Pathophysiology of oxidative stress in diabetes mellitus.

Oxidative stress is believed to play an important role, albeit not fully recognized, in the development of vascular complications in diabetes mellitus (DM) particularly type 2. In the majority of studies, attention was focused on lipid oxidation, specifically on that of low-density lipoproteins (LDLs). More recent investigations have revealed that it is not only the lipid but also the apolipoprotein moiety of LDL that becomes oxidatively modified resulting in the formation of insoluble aggregates. Consequently, it has been documented that LDL aggregation was due to the hydroxyl radical-induced dityrosine crosslinking between apo B monomers. In DM patients with atherosclerotic complications, intravascular fibrous deposits were shown to contain, in addition to oxidized LDL, a fibrin-like material (FLM). This material is immunologically identical to fibrin that is normally formed as a result of intravascular activation of the blood coagulation cascade. Although DM patients with vascular disease display increased concentration of plasma fibrinogen (Fbg), the precursor of fibrin, no markers of full blown activation of blood coagulation could be found.     

Basic science and applied science

A lecture was presented by the author at the Democratic Opinion Forum on Health Teaching and Research, organized by Mexico's National Health Institutes Coordinating Office, at National Cardiology Institute "Ignacio Chavez", where he presented a critical review of the conventional classification of basic and applied science, as well as his personal view on health science teaching and research. According to the author, "well-conducted science" is that "generating reality-checked knowledge" and "mis-conducted science" is that "unproductive or producing 'just lies' and 'non-fundable'. To support his views, the author reviews utilitarian and pejorative definitions of science, as well as those of committed and pure science, useful and useless science, and practical and esoterical science, as synonyms of applied and basic science. He also asserts that, in Mexico, "this classification has been used in the past to justify federal funding cutbacks to basic science, allegedly because it is not targeted at solving 'national problems' or because it was not relevant to priorities set in a given six-year political administration period". Regarding health education and research, the author asserts that the current academic programs are inefficient and ineffective; his proposal to tackle these problems is to carry out a solid scientific study, conducted by a multidisciplinary team of experts, "to design the scientific researcher curricula from recruitment of intelligent young people to retirement or death". Performance assessment of researchers would not be restricted to publication of papers, since "the quality of scientific work and contribution to the development of science is not reflected by the number of published papers". The English version of this paper is available at: http://www.insp.mx/salud/index.html     

Basic science highlights

The 14th Conference on Retroviruses and Opportunistic Infections generated a lot of excitement with the announcement of clinical studies employing the use of 2 new classes of antiretroviral drugs that target the viral integrase enzyme and the viral coreceptor CCR5. In addition, a number of presentations on cellular restriction factors provided surprises regarding the mechanism by which cellular restrictions antagonize viral infection. There was also much interest in studies presenting novel cellular cofactors of HIV-1 infection. The conference illustrated how basic science research is paying off. Essential steps in the viral life cycle, uncovered through basic research, are now being targeted by new classes of antiviral agents. In addition, basic science is unveiling potential new targets of antiretroviral therapy.     

Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury

The development of vascular disease has its origins in an initial insult to the vessel wall by biological or mechanical factors. The disruption of homeostatic mechanisms leads to alteration of the original architecture of the vessel and its biological responsiveness, contributing to acute or chronic diseases such as stroke, hypertension, and atherosclerosis. Endothelial dysfunction, macrophage infiltration of the vessel wall, and proliferation and migration of smooth muscle cells all involve different types of reactive oxygen species produced by various vessel wall components. Although basic science and animal research have clearly established the role of reactive oxygen species in the progression of vascular disease, the failure of clinical trials with antioxidant compounds has underscored the need for better antioxidant therapies and a more thorough understanding of the role of reactive oxygen species in cardiovascular physiology and pathology.     

Lead-induced hypertension: Role of oxidative stress

Chronic, low-level lead exposure causes hypertension in both animals and humans. The pathogenesis of leadinduced hypertension is multifactorial, including such diverse mechanisms as: inactivation of endogenous nitric oxide and downregulation of soluble guanylate cyclase by reactive oxygen species (ROS), leading to a functional deficiency in nitric oxide; heightened sympathetic activity and plasma norepinephrine together with depressed vascular and elevated renal β-adrenergic receptor density; elevated plasma angiotensin-converting enzyme (ACE) activity, plasma renin activity (PRA), angiotensin II (Ang-II), and aldosterone levels; increased kininase I and kininase II activities; lead-induced inhibition of vascular smooth muscle Na^+-K⁺ ATPase, leading to a rise in cellular Na⁺ and, hence, Ca²⁺; and a possible rise in endothelin and thromboxane generation. In this article, we present an overview of the epidemiology and proposed underlying mechanisms of lead-induced hypertension.     

Basic science for the clinician 54: CD5

The full story of what surface markers mean about the cells on which they reside twists and turns as the days go by, with previously accepted "truth" changing in light of new findings. Such is the case with CD5, a surface marker on most murine T cells, many thymocytes, and a subset of B cells. The precise role of CD5 in the murine and human immune responses has been a matter of intense speculation for many years. Recent work suggests that CD5 may have a fine-tuning or suppressive effect on signaling through the antigen receptors on both B and T cells. These CD5 B cells were initially thought to be a major source of autoantibodies and/or "natural antibodies," targeting broad arrays of carbohydrate and protein antigens. More recent studies support the latter contention-CD5 B cells do produce "natural antibodies," but the former is far from true-CD5 B cells are not the major source of autoantibodies. In fact, CD5 may be a major negative influence on antigen receptor driven-B-cell function and may serve to control autoimmunity rather than encourage it. Furthermore, another subset of CD5 B cells may represent a distinct regulatory population. CD5 expression is noted on more than three fourths of all T-cell lymphomas. CD5 may be a receptor of pathogen-associated molecular patterns; CD5 may be a marker of decreased dependence of B cells on certain circulating factors. Elevated levels of CD5 are found in a number of autoimmune disorders. Thus, although the precise mechanism is unclear, there is at the very least circumstantial evidence of a role for CD5 in the pathogenesis of autoimmunity and perhaps T cell-derived lymphoid malignancy. New findings put old claims to rest and open up new avenues for research, both basic and clinical, with therapeutic applications not far behind.     

Basic science for the clinician 53: mast cells

Mast cells stand at the interface between the innate immune system and the acquired (adaptive) immune response, serving as sentinels detecting invaders and directing a concerted and coordinated response. Mast cells reside immediately under body surfaces and within lymph nodes, near blood vessels and nerves, perfectly situated to for early detection and defense. They secrete a wide array of prostanoids, cytokines, chemokines, and other proteins mediators and modifiers of a variety of immune and inflammatory functions and bear surface markers suggesting broad functions, including as antigen-presenting cells. Although usually not given their due in medical school lectures, there is great likelihood that mast cells will be implicated in the pathogenesis of rheumatoid arthritis, scleroderma, multiple sclerosis, and perhaps cancer. Thus, better insights into mast cell functions and mast cell-derived effector molecules should command our attention as we move forward in better understanding disease immunopathogenesis and directed intelligent therapeutics development.     

Basic science for the clinician 51: the inflammasome

The innate immune system is packaged in a number of discrete, but intercommunicating, systems. The inflammasome is a multimolecular complex that detects intracellular foreign molecules of a variety of sorts and promptly promotes the secretion of IL-1β and IL-18. When all goes well, defense of the organism in the early period of infection is enhanced by this system; when certain elements of the inflammasomal systems go awry, inflammatory diseases of a variety of sorts result. A family of multimolecular detection systems are activated at times of infection and tissue damage; it is the dysfunction of this innate immune defense system that intrigues rheumatologists, as this is the cause of a series of newly described autoinflammatory diseases.     

Basic science for the clinician 55: CTLA-4

In physiological systems, for every "yang," there must be a "yin," for uncontrolled systems can run amok. This is the case for the T-cell compartment of the immune system, where activation must be modulated, dampened, and ultimately reversed; to not apply the brakes leads to dire consequences. In less than 20 years, CTLA-4 has emerged from being an orphan, next becoming a physiological star with ever-emerging effects, and finally to being a therapeutic target-an impressive example of evolution and one that continues. Understanding the costimulatory effects and mechanisms of CTLA-4 and the redundancies intrinsic to costimulation is important in understanding T-cell function and dysfunction in disease. A future article in this series will describe inducible T-cell costimulator, which is a normal by-pass to CTLA-4's effects.     

Phagocytes and oxidative stress

Neutrophils and other phagocytes manufacture O(2)(-) (superoxide) by the one-electron reduction of oxygen at the expense of NADPH. Most of the O(2)(-) reacts with itself to form H(2)O(2) (hydrogen peroxide). From these agents a large number of highly reactive microbicidal oxidants are formed, including HOCl (hypochlorous acid), which is produced by the myeloperoxidase-catalyzed oxidation of Cl(-) by H(2)O(2); OH(*) (hydroxyl radical), produced by the reduction of H(2)O(2) by Fe(++) or Cu(+); ONOO(-) (peroxynitrite), formed by the reaction between O(2)(-) and NO(*); and many others. These reactive oxidants are manufactured for the purpose of killing invading microorganisms, but they also inflict damage on nearby tissues, and are thought to be of pathogenic significance in a large number of diseases. Included among these are emphysema, acute respiratory distress syndrome, atherosclerosis, reperfusion injury, malignancy and rheumatoid arthritis.     

ADMA and oxidative stress

Elevated plasma concentrations of the endogenous nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) represent a novel risk factor for the development of endothelial dysfunction and a predictor for all-cause and cardiovascular mortality. However, it is unknown whether elevated ADMA plasma concentrations may be considered simply as a marker for cardiovascular disease or whether increased ADMA levels per se may predispose to the development of vascular disease. There is experimental and clinical evidence linking endothelial dysfunction to increased production of oxygen-derived free radicals such as superoxide anion. Oxidative stress has been shown to increase the activity of arginine methylating and ADMA degrading enzymes leading to increased ADMA concentrations. Interestingly, the endothelial nitric oxide synthase may become uncoupled in the presence of high ADMA levels further contributing to the vascular oxidative stress burden. It remains to be established to what extent ADMA is able to interact with eNOS in vivo. Possible mechanisms underlying increased oxidative stress in the setting of elevated ADMA concentrations and therapeutic implications will be discussed.     

脂联素与氧化应激关系的研究进展

脂联素是具有抗炎、抗动脉粥样硬化作用的脂肪细胞因子，在肥胖、糖尿病、冠心病等患者中血浆脂联素均降低，其机制尚未明确。体外培养及动物实验显示，氧化应激抑制脂联素mRNA表达和脂联素分泌，而脂联素又可调节氧化应激。临床研究显示，肥胖患者血浆脂联素与氧化应激指标呈负相关，在健康人两者无明显相关。脂联素可能抑制核因子-κB等途径，抑制氧化应激，具有抗氧化性。脂联素可能为治疗肥胖及肥胖相关性疾病提供新的药理靶点。     

氟中毒与氧化应激

复习了氟中毒与氧化应激关系的有关文献。从近年来多数研究资料来看,氟中毒的一定阶段确可发生自由基增高和氧化应激反应,但要确定氧化应激与氟化物所致各种损害之间的因果联系,则还有许多工作要做。     

Oxidative stress in surgery in an ageing population: Pathophysiology and therapy

Reactive oxygen species (ROS) play an important role in the regulation of normal cellular function. When ROS are produced in excess they can have detrimental effects, a state known as oxidative stress. Thus ROS play both physiological and pathophysiological roles in the body. In clinical practice oxidative stress and its counterpart, antioxidant capacity can be measured and can guide remedial therapy. Oxidative stress can have a negative impact in all forms of major surgery including cardiac surgery, general surgery, trauma surgery, orthopedic surgery and plastic surgery; this is particularly marked in an ageing population. Many different therapies to reduce oxidative stress in surgery have been tried with variable results. We conclude that in surgical patients the assessment of oxidative stress, improvement of the understanding of its role, both positive and negative, and devising appropriate therapies represent fruitful fields for future research.