Molecular mechanisms

2017 ◽  
Author(s):  
Claudia Monaco ◽  
Giuseppina Caligiuri
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Lipid Mediators ◽  
Signalling Pathways ◽  
Immunological Responses ◽  
Intracellular Signalling Pathways ◽  
Cell Surface Interactions ◽  
Atherosclerosis Development ◽  
Inflammatory Signalling

The development of the atherosclerotic plaque relies on specific cognate interactions between ligands and receptors with the ability to regulate cell recruitment, inflammatory signalling, and the production of powerful inflammatory and bioactive lipid mediators. This chapter describes how signalling is engaged by cell-cell surface interactions when the endothelium interacts with platelets and leukocytes enhancing leukocyte recruitment during atherogenesis. It also exemplifies intracellular signalling pathways induced by the activation of innate immune receptors, the most potent activators of inflammation in physiology and disease. Differences are highlighted in innate signalling pathways in metabolic diseases such as atherosclerosis compared to canonical immunological responses. Finally, the key lipid mediators whose production can affect endothelial function, inflammation, and atherosclerosis development are summarized. This Chapter will take you through these fundamental steps in the development of the atherosclerotic plaque by summarizing very recent knowledge in the field and highlighting recent or ongoing clinical trials that may enrich our ability to target cardiovascular disease in the future.

scholarly journals The molecular and cellular basis of corticosteroid resistance

2003 ◽  
Vol 179 (3) ◽  
pp. 301-310 ◽  
Author(s):  
IC Chikanza ◽  
D Kozaci ◽  
Y Chernajovsky
Keyword(s):  
Rheumatoid Arthritis ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Intracellular Signalling ◽  
Signalling Pathways ◽  
Peripheral Blood Mononuclear ◽  
Intracellular Signalling Pathways ◽  
Nf Kappab

Corticosteroids (CS) can modulate gene expression and are often used to treat a range of immunological and inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis. However, a proportion of patients fail to show an adequate response. On this basis patients have been subdivided into CS-sensitive (SS) and -resistant (SR) subgroups. The ability of CS to inhibit peripheral blood T cell proliferation in vitro has also been used similarly. In rheumatoid arthritis (RA), the in vitro-defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms responsible for this observation are unknown but they appear to involve a number of known molecular events related to the described mechanisms of action of CS. These include alterations in the functional status of CS receptor-alpha, perturbations of the cytokine and hormonal milieu and intracellular signalling pathways. Peripheral blood mononuclear cells (MNCs) from SR significantly overexpress activated NF-kappaB. In vitro, CS fail to significantly inhibit concanavalin A (conA)-induced NF-kappaB activation in MNCs from SR RA patients. The alterations in the intracellular signalling pathways may explain in part our observations seen in SR RA subjects, CS fail to significantly inhibit conA-induced interleukin (IL)-2 and IL-4 secretion and lipopolysaccharide-induced IL-8 and IL-1beta secretion in vitro. CS therapy fails to reduce the circulating levels of IL-8 and IL-1beta in RA patients. In asthma, CS fail to induce L10 in SR asthma patients. Other molecular mechanisms such as enhanced AP-1 expression and alterations in the MAP kinase pathway are most likely to be involved too and we are currently investigating such possibilities. A full understanding of the molecular basis of SR will lead to the development of more rational therapeutic strategies.

scholarly journals Molecular basis for specificity of the Met1-linked polyubiquitin signal

2016 ◽  
Vol 44 (6) ◽  
pp. 1581-1602 ◽  
Author(s):  
Paul R. Elliott
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Responses ◽  
Signalling Pathways ◽  
Post Translational Modification ◽  
Polyubiquitin Chains ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Ubiquitin Binding ◽  
Inflammatory Signalling ◽  
Unique Ability

The post-translational modification of proteins provides a rapid and versatile system for regulating all signalling pathways. Protein ubiquitination is one such type of post-translational modification involved in controlling numerous cellular processes. The unique ability of ubiquitin to form polyubiquitin chains creates a highly complex code responsible for different subsequent signalling outcomes. Specialised enzymes (‘writers’) generate the ubiquitin code, whereas other enzymes (‘erasers’) disassemble it. Importantly, the ubiquitin code is deciphered by different ubiquitin-binding proteins (‘readers’) functioning to elicit particular cellular responses. Ten years ago, the methionine1 (Met1)-linked (linear) polyubiquitin code was first identified and the intervening years have witnessed a seismic shift in our understanding of Met1-linked polyubiquitin in cellular processes, particularly inflammatory signalling. This review will discuss the molecular mechanisms of specificity determination within Met1-linked polyubiquitin signalling.

Mechanisms by which fatty acids regulate leucocyte function

2007 ◽  
Vol 113 (2) ◽  
pp. 65-77 ◽  
Author(s):  
Thais Martins de Lima ◽  
Renata Gorjão ◽  
Elaine Hatanaka ◽  
Maria Fernanda Cury-Boaventura ◽  
Erica Paula Portioli Silva ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Substantial Improvement ◽  
Lipid Mediators ◽  
Control Of Gene Expression ◽  
Intracellular Signalling Pathways ◽  
Activation Of Transcription ◽  
Associated Proteins

Fatty acids (FAs) have been shown to alter leucocyte function and thus to modulate inflammatory and immune responses. In this review, the effects of FAs on several aspects of lymphocyte, neutrophil and macrophage function are discussed. The mechanisms by which FAs modulate the production of lipid mediators, activity of intracellular signalling pathways, activity of lipid-raft-associated proteins, binding to TLRs (Toll-like receptors), control of gene expression, activation of transcription factors, induction of cell death and production of reactive oxygen and nitrogen species are described in this review. The rationale for the use of specific FAs to treat patients with impaired immune function is explained. Substantial improvement in the therapeutic usage of FAs or FA derivatives may be possible based on an improvement in the understanding of the precise molecular mechanisms of action with respect to the different leucocyte types and outcome with respect to the inflammatory responses.

scholarly journals Functional Active Genomics of Isoprene Biogenesis and resistance to cardiovascular diseases

2021 ◽  
Vol 2 (4) ◽  
pp. 73-78
Author(s):  
Anna Fedoriv ◽  
Ivan Fedoriv
Keyword(s):  
Fatty Acids ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Saturated Fatty Acids ◽  
Research Work ◽  
Energy Parameter ◽  
Chronic Inflammatory Disease ◽  
Early Stages ◽  
Atherosclerosis Development ◽  
Atherosclerotic Process

The pathologic development of the atherosclerotic process is often associated with the metabolism of saturated and unsaturated fatty acid. Substitution of the saturated fatty acids in nutrition for polyunsaturated fatty acids is traditionally associated with the lowering of risk of coronary breaches rise. Understanding the molecular mechanisms of the atherosclerosis development and progress is very important for early diagnostic and effective medical treatment of the above-mentioned disease. After a thorough analysis of the data available on the pathological atherosclerotic process, we have come to the conclusion that this disease begins from vascular smooth muscle cell (VSMC) impaired function. In the basis of the atherosclerosis development lies isoprenes biogenesis breach, caused by cholesterol and the products of its metabolism. Atherosclerosis is a chronic inflammatory disease of the media wall of large- and medium-sized arteries. And endothelium injury is a consequence of the pathologic process progressing in myocytes. Metabolic problems have become so relevant that it is time to form a metabolic policy. Real target programs for the prevention of the development of metabolic diseases and their diagnostics in the early stages of development should be developed. But in order to achieve this goal, it is necessary to know the real molecular mechanism of development of the early stages of metabolic diseases. It is necessary to recognize that the research work on the metabolic problem was carried out mainly in the plane of the functionally-energy parameter and captures only the consequences of the pathological process. And the very reason and early stages of metabolic diseases remained hidden from us, as they are depending on the pathology in the plane Regulatory, Information, Coordination and Functional active bioenergy system.

Tribbles in inflammation

2015 ◽  
Vol 43 (5) ◽  
pp. 1069-1074 ◽  
Author(s):  
Jessica Johnston ◽  
Shaghayegh Basatvat ◽  
Zabran Ilyas ◽  
Sheila Francis ◽  
Endre Kiss-Toth
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Innate Immune ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Disease Development ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Inflammatory Signalling

Inflammation is part of the physiological innate immune response to invading pathogens and tissue injury. However, unresolved inflammation leads to human disease. The tribbles (TRIB) family of pseudokinase proteins has been shown to modulate key inflammatory signalling pathways, including the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) networks. This review summarizes our current knowledge on TRIBs in the context of inflammation, both at the level of molecular mechanisms and in disease development.

Caspases and apoptosis

2002 ◽  
Vol 38 ◽  
pp. 9-19 ◽  
Author(s):  
Guy S Salvesen
Keyword(s):  
Cysteine Proteases ◽  
Signalling Pathways ◽  
Term Survival ◽  
Mature Adult ◽  
Intracellular Signalling Pathways ◽  
Adult Cell ◽  
Caspase Family ◽  
Cell Fragments ◽  
Pro Inflammatory Cytokines

The ability of metazoan cells to undergo programmed cell death is vital to both the precise development and long-term survival of the mature adult. Cell deaths that result from engagement of this programme end in apoptosis, the ordered dismantling of the cell that results in its 'silent' demise, in which packaged cell fragments are removed by phagocytosis. This co-ordinated demise is mediated by members of a family of cysteine proteases known as caspases, whose activation follows characteristic apoptotic stimuli, and whose substrates include many proteins, the limited cleavage of which causes the characteristic morphology of apoptosis. In vertebrates, a subset of caspases has evolved to participate in the activation of pro-inflammatory cytokines, and thus members of the caspase family participate in one of two very distinct intracellular signalling pathways.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

Periodontal Pathogens and Neuropsychiatric Health

2020 ◽  
Vol 20 (15) ◽  
pp. 1353-1397 ◽  
Author(s):  
Abhishek Wadhawan ◽  
Mark A. Reynolds ◽  
Hina Makkar ◽  
Alison J. Scott ◽  
Eileen Potocki ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Low Grade ◽  
Periodontal Pathogens ◽  
Synergistic Interactions ◽  
Brain Vasculature ◽  
Micro Rnas ◽  
Clinical Conditions ◽  
Low Grade Inflammation ◽  
Neuropsychiatric Illness

Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.

scholarly journals Immune Actions on the Peripheral Nervous System in Pain

2021 ◽  
Vol 22 (3) ◽  
pp. 1448
Author(s):  
Jessica Aijia Liu ◽  
Jing Yu ◽  
Chi Wai Cheung
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Process Integration ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Lipid Mediators ◽  
Cellular Changes

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

scholarly journals The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Natalie Eaton-Fitch ◽  
Hélène Cabanas ◽  
Stanley du Preez ◽  
Donald Staines ◽  
Sonya Marshall-Gradisnik
Keyword(s):  
Chronic Fatigue Syndrome ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Chronic Fatigue ◽  
Signalling Pathways ◽  
Cell Cytotoxicity ◽  
Fatigue Syndrome ◽  
Intracellular Signalling Pathways ◽  
Nk Cell Cytotoxicity

Abstract Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated. Methods NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured. Results Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients. Conclusion Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2. While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.

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