include plentiful MCs, the question as to the possible contribution of MCs to tumor development has progressively been emerging. In this chapter, the specific involvement of MCs in tumor biology and tumor fate will be considered, with particular emphasis on the capacity of these cells to stimulate tumor growth by promoting angiogenesis and lymphangiogenesis. Data from experimental carcinogenesis and from different tumor settings in human pathology will be summarized. Information to be presented will suggest that MCs may serve as a novel therapeutic target for cancer treatment.
TL;DR: The continued understanding of the MC in the context of infectious disease is likely to not only expand the scope of theMC in the normal processes of immunity, but provide new therapeutic targets to combat disease.
Abstract: Mast cells (MCs) were once considered only as effector cells in pathogenic IgE- and IgG-mediated responses such as allergy. However, developments over the last 15 years have suggested that MCs have evolved in vertebrates as beneficial effector cells that are involved in the very first inflammatory responses generated during infection. This pro-inflammatory environment has been demonstrated to be important for initiating innate responses in many different models of infection and more recently, in the development of adaptive immunity as well. Interestingly this latter finding has led to the discovery that small MC-activating compounds can behave as adjuvants in vaccine formulations. Thus, our continued understanding of the MC in the context of infectious disease is likely to not only expand our scope of the MC in the normal processes of immunity, but provide new therapeutic targets to combat disease.
TL;DR: Recent findings revealing important roles for miRNA in immunity and how miRNAs can regulate innate and adaptive immune responses are discussed.
Abstract: The regulation of gene expression at the posttranscriptional level has revealed important control levels for genes important to the immune system. MicroRNAs (miRNAs) are small RNAs that regulate gene expression by inhibiting protein translation or by degrading the mRNA transcript. A single miRNA can potentially regulate the expression of multiple genes and the proteins encoded. MiRNA can influence molecular signaling pathways and regulate many biological processes including immune function. Although the role of miRNAs in development and oncogenesis has been well characterized, their role in the immune system has only begun to emerge. During the past few years, many miRNAs have been found to be important in the development, differentiation, survival, and function of B and T lymphocytes, dendritic cells, macrophages, and other immune cell types. We discuss here recent findings revealing important roles for miRNA in immunity and how miRNAs can regulate innate and adaptive immune responses.
TL;DR: Basal trafficking to the intestine requires expression of α4β7 integrin and the chemokine receptor CXCR2 by the mast cell progenitors and expression of MAdCam-1 and VCAM-1 in the intestinal endothelium; and is also controlled by dendritic cells expressing the transcriptional regulatory protein T-bet.
Abstract: Mast cells are derived from the hematopoietic progenitors found in bone marrow and spleen. Committed mast cell progenitors are rare in bone marrow suggesting they are rapidly released into the blood where they circulate and move out into the peripheral tissues. This migration is controlled in a tissue specific manner. Basal trafficking to the intestine requires expression of α4β7 integrin and the chemokine receptor CXCR2 by the mast cell progenitors and expression of MAdCAM-1 and VCAM-1 in the intestinal endothelium; and is also controlled by dendritic cells expressing the transcriptional regulatory protein T-bet. None of these play a role in basal trafficking to the lung. With the induction of allergic inflammation in the lung, there is marked recruitment of committed mast cell progenitors to lung and these cells must express α4β7 and α4β1 integrins. Within the lung there is a requirement for expression of VCAM-1 on the endothelium that is regulated by CXCR2, also expressed on the endothelium. There is a further requirement for expression of the CCR2/CCL2 pathways for full recruitment of the mast cell progenitors to the antigen-inflamed lung.
TL;DR: The expression of sialic acids (Sia) is highly conserved in deuterostomes, i.e., from echinoderms to humans, where they constitute components of cell surface glycoproteins and gangliosides.
Abstract: The expression of sialic acids (Sia) is highly conserved in deuterostomes, i.e., from echinoderms to humans. They constitute components of cell surface glycoproteins and gangliosides, where they occupy mainly the terminal position as individual monosaccharides and, more rarely, as oligo- or polymers. They are frequently found in secreted glycoconjugates and in oligosaccharides, mainly of blood serum, milk, and mucus secretions [1, 2].
TL;DR: This review will focus on how certain IgG glycovariants impact different IgG-dependent effector functions and how this knowledge might be used to further improve the therapeutic effectiveness of this class of molecules.
Abstract: Immunoglobulin G (IgG) molecules are glycoproteins with dual functionality. While participating in the destruction of virally infected cells or healthy tissues during autoimmune disease, IgG antibodies are also used as a therapeutic agent to suppress IgG-triggered autoimmune disease and inflammation. Research of recent years has put the IgG-associated sugar moiety in the spotlight for regulating these opposing activities. This review will focus on how certain IgG glycovariants impact different IgG-dependent effector functions and how this knowledge might be used to further improve the therapeutic effectiveness of this class of molecules.