The FEBS journal
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In an attempt to identify potential therapeutic targets for the correction of muscle wasting, the gene expression of several pivotal proteins involved in protein metabolism was investigated in experimental atrophy induced by transient or definitive denervation, as well as in four animal models of muscular dystrophies (deficient for calpain 3, dysferlin, alpha-sarcoglycan and dystrophin, respectively). The results showed that: (a) the components of the ubiquitin-proteasome pathway are upregulated during the very early phases of atrophy but do not greatly increase in the muscular dystrophy models; (b) forkhead box protein O1 mRNA expression is augmented in the muscles of a limb girdle muscular dystrophy 2A murine model; and (c) the expression of cardiac ankyrin repeat protein (CARP), a regulator of transcription factors, appears to be persistently upregulated in every condition, suggesting that CARP could be a hub protein participating in common pathological molecular pathway(s). ⋯ However, a switch towards fast-twitch fibres is observed, suggesting that CARP plays a role in skeletal muscle plasticity. The observation that p21(WAF1/CIP1) is upregulated, put in perspective with the effects of CARP on the fibre type, fits well with the idea that the mechanisms at stake might be required to oppose muscle remodelling in skeletal muscle.
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The issue of how a newly synthesized polypeptide chain folds to form a protein with a unique three-dimensional structure, otherwise known as the 'protein-folding problem', remains a fundamental question in the life sciences. Over the last few decades, much information has been gathered about the mechanisms by which proteins fold. However, despite the vast topological diversity observed in biological structures, it was thought improbable, if not impossible, that a polypeptide chain could 'knot' itself to form a functional protein. ⋯ Their formation does not fit any current folding models or mechanisms, and therefore represents an important piece of the protein-folding puzzle. This article reviews the progress made towards discovering how nature codes for, and contends with, knots during protein folding, and examines the insights gained from both experimental and computational studies. Mechanisms to account for the formation of knotted structures that were previously thought unfeasible, and their implications for protein folding, are also discussed.
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Because clinical trials of pharmacological neuroprotective strategies in stroke have been disappointing, attention has turned to the brain's own endogenous strategies for neuroprotection. Two endogenous mechanisms have been characterized so far, namely ischemic preconditioning and ischemic postconditioning. The neuroprotective concept of preconditioning is based on the observation that a brief, noninjurious episode of ischemia is able to protect the brain from a subsequent longer ischemic insult. ⋯ Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and postconditioning. Unfortunately, so far, none of them has clearly identified the mechanism involved in preconditioning and postconditioning. The present article will review the main mechanisms reported to date to explain the neuroprotective effect of both ischemic preconditioning and postconditioning.
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Effective medical treatment for Parkinson's disease has been available for almost 40 years. After several years of treatment with L-dihydroxyphenylalanine (L-dopa, levodopa), however, fluctuations often occur. ⋯ New therapeutic methods, deep brain stimulation and duodenal infusion of L-dopa, have proven to be very effective in stabilizing the fluctuations. A clinical update of Parkinson's disease is presented together with a short review of these two methods.
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Rotenone, a widely used insecticide, has been shown to inhibit mammalian cell proliferation and to depolymerize cellular microtubules. In the present study, the effects of rotenone on the assembly of microtubules in relation to its ability to inhibit cell proliferation and mitosis were analyzed. We found that rotenone inhibited the proliferation of HeLa and MCF-7 cells with half maximal inhibitory concentrations of 0.2 +/- 0.1 microm and 0.4 +/- 0.1 microm, respectively. ⋯ It also inhibited the binding of colchicine to tubulin, perturbed the secondary structure of tubulin, and reduced the intrinsic tryptophan fluorescence of tubulin and the extrinsic fluorescence of tubulin-1-anilinonaphthalene-8-sulfonic acid complex, suggesting that it binds to tubulin. A dissociation constant of 3 +/- 0.6 microm was estimated for tubulin-rotenone complex. The data presented suggest that rotenone blocks mitosis and inhibits cell proliferation by perturbing microtubule assembly dynamics.