Some biochemical and pharmacological aspects of free radical-mediated tissue damage.
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Abstract:
Living in aerobic conditions carries a risk of oxidative stress, in connection with free radical deleterious action on tissues and cells. Free radical mechanisms have been implicated in the pathogenesis of many diseases, as well as in host defense against various invading microorganisms. A substantial body of evidence has been reported on free radical involvement in inflammation, ischaemia/reperfusion injury, atherosclerosis and many other pathologies. The aim of this paper is to review selected literature and opinions concerning free radical-induced damage to tissues and to present xenobiotic contribution to oxidative stress.Keywords:
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CD69分子はc-type lectinファミリーに属するII型の膜分子で,早期活性化マーカー分子としてリンパ球の活性化の指標として広く用いられている.機能の詳細はこれまであまり明らかにされていないが,炎症局所に浸潤する炎症細胞のほとんどがCD69を発現していることから,さまざまな炎症反応の誘導・維持に重要な役割を果たしていると考えられる.著者らはこれまでに生体内でのCD69分子の役割を解析する目的でCD69ノックアウトマウスを作製し,疾患との関わりの解析を進めてきた.その結果,CD69ノックアウトマウスでは関節炎やアレルギー性喘息が起きないことを見出した.アレルギー性喘息は抗CD69抗体の投与でも抑制され,治療効果が認められた.CD69分子はその他の炎症性疾患の発症にも関与している可能性が高く,難治性の炎症性疾患に対する新規治療法の開発において新しいターゲット分子になる可能性が示唆された.
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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of DR. Large clinical trials have clearly demonstrated that tight control of glycaemia and/or blood pressure significantly reduces the incidence and progression of DR. The mechanism by which hypertension interacts with diabetes to exacerbate the retinal disease is not completely understood. From experimental studies, increasing evidence demonstrates that chronic inflammation and oxidative stress are involved. In the present review, we summarize data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of DR. It is suggested that oxidative stress and inflammation may be common denominators of retinal damage in the presence of hypertension in diabetic patients. Keywords: Diabetes, DR, hypertension, inflammation, oxidative stress, renin-angiotensin system.
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The inflammation underlying rheumatoid arthritis (RA), being a multicomponent and multi-stage process, essentially determines the clinical polymorphism of the disease. The analysis of the literature data on the functional state of neutrophils as effector cells of rheumatoid inflammation, on the participation of polymorphonuclear leukocytes in the formation of the clinical picture of the disease is difficult: they are few, contradictory and rarely contain conclusions of applied significance. There is no consensus on the nature of chemotactic, phagocytic and bactericidal functions of neutrophils. In addition, the functional state of blood neutrophils, synovial fluid and related phenomena is currently an insufficiently studied aspect of the pathogenesis and clinic of rheumatoid arthritis.
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The role of inflammation in the pathogenesis of abdominal aortic aneurysms (AAA) is well established. The inflammatory process leads to protease-mediated degradation of the extracellular matrix and apoptosis of smooth muscle cells (SMC), which are the predominant matrix synthesizing cells of the vascular wall. These processes act in concert to progressively weaken the aortic wall, resulting in dilatation and aneurysm formation. Oxidative stress is invariably increased in, and contributes importantly to, the pathophysiology of inflammation. Moreover, reactive oxygen species (ROS) play a key role in regulation of matrix metalloproteinases and induction of SMC apoptosis. ROS may also contribute to the pathogenesis of hypertension, a risk factor for AAA. Emerging evidence suggests that ROS and reactive nitrogen species (RNS) are associated with AAA formation in animal models and in humans. Although experimental data are limited, several studies suggest that modulation of ROS production or activity may suppress AAA formation and improve experimental outcome in rodent models. Although a number of enzymes can produce injurious ROS in the vasculature, increasing evidence points toward a role for NADPH oxidase as a source of oxidative stress in the pathogenesis of AAA.
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The pathogenesis of atherosclerosis has not been well defined and many questions remain unanswered. Many studies have discussed the importance of inflammation as the first step in promoting endothelial dysfunction and atherosclerosis.The association of inflammatory markers such as fibrinogen and C reactive protein (CRP) with atherosclerosis and cardiovascular/cerebrovascular clinical events reinforces the pivotal role that inflammation plays in the atherosclerotic process.The humoral and cellular autoimmune response against antigens expressed in the endothelium and the greater prevalence of atherosclerosis in immune-mediated rheumatic diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) strongly suggest the involvement of autoimmunity in the atherosclerotic process. The role of inflammation and autoimmune responses in atherosclerosis are discussed in order to better understand their close link on its pathogenesis.
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Hypertension (HTN) is a major cause of stroke, left ventricular hypertrophy, congestive heart failure, arteriosclerosis, end-stage renal disease, and peripheral vascular disease. Oxidative stress and its constant companion, inflammation, play a critical part in the pathogenesis of many acute and chronic illnesses including HTN and its long-term complications. There is compelling evidence that oxidative stress, inflammation, and HTN are involved in a self-perpetuating vicious cycle which, if not interrupted, culminates in progressive target organ injury and dysfunction. This article is intended to review the available evidence for the role of oxidative stress and inflammation in the pathogenesis of HTN. In addition, evidence will be presented to demonstrate the role of HTN in the pathogenesis of oxidative stress and inflammation. Finally, evidence for participation of tissue angiotensin system in the vicious cycle of oxidative stress, inflammation, and HTN will be presented, and the approach to treatment of HTN-associated oxidative stress will be discussed.
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While several characteristics of systemic lupus erythematosus (SLE) have been investigated, the distinct pathogenetic mechanisms leading to autoimmunity and chronic inflammation are not understood yet. A central role for apo has been implicated in the pathogenesis of SLE and an increased rate of apo or a defective clearance of apo cells have repeatedly been described in SLE patients, which show elevated levels of alpha-interferon (αIFN) as well as an enhanced expression of αIFN-alpha inducible genes referred to as αIFN signature. Recent publications link αIFN and apo: apo cell-derived microparticles can directly stimulate plasmacytoid dendritic cells to secret αIFN. This review highlights the role of apo material as source for AAg and as a trigger for chronic inflammation in the pathogenesis of SLE.
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Osteoarthritis (OA) is the most prevalent joint degenerative disease leading to irreversible structural and functional changes in the joint and is a major cause of disability and reduced life expectancy in ageing population. Despite the high prevalence of OA, there is no disease modifying drug available for the management of OA. Oxidative stress, a result of an imbalance between the production of reactive oxygen species (ROS) and their clearance by antioxidant defense system, is high in OA cartilage and is a major cause of chronic inflammation. Inflammatory mediators, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are highly upregulated in OA joints and induce ROS production and expression of matrix degrading proteases leading to cartilage extracellular matrix degradation and joint dysfunction. ROS and inflammation are interdependent, each being the target of other and represent ideal target/s for the treatment of OA. Plant polyphenols possess potent antioxidant and anti-inflammatory properties and can inhibit ROS production and inflammation in chondrocytes, cartilage explants and in animal models of OA. The aim of this review is to discuss the chondroprotective effects of polyphenols and modulation of different molecular pathways associated with OA pathogenesis and limitations and future prospects of polyphenols in OA treatment.
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A substantial knowledge on the pathogenesis of diabetes mellitus (DM) by oxidative stress and inflammation is available. Berberine is a biologically active botanical that can combat oxidative stress and inflammation and thus ameliorate DM, especially type 2 DM. This article describes the potential of berberine against oxidative stress and inflammation with special emphasis on its mechanistic aspects. In diabetic animal studies, the modified levels of proinflammatory cytokines and oxidative stress markers were observed after administering berberine. In renal, fat, hepatic, pancreatic and several others tissues, berberine-mediated suppression of oxidative stress and inflammation was noted. Berberine acted against oxidative stress and inflammation through a very complex mechanism consisting of several kinases and signaling pathways involving various factors, including NF-κB (nuclear factor-κB) and AMPK (AMP-activated protein kinases). Moreover, MAPKs (mitogen-activated protein kinases) and Nrf2 (nuclear factor erythroid-2 related factor 2) also have mechanistic involvement in oxidative stress and inflammation. In spite of above advancements, the mechanistic aspects of the inhibitory role of berberine against oxidative stress and inflammation in diabetes mellitus still necessitate additional molecular studies. These studies will be useful to examine the new prospects of natural moieties against DM.
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