The role of frogs in the epidemiology of Weil's disease

Summary 1. A high percentage of frog sera (ofRana esculenta andRana fusca) reacts positively with respect to many pathogenic and apathogenic leptospira-strains; this reaction is highest (100%) with respect to the incomplete biotype ofL. icterohaemorrhagiae.2. Under natural conditions frogs do not excrete leptospirae with the urine and neither is this the case, when a single leptospira has somehow succeeded in penetrating into them. This penetration does not easily take place.3. By the inoculation of many virulent leptospirae it is possible to break the congenital immunity. Up till 3 days after the inoculation leptospirae can be detected in the blood, up till 7 days in the liver and kidneys. The frogs did not appear to fall ill.4. Frogs do not play a part in the epidemiology of Weil's disease.5. In normal frog sera precipitation of the agglutinins by means of ammonium sulphate and acetone alcohol could not be observed so definitely as in immune sera. Normal frog serum is thermostabile at 56–57°C., immune serum thermolabile at the same temperature. These differences are explained, in accordance withBordet, by the lesser strength of the antibodies in normal sera.     

The role of alpha-tocopherol in plant stress tolerance

Environmental stresses trigger a wide variety of plant responses, ranging from altered gene expression to changes in cellular metabolism and growth. A plethora of plant reactions exist to circumvent the potentially harmful effects caused by light, drought, salinity, extreme temperatures, pathogen infections and other stresses. Alpha-tocopherol is the major vitamin E compound found in leaf chloroplasts, where it is located in the chloroplast envelope, thylakoid membranes and plastoglobuli. This antioxidant deactivates photosynthesis-derived reactive oxygen species (mainly 1O2 and OH), and prevents the propagation of lipid peroxidation by scavenging lipid peroxyl radicals in thylakoid membranes. Alpha-tocopherol levels change differentially in response to environmental constraints, depending on the magnitude of the stress and species-sensitivity to stress. Changes in alpha-tocopherol levels result from altered expression of pathway-related genes, degradation and recycling, and it is generally assumed that increases of alpha-tocopherol contribute to plant stress tolerance, while decreased levels favor oxidative damage. Recent studies indicate that compensatory mechanisms exist to afford adequate protection to the photosynthetic apparatus in the absence of alpha-tocopherol, and provide further evidence that it is the whole set of antioxidant defenses (ascorbate, glutathione, carotenoids, tocopherols and other isoprenoids, flavonoids and enzymatic antioxidants) rather than a single antioxidant, which helps plants to withstand environmental stress.     

Parkinson disease: from pathology to molecular disease mechanisms

Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death.     

ANG II-induced cardiac molecular and cellular events: role of aldosterone

Chronic elevation of circulating ANG II is associated with cardiac remodeling in patients with hypertension and heart failure. The underlying mechanisms, however, are not completely defined. Herein, we studied ANG II-induced molecular and cellular events in the rat heart as well as their links to the redox state. We also addressed the potential contribution of aldosterone (ALDO) on ANG II-induced cardiac remodeling. In ANG II-treated rats, and compared with controls, we found: 1) the expression of proinflammatory/profibrogenic mediators was significantly increased in the perivascular space and at the sites of microscopic injury in both ventricles; 2) macrophages and myofibroblasts were primary repairing cells at these sites, together with increased fibrillar collagen volume; 3) apoptotic macrophages and myofibroblasts were evident at the same sites; 4) NADPH oxidase (gp91phox) was significantly enhanced at these regions and primarily expressed by macrophages, whereas superoxide dismutase and catalase levels remained unchanged; 5) plasma 8-isoprostane levels were significantly increased; and 6) blood pressure was significantly elevated. Losartan treatment completely prevented cardiac oxidative stress as well as molecular/cellular responses and normalized blood pressure. Spironolactone treatment partially suppressed the cardiac inflammatory/fibrogenic responses and redox state. Thus chronic elevation of circulating ANG II is accompanied by a proinflammatory/profibrogenic phenotype involving vascular and myocardial remodeling in both ventricles. Enhanced reactive oxygen species production at these sites and increased plasma 8-isoprostane indicate the involvement of oxidative stress in ANG II-induced cardiac injury. ALDO contributes, in part, to ANG II-induced cardiac molecular and cellular responses.     

Seipin: from human disease to molecular mechanism

The most-severe form of congenital generalized lipodystrophy (CGL) is caused by mutations in BSCL2/seipin. Seipin is a homo-oligomeric integral membrane protein in the endoplasmic reticulum that concentrates at junctions with cytoplasmic lipid droplets (LDs). While null mutations in seipin are responsible for lipodystrophy, dominant mutations cause peripheral neuropathy and other nervous system pathologies. We first review the clinical aspects of CGL and the discovery of the responsible genetic loci. The structure of seipin, its normal isoforms, and mutations found in patients are then presented. While the function of seipin is not clear, seipin gene manipulation in yeast, flies, mice, and human cells has recently yielded a trove of information that suggests roles in lipid metabolism and LD assembly and maintenance. A model is presented that attempts to bridge these new data to understand the role of this fascinating protein.     

Oxidized phospholipids: from molecular properties to disease

Oxidized lipids are generated from (poly)unsaturated diacyl- and alk(en)ylacyl glycerophospholipids under conditions of oxidative stress. The great variety of reaction products is defined by the degree of modification, hydrophobicity, chemical reactivity, physical properties and biological activity. The biological activities of these compounds may depend on both, the recognition of the particular molecular structures by specific receptors and on the unspecific physical and chemical effects on their target systems (membranes, proteins). In this review, we aim at highlighting the molecular features that are essential for the understanding of the biological actions of pure oxidized phospholipids. Firstly, their chemical structures are described as a basis for an understanding of their physical and (bio)chemical properties in membrane- and protein-bound form. Secondly, the biological activities of oxidized phospholipids are discussed in terms of their unspecific effects on the membrane level as well as their potential interactions with specific targets (receptors) affecting a large set of (signaling) molecules. Finally, the role of oxidized phospholipids as important mediators in pathophysiology is discussed with emphasis on atherosclerosis.     

The molecular role of mast cells in atherosclerotic cardiovascular disease

Human atherosclerosis has many characteristics of an inflammatory disorder. Recent data suggest that mast cells might be important in the pathogenesis of atherosclerotic disease. By secretion of pro-inflammatory cytokines, mast cells can assist in the recruitment of monocytes and lymphocytes into vascular tissue, thereby propagating the inflammatory response. Mast cell enzymes might activate pro-metalloproteinases, thereby destabilizing atheromatous plaques. Mast cells can facilitate foam cell formation by promoting cholesterol accumulation. However, mast cell tryptase could slow thrombus formation at sites of plaque rupture by interfering with coagulation. Therefore, mast cells can modulate coronary artery disease by both facilitatory and inhibitory pathways.     

The role of sex steroids on cellular events involved in vascular disease

In this work we checked the hypothesis whether estrone, progesterone, and testosterone are able to modulate the interactions between platelets, monocytes, and endothelial cells either under basal or inflammatory conditions. Using adhesion assays we demonstrated that pretreatment of endothelial cells with estrone, progesterone, or testosterone prevented monocytes and platelets adhesion induced by the proinflammatory agent bacterial lipopolysaccharide. The hormones reduced the expression of mRNA of ICAM-1, VCAM-1, and P-selectin, endothelial surface proteins that mediate monocytes and platelets adhesion respectively. Integrins are the main leukocyte proteins that allow firm adhesion. Using flow cytometry we showed that estrone treatment of monocytes reduced CD11b and CD11c expression, either under basal or injury (lipopolysaccharide) conditions. The three steroids inhibited platelet aggregation in a nitric oxide dependent manner. Platelet function was not affected by the steroid treatment. The molecular mechanisms of action exerted by the steroids included the participation of the intracellular signaling pathways PKC, MAPK, and PI3K, which selectively and differentially mediate the stimulation of nitric oxide release. We evidence that estrone, progesterone, and testosterone modulate monocyte and platelet adhesion to endothelial cells, events that play a major role in the initiation and progression of vascular lesions. The steroid action was evidenced under basal or inflammatory conditions. The mechanisms of action exerted by the steroids included stimulation of nitric oxide production and the participation of PKC, MAPK, and PI3K systems.     

Hypothetical role of RNA damage avoidance in preventing human disease

Most of nucleic acids damaging agents are not only restricted to DNA but equally affect DNA and RNA molecules. Considering that RNA damage could be very toxic for the cell, a property used by some cancer treatments, it would not be unexpected to find out that several proteins may be involved in RNA damage avoidance mechanisms helping cells to counteract such cytotoxic effects. Up to now, only one specific repair mechanism allowing cells to deal with toxic effects of methylated RNA have been described. However, there are in the literature several data suggesting that this study may only be the tip of the iceberg and that cells might be able to counteract the deleterious effects of a large variety of RNA damage. In this review, we will discuss the different proteins that may be involved in the mechanism of RNA damage avoidance and their potential role in human diseases.     

Species differences in adrenal lipid peroxidation: role of alpha-tocopherol

Previous reports have noted high levels of lipid peroxidation (LP) in vitro in a variety of adrenocortical preparations. However, we have observed that susceptibility to adrenal LP seems to vary considerably from species to species. The current study was done to confirm these apparent species differences in adrenal LP in vitro and to determine if they were attributable to differences in alpha-tocopherol content. Incubation of mitochondrial or microsomal preparations from guinea pig or rabbit adrenal glands with ferrous ion (Fe2+) caused a time-dependent increase in the formation of thiobarbituric acid reactive substances (TBARS) accompanied by depletion of alpha-tocopherol. By contrast, incubation of adrenal mitochondria or microsomes from rats or monkeys with Fe2+ had little or no detectable effect on TBARS and basal adrenal alpha-tocopherol levels were five to ten-fold greater than those in guinea pigs or rabbits. In addition, there was little change in alpha-tocopherol concentrations during incubation of rat or monkey adrenal tissue. Dietary alpha-tocopherol deficiency in rats reduced adrenal alpha-tocopherol to concentrations approximating those in guinea pigs. Incubation with Fe2+ induced high levels of TBARS in adrenal mitochondria and microsomes from the alpha-tocopherol deficient rats. Conversely, dietary alpha-tocopherol supplementation in rabbits increased adrenal alpha-tocopherol levels and prevented Fe2+ induced TBARS formation in mitochondria and microsomes. The results indicate that there are large species differences in adrenal susceptibility to LP in vitro and that these differences are at least partly attributable to species differences in adrenal alpha-tocopherol concentrations.     

Prevalence and molecular epidemiology of equine piroplasmosis in China: a neglected tick-borne disease

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