Septic shock is a serious problem in critically ill and surgical patients throughout the world. It is a systemic inflammatory response caused by excessive secretion of proinflammatory mediators, such ...as tumor necrosis factor-α, mainly induced by endotoxin, a major component of the Gram-negative bacterial outer membrane. Experimental evidence suggests that reactive oxygen species (ROS) may be important mediators of cellular injury during endotoxemia, either as a result of macromolecular damage or by interfering with extracellular and intracellular regulatory processes. In addition, nitric oxide is thought to play a key role in the pathogenesis of sepsis. This review begins with a brief overview of the toxic effects of endotoxin at organism level, paying particular attention to cardiovascular damage. It continues by analysing the mechanism by which endotoxin is recognized by specific cells of the immune system, which then respond to bacterial infection and the pathway leading to nuclear factor-κB activation and proinflammatory gene transcription. With regard to this process, the review focuses on the involvement of reactive oxygen and nitrogen species. Lastly, the protective role of antioxidants against endotoxin toxicity and their potential clinical use is discussed.
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•1.5µm porous spheres of BaFe12O19 were synthetized by the sol-gel method.•Surfactant Tween20 (C58H114O26) enabled the creation of the mesoporous structure.•Polystyrene spheres (PS) ...were used as the template for the formation of macropores.•Spheres resembled a nest or ball-of-yarn type of elongated BaFe12O19 crystals.•Magnetic properties are evaluated as function of the calcination temperature.
Porous spherical aggregates of barium hexaferrite (BaFe12O19) with 1.5µm in diameter were synthetized by the surfactant-assisted sol-gel method. The surfactant Tween20 (C58H114O26), which enables mesoporous structures, as well as polystyrene spheres (PS), as the template agent for the formation of macropores, were used. Two synthetic routes (hereafter named A and B), whose difference was the absence or presence of PS, were followed for synthesis. X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) in high resolution mode (HRTEM) were used for characterization. Size and morphology of the spheres were similar in both cases and they resemble a nest or ball-of-yarn type structure. Pore size and BaFe12O19 crystal size produced by the two routes are different. The magnetic properties of the spheres were evaluated using a vibrating sample magnetometer (VSM) as function of the calcination temperature. The spheres present ferromagnetic behavior in both routes.
AbstractThe effectiveness and safety of macitentan, a dual endothelin-receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), were shown in an extensive ...clinical trial oriented towards morbidity and mortality events. Our aim was to describe a single centre's experience of the utilization of macitentan in patients with PAH in clinical practice settings. Thirteen patients with different aetiologies and previous PAH treatments were studied. After 12 months of macitentan treatment, 11 patients improved their functional class (FC), all patients improved their 6-minute walk distance (6MWD) test, and 10 patients lowered their NT-proBNP plasma levels. Additionally, cardiac imaging parameters were also improved. No cases resulted in hospitalization, septostomy, transplant or death.
The relationship of oxidative stress with maximum life span (MLSP) in different vertebrate species is reviewed. In all animal groups the endogenous levels of enzymatic and non-enzymatic antioxidants ...in tissues negatively correlate with MLSP and the most longevous animals studied in each group, pigeon or man, show the minimum levels of antioxidants. A possible evolutionary reason for this is that longevous animals produce oxygen radicals at a low rate. This has been analysed at the place where more than 90% of oxygen is consumed in the cell, the mitochondria. All available work agrees that, across species, the longer the life span, the lower the rate of mitochondrial oxygen radical production. This is true even in animal groups that do not conform to the rate of living theory of aging, such as birds. Birds have low rates of mitochondrial oxygen radical production, frequently due to a low free radical leak in their respiratory chain. Possibly the low rate of mitochondrial oxygen radical production of longevous species can decrease oxidative damage at targets important for aging (like mitochondrial DNA) that are situated near the places of free radical generation. A low rate of free radical production can contribute to a low aging rate both in animals that conform to the rate of living (metabolic) theory of aging and in animals with exceptional longevities, like birds and primates. Available research indicates there are at least two main characteristics of longevous species: a high rate of DNA repair together with a low rate of free radical production near DNA. Simultaneous consideration of these two characteristics can explain part of the quantitative differences in longevity between animal species.
Mitochondrial proton leak is the largest single contributor to the standard metabolic rate (SMR) of a rat, accounting for about 20% of SMR. Yet the mechanisms by which proton leak occurs are ...incompletely understood. The available evidence suggests that both phospholipids and proteins in the mitochondrial inner membrane are important determinants of proton conductance. The uncoupling protein 1 homologues (e.g. UCP2, UCP3) may play a role in mediating proton leak, but it is unlikely they account for all of the observed proton conductance. Experimental data regarding the functions of these proteins include important ambiguities and contradictions which must be addressed before their function can be confirmed. The physiological role of the proton leak, and of the uncoupling protein 1 homologues, remains similarly unclear.
Birds are unique since they can combine a high rate of oxygen consumption at rest with a high maximum life span (MLSP). The reasons for this capacity are unknown. A similar situation is present in ...primates including humans which show MLSPs higher than predicted from their rates of O2 consumption. In this work rates of oxygen radical production and O2 consumption by mitochondria were compared between adult male rats (MLSP = 4 years) and adult pigeons (MLSP = 35 years), animals of similar body size. Both the O2 consumption of the whole animal at rest and the O2 consumption of brain, lung and liver mitochondria were higher in the pigeon than in the rat. Nevertheless, mitochondrial free radical production was 2-4 times lower in pigeon than in rat tissues. This is possible because pigeon mitochondria show a rate of free radical production per unit O2 consumed one order of magnitude lower than rat mitochondria: bird mitochondria show a lower free radical leak at the respiratory chain. This result, described here for the first time, can possibly explain the capacity of birds to simultaneously increase maximum longevity and basal metabolic rate. It also suggests that the main factor relating oxidative stress to aging and longevity is not the rate of oxygen consumption but the rate of oxygen radical production. Previous inconsistencies of the rate of living theory of aging can be explained by a free radical theory of aging which focuses on the rate of oxygen radical production and on local damage to targets relevant for aging situated near the places where free radicals are continuously generated.
Mitochondrial respiratory chain (MRC) complexes I, III, and IV associate into a variety of supramolecular structures known as supercomplexes and respirasomes. While COX7A2L was originally described ...as a supercomplex-specific factor responsible for the dynamic association of complex IV into these structures to adapt MRC function to metabolic variations, this role has been disputed. Here, we further examine the functional significance of COX7A2L in the structural organization of the mammalian respiratory chain. As in the mouse, human COX7A2L binds primarily to free mitochondrial complex III and, to a minor extent, to complex IV to specifically promote the stabilization of the III2+IV supercomplex without affecting respirasome formation. Furthermore, COX7A2L does not affect the biogenesis, stabilization, and function of the individual oxidative phosphorylation complexes. These data show that independent regulatory mechanisms for the biogenesis and turnover of different MRC supercomplex structures co-exist.
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•COX7A2L preferentially interacts with respiratory chain complex III•COX7A2L is essential to stabilize the III2+IV supercomplex•COX7A2L is not necessary for biogenesis or maintenance of the respirasome•Biogenesis of the III2+IV supercomplex is not necessary for respirasome formation
Previous studies highlight different roles for COX7A2L in the structural organization of the mitochondrial respiratory chain. Pérez-Pérez et al. find that mammalian COX7A2L preferentially associates with complex III to stabilize supercomplex III2+IV in a respirasome-independent manner, indicating coexistence of independent regulatory mechanisms for the biogenesis and turnover of these structures.
Birds have a much higher maximum longevity (MLSP) than mammals of similar metabolic rate. Recent data showed that pigeon mitochondria produce oxygen radicals at a rate much slower than rat ...mitochondria, in spite of showing similar levels of oxygen consumption (
Free Rad. Res., 21 (1994) 317–328). Since oxidative damage from and to mitochondria seems important in relation to aging and longevity, and mitochondrial membranes are situated at the place where oxygen radicals are generated, we studied protein and lipid peroxidation and fatty acid composition of the three main membrane phospholipids of liver mitochondria from rats (MLSP = 4 years) and pigeons (MLSP = 35 years). It was found that pigeon mitochondria show lower levels of fatty acid unsaturation than rat mitochondria in the three lipid fractions, mainly due to a substitution of highly unsaturated fatty acids (20:4 and 22:6) by linoleic acid (18:2), and that these mitochondria are more resistant to lipid peroxidation. Previous research has also obtained exactly the same major difference in fatty acid composition in human mitochondria when compared to those of rat. Thus, present information suggests that the liver mitochondrial membranes of especially long-lived species show both a low level of free radical production and a low degree of fatty acid unsaturation as important constitutive protective traits to slow down aging.
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