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

Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS production and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging, antioxidant therapy could positively affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.

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Oxidative stress, aging, and diseases.

Free radicals and oxidants play a dual role as both toxic and beneficial compounds, since they can be either harmful or helpful to the body. They are produced either from normal cell metabolisms in situ or from external sources (pollution, cigarette smoke, radiation, medication). When an overload of free radicals cannot gradually be destroyed, their accumulation in the body generates a phenomenon called oxidative stress. This process plays a major part in the development of chronic and degenerative illness such as cancer, autoimmune disorders, aging, cataract, rheumatoid arthritis, cardiovascular and neurodegenerative diseases. The human body has several mechanisms to counteract oxidative stress by producing antioxidants, which are either naturally produced in situ, or externally supplied through foods and/or supplements. This mini-review deals with the taxonomy, the mechanisms of formation and catabolism of the free radicals, it examines their beneficial and deleterious effects on cellular activities, it highlights the potential role of the antioxidants in preventing and repairing damages caused by oxidative stress, and it discusses the antioxidant supplementation in health maintenance.

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Free Radicals, Antioxidants in Disease and Health

Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. ROS can play, and in fact they do it, several physiological roles (i.e., cell signaling), and they are normally generated as by-products of oxygen metabolism; despite this, environmental stressors (i.e., UV, ionizing radiations, pollutants, and heavy metals) and xenobiotics (i.e., antiblastic drugs) contribute to greatly increase ROS production, therefore causing the imbalance that leads to cell and tissue damage (oxidative stress). Several antioxidants have been exploited in recent years for their actual or supposed beneficial effect against oxidative stress, such as vitamin E, flavonoids, and polyphenols. While we tend to describe oxidative stress just as harmful for human body, it is true as well that it is exploited as a therapeutic approach to treat clinical conditions such as cancer, with a certain degree of clinical success. In this review, we will describe the most recent findings in the oxidative stress field, highlighting both its bad and good sides for human health.

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Oxidative Stress: Harms and Benefits for Human Health

Free radicals and other oxidants have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. The free radicals, both the reactive oxygen species (ROS) and reactive nitrogen species (RNS), are derived from both endogenous sources (mitochondria, peroxisomes, endoplasmic reticulum, phagocytic cells etc.) and exogenous sources (pollution, alcohol, tobacco smoke, heavy metals, transition metals, industrial solvents, pesticides, certain drugs like halothane, paracetamol, and radiation). Free radicals can adversely affect various important classes of biological molecules such as nucleic acids, lipids, and proteins, thereby altering the normal redox status leading to increased oxidative stress. The free radicals induced oxidative stress has been reported to be involved in several diseased conditions such as diabetes mellitus, neurodegenerative disorders (Parkinson’s disease-PD, Alzheimer’s disease-AD and Multiple sclerosis-MS), cardiovascular diseases (atherosclerosis and hypertension), respiratory diseases (asthma), cataract development, rheumatoid arthritis and in various cancers (colorectal, prostate, breast, lung, bladder cancers). This review deals with chemistry, formation and sources, and molecular targets of free radicals and it provides a brief overview on the pathogenesis of various diseased conditions caused by ROS/RNS.

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Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

Oxyl radicals, redox-sensitive signalling cascades and antioxidants

Synthesis and evaluation of new difluoromethyl azoles as antileishmanial agents

Nitric oxide synthase (NOS) characterization in Leishmania amazonensis axenic amastigotes.

The present report explores a comparative analysis of nitric oxide (NO(*)) production by three different species of Leishmania (L. amazonensis, L. braziliensis and L. chagasi). Among these species, L. braziliensis produced the highest amount of NO(*), measured in the supernatants of promastigotes cultures as nitrite, a stable by-product derived from NO(*). We have previously described the expression of a constitutive nitric oxide synthase (cNOS) in L. amazonensis promastigotes and axenic amastigotes. Comparing those results with the present work, using immunofluorescence assay, it was shown that both L. braziliensis and L. chagasi also express a cNOS. Immunostaining experiments showed that promastigotes from early passages of these species in culture had a strong immunoreactivity against anti-cNOS and anti-endothelial cell NOS, in comparison with the same parasite cultured for long time, suggesting a correlation between the NO(*) production and the presence of metacyclic forms prominent in those newly isolated parasites. These data corroborate findings of a higher NO(*) production by those parasites, following the growth curve. The relationship between the two NO(*)-generating systems in the parasite and in their host cell warrants further investigation. The presence of cNOS raises the possibility of a similar type of cross-talk or down-regulation between the NO(*) signaling systems in host cells and the lower eukaryotic-like Leishmania sp.

Comparative analysis of the nitric oxide production by Leishmania sp.

Leishmanioses sao doencas causadas por protozoarios do genero Leishmania sp., que se apresentam na forma promastigota ou amastigota; os promastigotas infectam o inseto vetor e os amastigotas sao as formas infectivas antes presentes em macrofagos humanos. O tratamento utilizado pela clinica tem se mostrado ineficaz; os farmacos utilizados se apresentam na forma injetavel, o que dificulta o tratamento, ja que o paciente, para ser tratado, deve ser internado para as aplicacoes - que sao dolorosas - e assim muitos pacientes desistem do tratamento. Outra razao para a internacao e a monitoracao dos efeitos colaterais causados pelos farmacos. Por estas razoes a quimioterapia para leishmaniose tem sido objeto de estudo de muitos laboratorios de pesquisa, os quais tem testado outras substâncias quimicas e extratos de plantas com a finalidade de se encontrar novos agentes leishmanicidas com menores efeitos colaterais e otima biodisponibilidade. Alem disso, pesquisam-se, tambem, outras formas farmaceuticas que viabilizem a aplicacao desses farmacos, o que tornaria desnecessaria a internacao do paciente para se efetuar o tratamento. Este artigo visa discutir os recentes avancos da quimioterapia utilizada para as leishmanioses e, tambem, apresentar os aspectos farmacologicos e bioquimicos da participacao de moleculas intracelulares do parasita como alvos de farmacos.

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Marcelo Genestra

Papers

Oxyl radicals, redox-sensitive signalling cascades and antioxidants

Synthesis and evaluation of new difluoromethyl azoles as antileishmanial agents

Nitric oxide synthase (NOS) characterization in Leishmania amazonensis axenic amastigotes.

Comparative analysis of the nitric oxide production by Leishmania sp.

Recentes avanços da quimioterapia das leishmanioses: moléculas intracelulares como alvo de fármacos