- Free radicals and antioxidants in normal physiological functions and human disease
Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
- ROS as signalling molecules in T cells--evidence for abnormal redox signalling in the autoimmune disease, rheumatoid arthritis
Reactive oxygen species are recognised as important signalling molecules within cells of the immune system. This is, at least in part, due to the reversible activation of kinases, phosphatases and transcription factors by modification of critical thiol residues. However, in the chronic inflammatory disease rheumatoid arthritis, cells of the immune system are exposed to increased levels of oxidative stress and the T cell becomes refractory to growth and death stimuli. This contributes to the perpetuation of the immune response. As many of the effective therapies used in the treatment of rheumatoid arthritis modulate intracellular redox state, this raises the question of whether increased oxidative stress is causative of T-cell hyporesponsiveness. To address this hypothesis, this review considers the putative sources of ROS involved in normal intracellular signalling in T cells and the evidence in support of abnormal ROS fluxes contributing to T-cell hyporesponsiveness.
- The role of reactive oxygen species in homeostasis and degradation of cartilage
This review of the literature supports the concept that ROS are not only deleterious agents involved in cartilage degradation, but that they also act as integral factors of intracellular signaling mechanisms. Further investigation is required to support the concept of antioxidant therapy in the management of joint diseases.
- Advances in understanding the genetic basis of rheumatoid arthritis and osteoarthritis: implications for therapy
It is thought that excess, damaging, ROS/RNS may arise from an imbalance between the production and removal of these chemical species. Polymorphisms in genes that encode enzymes involved in either generating or degrading ROS/RNS may contribute to such an imbalance. In the last few years, polymorphisms in such genes have indeed been identified as risk factors for rheumatic diseases.
- The role of nitric oxide in tissue destruction
Nitric oxide (NO) is synthesized via the oxidation of arginine by a family of nitric oxide synthases (NOS), which are either constitutive (ie. endothelial (ec)NOS and neuronal (nc)NOS) or inducible (iNOS). The production of nitric oxide plays a vital role in the regulation of physiological processes, host defence, inflammation and immunity. Pro-inflammatory effects include vasodilation, oedema, cytotoxicity and the mediation of cytokine-dependent processes that can lead to tissue destruction. Nitric oxide-dependent tissue injury has been implicated in a variety of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis and osteoarthritis. Conversely, the production of NO by endothelial cell NOS may serve a protective, or anti-inflammatory, function by preventing the adhesion and release of oxidants by activated neutrophils in the microvasculature. In this chapter we describe the multifaceted role of nitric oxide in inflammation and address the potential therapeutic implications of NOS inhibition.
- Nitric oxide downregulates interleukin 1beta (IL-1beta) stimulated IL-6, IL-8, and prostaglandin E2 production by human chondrocytes
OBJECTIVE: To investigate the effects of endogenously produced nitric oxide (NO) on interleukin 6 (IL-6), IL-8, prostaglandin E2 (PGE2), and proteoglycan production by human chondrocytes. METHODS: Human articular chondrocytes were isolated from their extracellular matrix by triple successive enzymatic digestion of the cartilage and cultured 48 h in a well defined culture medium. IL-6 and IL-8 were directly assayed into culture media by specific enzyme amplified sensitivity immunoassays. Proteoglycans and PGE2 were quantified by specific radioimmunoassays. Cell culture media were assayed for NO2 using a spectrophotometric assay based upon the Griess reaction. RESULTS: Unstimulated chondrocytes produced low levels of NO, IL-6, IL-8, and PGE2. Production was significantly stimulated by IL-1beta and lipopolysaccharide (LPS). As well, proteoglycan synthesis was profoundly inhibited by IL-1beta and LPS. Inhibition of NO synthesis with the competitive inhibitor NG-monomethyl-L-arginine (L-NMMA) led to enhancement of IL-6, IL-8, and PGE2 production stimulated by either IL-1beta alone or in combination with LPS, whereas the inhibition of proteoglycan production by IL-1beta was not modified by L-NMMA. CONCLUSION: LPS and IL-1beta stimulated IL-6, IL-8, and PGE2 production are downregulated by endogenously produced NO, which could limit the inflammatory reaction occurring in arthritis.
Maagdarmstoornissen: Candida infectie - Prikkelbaredarmsyndroom - Crohn - Colitus Ulcerosa - CVS/ME: Chronische vermoeidheid Syndroom - Diabetische complicaties: Bloeduiker stabilisatie - Neuropathie - Retinopathie - Nefropathie - Hart- en vaatziekten: Cardiomyopathie en Hartfalen - Hoge bloeddruk - Cholesterol verlaging - Aderverkalking (atherosclerose) - Spataderen - Levensverlenging: 100 jaren jong - DHEA - Melatonine - 65+ - Kanker: - Ondersteuningstherapie bij kanker - Bot en gewrichtsaandoeningen: - Artrose - Artritis - Osteoporose - Fibromyalgie: - Fibromyalgie - Urinewegaandoeningen: - Prostaatklachten - Blaasontsteking - Vrouwenklachten: Menopauze - Premenstrueelsyndroom - Overgewicht: - Overgewicht - SLIM - Oogaandoeningen: Staar - Slecht zien Andere artikelen: - HPU - Astma - Multiple Sclerose - Psoriasis - Depressie