1,720,958 research outputs found
Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice
No full textInhibitors of angiotensin converting enzymes (ACE) are clinically used to control cardiomyopathy in patients of Duchenne muscular dystrophy. Various evidences suggest potential usefulness of long-term treatment with ACE inhibitors to reduce advanced fibrosis of dystrophic muscle in the mdx mouse model. However, angiotensin II is known to exert pro-inflammatory and pro-oxidative actions that might contribute to early events of dystrophic muscle degeneration. The present study has been aimed at evaluating the effects of an early treatment with enalapril on the pathology signs of exercised mdx mouse model. The effects of 1 and 5 mg/kg enalapril i.p. for 4-8 weeks have been compared with those of 1 mg/kg α-methylprednisolone (PDN), as positive control. Enalapril caused a dose-dependent increase in fore limb strength, the highest dose leading to a recovery score similar to that observed with PDN. A dose-dependent reduction of superoxide anion production was observed by dihydroethidium staining in tibialis anterior muscle of enalapril-treated mice, approaching the effect observed with PND. In parallel, a significant reduction of the activated form of the pro-inflammatory Nuclear Factor-kB has been observed in gastrocnemious muscle. Histologically, 5 mg/kg enalapril reduced the area of muscle necrosis in both gastrocnemious muscle and diaphragm, without significant effect on non-muscle area. In parallel no significant changes have been observed in both muscle TGF-β1 and myonuclei positive to phosphorylated Smad2/3. Myofiber functional indices were also monitored by microelectrodes recordings. A dose-dependent recovery of macroscopic chloride conductance has been observed upon enalapril treatment in EDL muscle, with minor effects being exerted in diaphragm. However a modest effect, if any, was found on mechanical threshold, a functional index of calcium homeostasis. No recovery was observed in creatine kinase and lactate dehydrogenase. Finally the results suggest the ability of enalapril to blunt angiotensin-II dependent activation of pro-inflammatory and pro-oxidant pathways which may be earlier events with respect to the pro-fibrotic ones, and may in part account for both functional impairment and muscle necrosis. The PDN-like profile may corroborate the combined use of the two classes of drugs in DMD patients so to potentiate the beneficial effects at skeletal muscle level, while reducing both spontaneous and PDN-aggravated cardiomyopathy
Evaluation of potential synergistic action of a combined treatment with alpha-methyl-prednisolone and taurine on the mdx mouse model of Duchenne muscular dystrophy.
No full textAims: Glucocorticoids are the sole drugs clinically used
in Duchenne muscular dystrophy, in spite of the relevant
side effects. Combination of glucocorticoids with synergistic
drugs may be one strategy to lower doses and
control side effects, meanwhile providing wider control
of the complex pathology. This study is a preclinical
evaluation of the effect of a combined treatment of amethyl-
prednisolone (PDN) with taurine, a safe aminoacid
with positive effects on some pathology-related
events. Methods: PDN (1 mg/kg/day i.p.) and taurine
(1 g/kg/day orally) were administered either alone or in
combination, for 4–8 weeks to male dystrophic mdx mice
chronically exercised on a treadmill. Effects were assessed
in vivo and ex vivo with a variety of methodological
approaches. Results: In vivo, each treatment significantly
increased fore limb strength, a marked synergistic effect
being observed with the combination PDN + taurine. Exvivo, PDN + taurine completely restored the mechanical
threshold, an electrophysiological index of calcium
homeostasis, of extensor digitorum longus myofibres and
the benefit was greater than for PDN alone. In parallel,
the overactivity of voltage-independent cation channels
in dystrophic myofibres was reduced. No effects were
observed on plasma levels of creatine kinase, while
lactate dehydrogenase was decreased by taurine and, to a
minor extent, by PDN + taurine. A similar histology
profile was observed in PDN and PDN + taurine-treated
muscles. PDN + taurine significantly increased taurine
level in fast-twitch muscle and brain, by high-pressure
liquid chromatography analysis. Conclusions: The combination
PDN + taurine has additive actions on in vivo
and ex vivo functional end points, with less evident
advantages on histopathology and biochemical markers
of the disease
Potential role of sirtuin-1 as druggable target in muscular dystrophy: effect of a chronic resveratrol treatment on in vivo and ex vivo pathological signs of dystrophic mdx mouse
No full textParallel effects of α-methyl-prednisolone on skeletal muscle and brain of mdx mice: Identification of a novel mechanism of action.
No full textGlucocorticoids are clinically used in Duchenne muscular dystrophy although their mechanism of action is largely unclear. Part of their effect in dystrophic muscle can be mediated by the enhancement of utrophin expression; however the impact of this increase on dystrophin–glycoprotein complex (DGC) is unknown. In the present work we assessed the effect of a chronic treatment with α-methyl-prednisolone (PDN) (4–6 weeks at 1 mg/kg day) in the exercised mdx mouse model, on the expression of utrophin and key proteins of the DGC in skeletal muscle. We found a significant increase in expression of utrophin, α and β dystroglycan and DGC-bound aquaporin (AQP)-4 at both mRNA and protein level in PDN-treated muscles. Interestingly, this was paralleled by a normalization of phosphorylation state of β-dystroglycan and an increase in laminin. Immunohistochemistry supported the correct sarcolemmal localization of the proteins. On pathology-related signs, PDN increased mdx mouse force in vivo, while ex vivo it ameliorated calcium homeostasis and reduced signs of myofiber degeneration; however plasma creatine kinase and susceptibility to eccentric contraction were not ameliorated. In parallel we also assessed the impact of PDN treatment on blood–brain barrier (BBB), based on its serious impairment in mdx mice and on the clinical use of glucocorticoids in disorders characterized by leaky BBB. Interestingly, we found a restoration of key BBB markers at level of endothelium (ZO-1 and occludin), pericytes (desmin) and glial cells (glial fibrillary acidic protein, GFAP) in PDN-treated mdx mice. In parallel, an increase of mRNA and protein content of DGC (α–β dystroglycan complex Dp 71, AQP4), and a rescue of the phosphorylation state of AQP4 and β dystroglycan were found. Then PDN exerts a positive action on DGC in both muscle and brain, disclosing a novel mechanism of action whose impact on therapeutic effect deserves to be better investigated (Supported by Duchenne Parent Project NL)
Growth hormone secretagogues exert differential effects on skeletal muscle calcium homeostasis in male rats depending on the peptidyl/non-peptidyl structure
Full text linkTheorexigenicandanaboliceffectsinducedbyghrelinandthesyntheticGHsecretagogues(GHSs)
are thought to positively contribute to therapeutic approaches and the adjunct treatment of a
number of diseases associated with muscle wasting such as cachexia and sarcopenia. However,
manyquestionsaboutthepotentialutilityandsafetyofGHSsinboththerapyandskeletalmuscle
functionremainunanswered.Byusingfura-2cytofluorimetrictechnique,wedeterminedtheacute
effectsofghrelin,aswellasofpeptidylandnonpeptidylsyntheticGHSsoncalciumhomeostasis,
a critical biomarker of muscle function, in isolated tendon-to-tendon male rat skeletal muscle
fibers.ThesyntheticnonpeptidylGHSs,butnotpeptidylghrelinandhexarelin,wereabletosignificantlyincreaserestingcytosoliccalcium[Ca2]i.ThenonpeptidylGHS-induced[Ca2]
iincrease
was independent of GHS-receptor 1a but was antagonized by both thapsigargin/caffeine and
cyclosporineA,indicatingtheinvolvementofthesarcoplasmicreticulumandmitochondria.EvaluationoftheeffectsofapseudopeptidylGHSandanonpeptidylantagonistoftheGHS-receptor
1a together with a drug-modeling study suggest the conclusion that the lipophilic nonpeptidyl
structureofthetestedcompoundsisthekeychemicalfeaturecrucialfortheGHS-inducedcalcium
alterationsintheskeletalmuscle.Thus,syntheticGHSscanhavedifferenteffectsonskeletalmuscle
fibersdependingontheirmolecularstructures.Thecalciumhomeostasisdysregulationspecifically
induced by the nonpeptidyl GHSs used in this study could potentially counteract the beneficial
effects associated with these drugs in the treatment of muscle wasting of cachexia- or other
age-related disorders
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
- …
