Hypoxia, oxidative stress and inflammation
TL;DR: Understanding the complex interplay between hypoxia-induced signaling pathways, oxidative stress and mitochondrial function will provide better insight into the underlying mechanisms of disease pathogenesis.
About: This article is published in Free Radical Biology and Medicine.The article was published on 2018-09-01. It has received 278 citations till now. The article focuses on the topics: Oxidative stress & Synovial Cell.
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TL;DR: The fact that not all individuals exposed to the same environmental risk factors develop obesity supports the hypothesis of the existence of underlying genetic and epigenetic elements.
Abstract: The fact that not all individuals exposed to the same environmental risk factors develop obesity supports the hypothesis of the existence of underlying genetic and epigenetic elements. There is suggestive evidence that environmental stimuli, such as dietary pattern, particularly during pregnancy and early life, but also in adult life, can induce changes in DNA methylation predisposing to obesity and related comorbidities. In this context, the DNA methylation marks of each individual have emerged not only as a promising tool for the prediction, screening, diagnosis, and prognosis of obesity and metabolic syndrome features, but also for the improvement of weight loss therapies in the context of precision nutrition. The main objectives in this field are to understand the mechanisms involved in transgenerational epigenetic inheritance, and featuring the nutritional and lifestyle factors implicated in the epigenetic modifications. Likewise, DNA methylation modulation caused by diet and environment may be a target for newer therapeutic strategies concerning the prevention and treatment of metabolic diseases.
117 citations
Cites background from "Hypoxia, oxidative stress and infla..."
...Hypoxic conditions favour the increase of reactive oxygen species and oxidative stress, both described as important inflammatory mediators [66]....
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TL;DR: There is evidence to support the inflammation-driven pathways in the pathogenesis of fibromyalgia, however, further research is required to fully understand the network of inflammation and its possible role in diagnosis and/or treatment of Fibromyalgia.
Abstract: Fibromyalgia is a multifaceted disease. The clinical picture of fibromyalgia covers numerous comorbidities. Each comorbidity stands as a distinct condition. However, common pathophysiologic factors are occupied in their background. Along with the genetic, environmental and neuro-hormonal factors, inflammation has been supposed to have role in the pathogenesis of fibromyalgia. The aim of the present article was to review the current literature regarding the potential role of inflammation in the pathogenesis and treatment of fibromyalgia. A literature search was conducted through PubMed/MEDLINE and Web of Science databases using relevant keywords. Recent evidence on this highly studied topic indicates that fibromyalgia has an immunological background. Cytokines/chemokines, lipid mediators, oxidative stress and several plasma-derived factors underlie the inflammatory state in fibromyalgia. There are potential new therapeutic options targeting inflammatory pathways in fibromyalgia patients. In conclusion, there is evidence to support the inflammation-driven pathways in the pathogenesis of fibromyalgia. However, further research is required to fully understand the network of inflammation and its possible role in diagnosis and/or treatment of fibromyalgia.
64 citations
Cites background from "Hypoxia, oxidative stress and infla..."
...Oxidative damage causes further inflammation, creating a vicious cycle [48]....
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TL;DR: Current knowledge of the relevance of 4-HNE as "the second messenger of reactive oxygen species" (ROS) in redox signaling of representative major stress-associated diseases is briefly summarized.
58 citations
TL;DR: In this article, the authors provide a brief overview of the potential pharmacological mechanisms of THMs (active constituents, extracts, and prescriptions) in RA treatment, including anti-RA effects and therapeutic targets of distinct dosage forms of traditional herbal medicines (THMs).
58 citations
TL;DR: In this paper, metabolic mis-regulation is identified as a fundamental pathogenic pathway in all phases of rheumatoid arthritis, with each phase of disease linked to immune cell dysfunction.
Abstract: Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.
51 citations
References
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TL;DR: It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.
Abstract: Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.
4,845 citations
TL;DR: In this article, the authors propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions, which leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.
Abstract: If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.
4,361 citations
TL;DR: It is shown that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome, and may explain the frequent association of mitochondrial damage with inflammatory diseases.
Abstract: An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
3,985 citations
TL;DR: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
Abstract: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
3,975 citations
TL;DR: A hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production is revealed.
3,193 citations