Experientia supplementum (2012)最新文献

Diet plays a fundamental role in the nutritional status, in the homeostasis and in the capacity of an individual to adapt to the environment. A proper or an inadequate nutrition has an impact on the persistence, remission and incidence of various conditions, including the infectious diseases. Consequently, nutrition has a crucial importance on survival rates and health recovery of individuals or even populations around the globe. The synergistic relationship between nutritional needs and infectious processes has been demonstrated conclusively in diverse studies. This chapter will discuss the most important nutrients, their most common natural dietary sources, the different digestive processes for each one as well as the absorption, transport, storage, excretion and function of each of the nutrients within the organism. We also go through some concepts on the interaction between nutrition and the immune system, as well as examples on the influence of nutrition or specific nutrients on some infectious diseases, and their influence on the gene expression.

Traumatic injury as one of the world's most relevant but neglected health concerns results in modulated inflammasome activity, which is closely linked to the development of post-injury complications. Cytokine-producing capacity of cells is important for the appropriate immune response to trauma and requires not only synthesis and transcription of inflammasome components but also their activation. Unfortunately, the precise role of inflammasome in trauma is still largely unknown. However, in the following chapter, we provide an overview on the best described inflammasomes in the various settings of trauma, introducing the recent findings on the up-to-date best described NLRP inflammasomes and underlying cytokines in the inflammatory response to trauma.

Damage-associated molecular patterns (DAMPs) or alarmins are endogenous danger signals that are derived from damaged cells and extracellular matrix degradation, capable of triggering innate immune response to promote tissue damage repair. Hemolytic or hemorrhagic episodes are often associated with inflammation, even when infectious agents are absent, suggesting that damaged red blood cells (RBCs) release DAMPs.Hemoglobin (Hb) composes 96% of the dry weight of RBCs; therefore upon hemolysis, tremendous amounts of Hb are released into the extracellular milieu. Hb oxidation occurs outside the protective environment of RBCs, leading to the formation of different Hb oxidation products and heme. Heme acts as a prototypic DAMP participating in toll-like receptor as well as intracellular nucleotide-binding oligomerization domain-like receptor signaling. Oxidized Hb forms also possess some inflammatory actions independently of their heme releasing capability. Non-Hb-derived DAMPs such as ATP, interleukin-33, heat shock protein 70, as well as RBC membrane-derived microparticles might also contribute to the innate immune response triggered by hemolysis/hemorrhage.In this chapter we will discuss the inflammatory properties of RBC-derived DAMPs with a particular focus on Hb derivatives, as well as therapeutic potential of the endogenous Hb and heme-binding proteins haptoglobin and hemopexin in the prevention of hemolysis/hemorrhage-associated inflammation.

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.

Microbes have developed a series of strategies to overcome the defense mechanisms of the infected host. During pathogen-host coevolution, they develop strategy to manipulate cellular machinery particularly in subverting mitochondrion function. Mitochondria are highly dynamic organelles that constantly remodel their structure. In particular, shaping and cellular distribution of the mitochondrial network is maintained in large part by the conserved activities of mitochondrial division, fusion, motility, and tethering. Mitochondria have been long recognized for their role in providing energy production, calcium metabolism, and apoptosis. More recently, mitochondria have been also shown to serve as a platform for innate immune response. In this context, mitochondrial dynamics and shaping is not only essential to maintain cristae structure and bioenergetic to fuel cellular demands but contribute to regulate cellular function such as innate immune response and mitochondrial permeabilization. Due to their key role in cell survival, mitochondria represent attractive targets for pathogens. Therefore, microbes by manipulating mitochondrial dynamics may escape to host cellular control. Herein, we describe how mitochondrial bioenergetics, dynamics, and shaping are impacted during microbe infections and how this interplay benefits to pathogens contributing to the diseases.

Inflammasomes are large innate cytoplasmic complexes that play a major role in promoting inflammation in the lung in response to a range of environmental and infectious stimuli. Inflammasomes are critical for driving acute innate immune responses that resolve infection and maintain tissue homeostasis. However, dysregulated or excessive inflammasome activation can be detrimental. Here, we discuss the plethora of recent data from clinical studies and small animal disease models that implicate excessive inflammasome responses in the pathogenesis of a number of acute and chronic respiratory inflammatory diseases. Understanding of the role of inflammasomes in lung disease is of great therapeutic interest.

Neuroinflammation is a common pathological feature in almost all neurological diseases and is a response triggered as a consequence of the chronic activation of the innate immune response in the CNS against a variety of stimuli, including infection, traumatic brain injury, toxic metabolites, aggregated proteins, or autoimmunity. Crucial mediators of this neurinflammatory process are the intracellular protein complexes known as inflammasomes which can be triggered by pathogens as well as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). However, chronic inflammasome activation can eventually result in cellular death and tissue damage, leading to the release of DAMPs that can reactivate the inflammasome, thereby propagating a vicious cycle of inflammation. The primary cells involved in CNS inflammasome activation are the immunocompetent microglia and the infiltrating macrophages into the CNS. However, astrocytes and neurons also express inflammasomes, and the understanding of how they are engaged in the pathogenesis of a variety of neurological diseases is crucial to develop effective therapeutic approaches for CNS pathologies that are propagated by chronic inflammasome activation. This chapter covers the activation mechanisms of relevant inflammasomes in the brain and summarizes their roles in the pathogenesis and progression of different neurological conditions.

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.

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.

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.