Experientia supplementum (2012)最新文献

Cardiovascular disease (CVD) is the number one cause of death worldwide. The pathogenesis of various disease entities that comprise the area of CVD is complex and multifactorial. Inflammation serves a central role in these complex aetiologies. The inflammasomes are intracellular protein complexes activated by danger-associated molecular patterns (DAMPs) present in CVD such as atherosclerosis and myocardial infarction (MI). After a two-step process of priming and activation, inflammasomes are responsible for the formation of pro-inflammatory cytokines interleukin-1β and interleukin-18, inducing a signal transduction cascade resulting in a strong immune response that culminates in disease progression. In the past few years, increased interest has been raised regarding the inflammasomes in CVD. Inflammasome activation is thought to be involved in the pathogenesis of various disease entities such as atherosclerosis, MI and heart failure (HF). Interference with inflammasome-mediated signalling could reduce inflammation and attenuate the severity of disease. In this chapter we provide an overview of the current literature available on the role of inflammasome inhibition as a therapeutic intervention and the possible clinical implications for CVD.

The cofactors nicotinamide adenine dinucleotide (NAD⁺) and its phosphate form, NADP⁺, are crucial molecules present in all living cells. The delicate balance between the oxidized and reduced forms of these molecules is tightly regulated by intracellular metabolism assuring the maintenance of homeostatic conditions, which are essential for cell survival and proliferation. A recent cluster of data has highlighted the importance of the intracellular NAD⁺/NADH and NADP⁺/NADPH ratios during host-pathogen interactions, as fluctuations in the levels of these cofactors and in precursors' bioavailability may condition host response and, therefore, pathogen persistence or elimination. Furthermore, an increasing interest has been given towards how pathogens are capable of hijacking host cell proteins in their own advantage and, consequently, alter cellular redox states and immune function. Here, we review the basic principles behind biosynthesis and subcellular compartmentalization of NAD⁺ and NADP⁺, as well as the importance of these cofactors during infection, with a special emphasis on pathogen-driven modulation of host NAD⁺/NADP⁺ levels and contribution to the associated immune response.

Inflammasomes influence a diverse range of kidney disease, including acute and chronic kidney diseases, and those mediated by innate and adaptive immunity. Both IL-18 and in particular IL-1β are validated therapeutic targets in several kidney diseases. In addition to leukocyte-derived inflammasomes, renal tissue cells express functional inflammasome components. Furthermore, a range of endogenous substances that directly activate inflammasomes also mediate kidney injury. Many of the functional studies have focussed on the NLRP3 inflammasome, and there is also evidence for the involvement of other inflammasomes in some conditions. While, at least in some disease, the mechanistic details of the involvement of the inflammasome remain to be elucidated, therapies focussed on inflammasomes and their products have potential in treating kidney disease in the future.

One of the main steps in the development of the life in the earth is multicellularity. It enables cell differentiation and the development of morphological structures within an organism and is an essential factor in how to recognize friendly cells that are part of the multicellular organism and which foreign organisms can be harmful. Recognition includes devices such as the major histocompatibility complex (MHC), and the pattern recognition receptors (PRRs). PRRs are a group of proteins expressed by cells of the innate immune system that identify two classes of products: pathogen-associated molecular patterns (PAMPs), related to microbial pathogens, and damage-associated molecular patterns (DAMPs), associated with cell components that are released during cell damage or death. All these activate the inflammasome, which is a multiprotein oligomer that includes caspase 1, PYCARD, NALP, and caspase 5 (also known as caspase 11 or ICH-3). It is responsible for activation of inflammatory processes and has been shown to induce cell pyroptosis, a programmed cell death distinct from apoptosis, and promotes the maturation of the inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18). We review whether inflammasome is related to diseases that can occur in the oral cavity. The mouth is always a possible environment for the development of pathological conditions because of the wide variety of microorganisms. Small variations in the equilibrium of the oral flora can cause disorders that could affect the organism in a systemic form. We provide data on periodontal disease, candidiasis, herpes virus, oral cancer, caries, and other oral diseases. There are very few papers that study this issue; therefore, we need more investigation and publications about inflammatory molecular processes, and more specifically, related to the inflammasome complex.

Modulation of inflammasomes has tremendous therapeutic potential and is hotly pursued by industry and academia alike. Indeed a growing number of patents are emerging to protect the intellectual property in valuable compound classes. This chapter focusses specifically on the suite of small-molecule NLRP3 inflammasome inhibitors published, as specific modulation of other inflammasomes is not yet well established. Synthetic molecules, known drugs and natural product NLRP3 modulators will be detailed. Some of the molecular classes discussed have been extensively characterised through cell-based screening, pharmacokinetic profiling and therapeutic proof of concept animal models. However, many inhibitors lack rigorous studies and/or have multiple activities of which NLRP3 modulation is only one. While this is not intended as an exhaustive list, it should give an impression of the range of structures and strategies that are being used, alongside challenges encountered, in an effort to exploit the significant therapeutic benefits of targeting inflammasomes.

Microscopy allows for the characterization of small objects invisible to the naked eye, a technique that, since its conception, has played a key role in the development across nearly every field of science and technology. Given the nanometer size of the materials explored in the field of nanotechnology, the contributions of modern microscopes that can visualize these materials are indispensable, and the ever-improving technology is paramount to the future success of the field. This chapter will focus on four fundamental areas of microscopy used in the field of nanotechnology including fluorescence microscopy (Sect. 3.1), particle tracking and photoactivated localization microscopy (Sect. 3.2), quantum dots and fluorescence resonance energy transfer (Sect. 3.3), and cellular MRI and PET labeling (Sect. 3.4). The functionality, as well as the current and recommended usage of each given imaging system, will be discussed.

Mutations in inflammasome genes are responsible for rare monogenic and polygenic autoinflammatory diseases. On the other side, genetic polymorphisms in the same molecules contribute to the development of common multifactorial diseases (i.e., autoimmune diseases, cardiovascular pathologies, cancer). In this chapter we depicted the current knowledge about inflammasome genetics.

A systems approach to elucidate the effect of infection on cell metabolism provides several opportunities from a better understanding of molecular mechanisms to the identification of potential biomarkers and drug targets. This is obvious from the fact that we have witnessed the accelerated use of computational systems biology in the last five years to study metabolic changes in pathogen and/or host cells in response to infection. In this chapter, we aim to present a comprehensive review of the recent research by focusing on genome-scale metabolic network models of pathogen-host systems and genome-wide metabolomics and fluxomics analysis of infected cells.

T cells play a pivotal role in sensitization and elicitation of type IV allergic reactions. While T helper cells sustain and maintain the differentiation of further effector cells, regulatory T cells are involved in control of cytokine release and proliferation, and T killer cells execute cellular lysis, thereby leading to certain levels of tissue damage. According to their central role, the widely applied and OECD-supported test method for the assessment of the sensitization potential of a chemical, i.e., the local lymph node assay (LLNA), relies on the detection of the immune-responsive proliferation of lymphocytes. However, most sensitization assays recently developed take advantage of the initiators of sensitization, dendritic cells (DCs) or DC-like cell lines. Here, we focus on inhibitory molecules expressed on the surface of DCs and their corresponding receptors on T cells. We summarize insight into the function of CTLA-4, the ligands of inducible co-stimulators (ICOSs), and on the inhibitory receptor programmed death (PD). The targeting of immune cell surface receptors by inhibitory molecules holds some promise with regard to the development of T cell-based sensitization assays. Firstly, a broader and more sensitive dynamic range of detection could be achieved by blocking inhibitors or by removing inhibiting regulatory T cells from the assays. Secondly, the actual expression levels of inhibitory molecules could be also a valuable indicator for the process of sensitization. Finally, inhibitory molecules in coculture test systems are supposed to have a major influence on DCs by reverse signaling, thereby affecting their differentiation and maturation status in a feedback loop. In conclusion, inhibitory ligands of DC surface receptors and/or their cognate receptors on T cells could serve as useful tools in cell-based assays, directly influencing toxicological endpoints such as sensitization.