130 research outputs found
0012: Cardiac effects of a treatment with prolyl-hydroxylase inhibitors (PHI), used to improve exercise performance, in sedentary and trained rats
Stabilization of the Hypoxia Inducible Factor (HIF) using prolyl-hydroxylase inhibitors (PHI) leads to an EPO synthesis which is suspected to be used as a doping practice. Such a treatment is suspected to improve endurance performance by increasing oxygen transport. However the effects of a PHI treatment on heart morphology and function has never been investigated. Therefore the aim of this study was to evaluate whether potential effects of PHI on cardiac function could contribute to explain its beneficial effect on aerobic performance.We tested the effects of a 1 week treatment with a PHI (DMOG, 150mg.kg–1, I.P.) or a placebo (NaCl) on both sedentary (Sed) and trained rats (Ex; trained during 5 weeks before treatment started; 40min at 25m.min–1 per day; 5days/week). Our first result was that PHI increased running performance (+12%, p<0,05) in both Sed and Ex groups. This increased performance was associated with a major increase in total hemoglobin in PHI-treated animals (+13% p<0,05). However, regarding cardiac function and cardiac remodeling no beneficial effect of PHI was observed. Indeed, in hearts of sedentary as well as exercised rats no significal change in any morphological parameters (LVEDs, LVEDd, AWTd, PWTd and RWT) was found. Moreover, no change in systolic function likely to explain enhanced exercise performance was observed in PHI-treated hearts, when evaluated by intraventricular pressure probe (Millar®). Finally it is interesting to note that in sedentary rat hearts an impairment of diastolic function characterized by an altered E/A and dp/dtmin ratios was found when they were challenged with isoproterenol (0,5mg.kg-1). These last results obtained in sedentary hearts could suggest that a more prolonged treatment with such PHI could have deleterious consequences on heart health and point out the danger of such a doping strategy; however, this point remains to be more precisely investigated
HIV-1 Vpr-Induced Apoptosis Is Cell Cycle Dependent and Requires Bax but Not ANT
The HIV-1 accessory protein viral protein R (Vpr) causes G(2) arrest and apoptosis in infected cells. We previously identified the DNA damage–signaling protein ATR as the cellular factor that mediates Vpr-induced G(2) arrest and apoptosis. Here, we examine the mechanism of induction of apoptosis by Vpr and how it relates to induction of G(2) arrest. We find that entry into G(2) is a requirement for Vpr to induce apoptosis. We investigated the role of the mitochondrial permeability transition pore by knockdown of its essential component, the adenine nucleotide translocator. We found that Vpr-induced apoptosis was unaffected by knockdown of ANT. Instead, apoptosis is triggered through a different mitochondrial pore protein, Bax. In support of the idea that checkpoint activation and apoptosis induction are functionally linked, we show that Bax activation by Vpr was ablated when ATR or GADD45α was knocked down. Certain mutants of Vpr, such as R77Q and I74A, identified in long-term nonprogressors, have been proposed to inefficiently induce apoptosis while activating the G(2) checkpoint in a normal manner. We tested the in vitro phenotypes of these mutants and found that their abilities to induce apoptosis and G(2) arrest are indistinguishable from those of HIV-1(NL4–3) vpr, providing additional support to the idea that G(2) arrest and apoptosis induction are mechanistically linked
Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications
Sodium retention and edema are common features of nephrotic syndrome that are classically attributed to hypovolemia and activation of the renin–angiotensin–aldosterone system. However, numbers of clinical and experimental findings argue against this underfill theory. In this review we analyze data from the literature in both nephrotic patients and experimental models of nephrotic syndrome that converge to demonstrate that sodium retention is not related to the renin–angiotensin–aldosterone status and that fluid leakage from capillary to the interstitium does not result from an imbalance of Starling forces, but from changes of the intrinsic properties of the capillary endothelial filtration barrier. We also discuss how most recent findings on the cellular and molecular mechanisms of sodium retention has allowed the development of an efficient treatment of edema in nephrotic patients
Characterization of the Molecular Determinants of Primary HIV-1 Vpr Proteins: Impact of the Q65R and R77Q Substitutions on Vpr Functions
Although HIV-1 Vpr displays several functions in vitro, limited information exists concerning their relevance during infection. Here, we characterized Vpr variants isolated from a rapid and a long-term non-progressor (LTNP). Interestingly, vpr alleles isolated from longitudinal samples of the LTNP revealed a dominant sequence that subsequently led to diversity similar to that observed in the progressor patient. Most of primary Vpr proteins accumulated at the nuclear envelope and interacted with host-cell partners of Vpr. They displayed cytostatic and proapoptotic activities, although a LTNP allele, harboring the Q65R substitution, failed to bind the DCAF1 subunit of the Cul4a/DDB1 E3 ligase and was inactive. This Q65R substitution correlated with impairment of Vpr docking at the nuclear envelope, raising the possibility of a functional link between this property and the Vpr cytostatic activity. In contradiction with published results, the R77Q substitution, found in LTNP alleles, did not influence Vpr proapoptotic activity
Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense
Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs—activated by nucleic acids and particularly specialized in viral recognition—have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface—activated by compounds other than nucleic acids—have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease
Aspects de la plasticité musculaire squelettique liés à l'exercice physique et aux variations des flux métaboliques
L’exercice en force/résistance couplé à la prise d’acides aminés branchés comme stratégie de prise de masse musculaire
L’exercice en force/résistance couplé à la prise d’acides aminés branchés comme stratégie de prise de masse musculaire. 15. Congrès international de l’ACAPS (Association de Chercheurs en Activités Physiques et Sportives
L’exercice en force/résistance couplé à la prise d’acides aminés branchés comme stratégie de prise de masse musculaire
L’exercice en force/résistance couplé à la prise d’acides aminés branchés comme stratégie de prise de masse musculaire. 15. Congrès international de l’ACAPS (Association de Chercheurs en Activités Physiques et Sportives
Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention
Identification of cost-effective interventions to maintain muscle mass, muscle strength, and physical performance during muscle wasting and aging is an important public health challenge. It requires understanding of the cellular and molecular mechanisms involved. Muscle-deconditioning processes have been deciphered by means of several experimental models, bringing together the opportunities to devise comprehensive analysis of muscle wasting. Studies have increasingly recognized the importance of fatty infiltrations or intermuscular adipose tissue for the age-mediated loss of skeletal-muscle function and emphasized that this new important factor is closely linked to inactivity. The present review aims to address three main points. We first mainly focus on available experimental models involving cell, animal, or human experiments on muscle wasting. We next point out the role of intermuscular adipose tissue in muscle wasting and aging and try to highlight new findings concerning aging and muscle-resident mesenchymal stem cells called fibro/adipogenic progenitors by linking some cellular players implicated in both FAP fate modulation and advancing age. In the last part, we review the main data on the efficiency and molecular and cellular mechanisms by which exercise, replacement hormone therapies, and β-hydroxy-β-methylbutyrate prevent muscle wasting and sarcopenia. Finally, we will discuss a potential therapeutic target of sarcopenia: glucose 6-phosphate dehydrogenase
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