抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

https://zenodo.org/record/1258475/files/article.pdf

Electron transfers in chemistry and biology

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction by oxyhemoglobin. The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks. Nitric oxide is not necessarily short lived and is intrinsically no more reactive than oxygen. The reactivity of nitric oxide per se has been greatly overestimated in vitro because no drain is provided to remove nitric oxide. Nitric oxide persists in solution for several minutes in micromolar concentrations before it reacts with oxygen to form much stronger oxidants like nitrogen dioxide. Nitric oxide is removed within seconds in vivo by diffusion over 100 microns through tissues to enter red blood cells and react with oxyhemoglobin. The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO-). Nitric oxide is the only biological molecule produced in high enough concentrations to out-compete superoxide dismutase for superoxide. Peroxynitrite reacts relatively slowly with most biological molecules, making peroxynitrite a selective oxidant. Peroxynitrite modifies tyrosine in proteins to create nitrotyrosines, leaving a footprint detectable in vivo. Nitration of structural proteins, including neurofilaments and actin, can disrupt filament assembly with major pathological consequences. Antibodies to nitrotyrosine have revealed nitration in human atherosclerosis, myocardial ischemia, septic and distressed lung, inflammatory bowel disease, and amyotrophic lateral sclerosis.

Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.

Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.

Role of free radicals and catalytic metal ions in human disease: an overview.

Otto Warburg pioneered quantitative investigations of cancer cell metabolism, as well as photosynthesis and respiration. Warburg and co-workers showed in the 1920s that, under aerobic conditions, tumour tissues metabolize approximately tenfold more glucose to lactate in a given time than normal tissues, a phenomenon known as the Warburg effect. However, this increase in aerobic glycolysis in cancer cells is often erroneously thought to occur instead of mitochondrial respiration and has been misinterpreted as evidence for damage to respiration instead of damage to the regulation of glycolysis. In fact, many cancers exhibit the Warburg effect while retaining mitochondrial respiration. We re-examine Warburg's observations in relation to the current concepts of cancer metabolism as being intimately linked to alterations of mitochondrial DNA, oncogenes and tumour suppressors, and thus readily exploitable for cancer therapy.

Otto Warburg's contributions to current concepts of cancer metabolism

Peroxynitrite [oxoperoxonitrate(1-), ONOO-] may be formed in vivo from superoxide and nitric oxide. The anion is stable, but the acid (pKa = 6.8) decays to nitrate with a rate of 1.3 s-1 at 25 degrees C. The experimental activation parameters of this process are delta H++ = +18 +/- 1 kcal/mol, delta S++ = +3 +/- 2 cal/(mol.K), and delta G++ = +17 +/- 1 kcal/mol. Peroxynitrite (or its protonated form) oxidizes some compounds such as thiols and thioethers in a biomolecular reaction. The reactions with glutathione and cysteine have activation enthalpies of 10.9 and 9.7 kcal/mol, respectively, which are lower than that of the isomerization reaction. Peroxynitrite reacts with other compounds such as dimethyl sulfoxide and deoxyribose in a unimolecular reaction for which the activation of peroxynitrite is rate-limiting. In theory, activation could involve (1) heterolysis to OH- and NO2+ (delta rxn Gzero' = 13 kcal/mol at pH 7) or (2) homolysis to .OH and .NO2 (delta rxn Gzero = 21 kcal/mol), and these processes also could be involved in the isomerization to nitrate. However, thermodynamic and kinetic considerations indicate that neither process is feasible, although binding to metal ions may reduce the large activation energy associated with heterolysis. An intermediate closely related to the transition state for isomerization of ONOOH to HONO2 may be the strongly oxidizing intermediate responsible for hydroxyl radical-like oxidations mediated by ONOOH. Thus, peroxynitrite reacts with different compounds by at least two distinct mechanisms, and the hydroxyl radical is not involved in either.

Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide.

Nature Reviews Cancer 11, 325–337 (2011) The acknowledgement for the source of Figure 1 on page 327 of this article was incorrect and has now been corrected online.

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Erratum: Otto Warburg's contributions to current concepts of cancer metabolism

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Willem H. Koppenol

Papers

Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.

Otto Warburg's contributions to current concepts of cancer metabolism

Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide.

Erratum: Otto Warburg's contributions to current concepts of cancer metabolism

ALS, SOD and peroxynitrite