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Resumos apresentados no Congresso da FASEB - 2009 (25/04/09)
USA - o Congresso da Faseb reune os pesquisadores das ciências básicas; neste ano foram apresentadas várias pesquisas envolvendo a distrofia muscular; destas, as sete mais importantes são as apresentadas abaixo. As mais importantes são : o uso de sildenafil (viagra) que demonstra resultados positivos na prevenção da doença cardíaca em camundongos com distrofia muscular; a que demostra que o resveratrol, uma substância presente na casca da uva reduz as alterações patológicas em camundongos com distrofia muscular; a que demonstra que uma droga nova (EUK-134) tem efeito antioxidante e reduz a lesão muscular em camundongos com distrofia muscular. A pesquisa mais curiosa demonstra que os camundongos com distrofia muscular inoculados com células tumorais tem uma melhor evolução do tumor.
FASEB Meeting 2009:
1) Resveratrol feeding may be therapeutic for dystrophic skeletal muscle
Joshua T. Selsby1,2, Kevin Morine2, Klara Pendrak2, Z. Tian3, Erica Blanco3, Elisabeth R Barton3, H Lee Sweeney2. 1Animal Science, Iowa State University, Ames, IA, 2Physiology, 3Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA
Increased PGC-1α, either through a transgenic animal or gene transfer, provides therapeutic benefit to dystrophic skeletal muscle likely by increasing slow and oxidative protein expression. Resveratrol has been shown to activate SIRT-1, a known deacetylase capable of acting on and increasing the activity of PGC-1α. The purpose of this investigation was to determine if resveratrol supplementation could rescue dystrophic skeletal muscle. We hypothesized that daily feeding of resveratrol would improve muscle function in a similar fashion as PGC-1α overexpression. To test this hypothesis, 1-mo old mdx mice were either fed a control diet (Con) or a diet containing resveratrol at 100 mg/kg/day (Res) for 8 wks. Following intervention, absolute muscle mass was reduced 18-30% in the Res group compared to Con, however, body mass was also reduced in the Res group by 20% compared to Con. Relative muscle mass was similar between groups, except for the EDL, which was significantly smaller in the Res group. Solei in the Res group were more fatigue resistant than in the Con group, however, resistance to contraction induced injury was similar between groups. These data indicate that partial rescue of dystrophic pathology is possible through resveratrol. Perhaps, alternative sources or doses of resveratrol will provide a greater response.
2) Postnatal PGC-1α
over-expression improves muscle function in a mouse model of Duchenne muscular dystrophyJoshua T. Selsby1,2, Kevin Morine2, Klara Pendrak2, Z. Tian3, Erica Blanco3, Elisabeth R Barton3, H Lee Sweeney2. 1Animal Science, Iowa State University, Ames, IA, 2Physiology, 3Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA
PGC-1α has received a great deal of attention due to its potential to induce oxidative and slow proteins. The purpose of this investigation was to: 1) extend observations made in an initial study demonstrating transgenic over-expression of PGC-1α reduced dystrophic pathology 2) eliminate effects that could have taken place during development. Neonatal mdx mice were injected in the right hind limb with 1x1011 gc of AAV causing overexpression of PGC-1α and sacrificed at 4 (n=6) or 6 wks of age (n=5). Muscle mass was reduced in limbs over-expressing PGC- 1α at 4 and 6 wks, however, tetantic force and specific force in the soleus and EDL were either maintained or improved when compared to control limbs. PGC-1α over-expression caused EDLs to be more resistant to damage at 6 wks and the soleus to be more fatigue resistant at 4 and 6 wks compared to control limbs. PGC- 1α increased expression of slow proteins as utrophin was increased nearly 2-fold and type I myosin heavy chain nearly 3-fold as well as expression of oxidative proteins as cytochrome C and uncoupling protein-1 were increased approximately 2-fold, complex IV subunit IV (cytochrome C oxidase) was increased 1.5- fold and myoglobin was increased 3-fold in limbs over-expressing PGC-1α compared to control limbs. These data demonstrate the potential therapeutic role of the PGC-1α pathway for dystrophic skeletal muscle.
3) EUK-134, a synthetic superoxide dismutase/catalase mimetic, protects against loss of muscle mass/body mass in diaphragm and gastrocnemius in mdx mice
Jong-Hee Kim1, BR Macias2, C Canon2, S Courtney2, John M Lawler2. 1Health and Kinesiology, Texas A&M University, College Station, TX, 2Texas A&M University, College Station, TX Duchenne muscular dystrophy (DMD) is characterized by devastating muscle degeneration associated with oxidative stress, loss of contractile tissue, muscle atrophy, muscle weakness and increased fibrosis in respiratory and locomotor muscles. We tested the hypothesis that protection against oxidative stress via the catalase/superoxide dismutase mimetic EUK-134 will prevent reduction of diaphragm and skeletal muscle mass/body mass during the early inflammatory phase (20-28 days) in mdx mice. C57BL(wild type) and mdx mice were given EUK-134 (30mg/kg body weight/day, i.p., injection) for 8 days, beginning at 20 days of age. Body mass was significantly lower in mdx mice (-37.7%) than wild type but, EUK-134 increased body mass by 15.5% in mdx mice. Absolute muscle mass was lower in diaphragm (-44.3%), gastrocnemius (-53.6%), tibialis anterior (-58.1%) in mdx mice. Muscle mass/body mass was lower in diaphragm (-11.4%), gastrocnemius (-26.3%), tibialis anterior (-34.4%), but not heart, plantaris, soleus, extensor digitorum longus in mdx mice. EUK- 134 had a significant positive effect in protecting against reduced muscle mass/body mass in diaphragm (+38.7%) and gastrocnemius (+27.1%) in mdx mice. These data indicate that EUK-134 provide protection against reduced muscle mass/body mass in diaphragm and gastrocnemius in mdx mice during this early phase of muscular dystrophy.
4) Transgenic Overexpression of AlphaBeta1 Integrin Stimulates p70S6K Phosphorylation in Mice with a Severe Form of Muscular Dystrophy
Marni Della Boppart1, Stephen J Kaufman2. 1Kinesiology and Community Health, 2Cell and Developmental Biology, University of Illinois, Urbana, IL
MCK-driven transgenic expression of the alpha7 integrin can ameliorate pathology in a mouse model of Duchenne muscular dystrophy (mdx/utrn-/-) and thus compensate for the loss of dystrophin in diseased mice. In spite of the beneficial effects of the alpha7 integrin in protecting mice from dystrophy, identification of molecular signaling events responsible for these changes remain to be established. PURPOSE: To determine a role for signaling in the amelioration of muscular dystrophy by alpha7 integrin. METHODS: Five wk wild type, mdx/utrn-/-, and alpha7BX2-mdx/utrn-/- gastrocnemius muscles (n=3-8/group) were dissected and extracted. Activation of PI3K, ILK, AKT, mTOR, p70S6K, GSK-3, and p38 was measured using in vitro activity assays or phosphospecific antibodies and western blotting. RESULTS: Significant increases in ILK activity (2.0-fold), AKT- (P) (2.3-fold), mTOR-(P) (57%), p70S6K-(P) (11.7-fold), and ERK-(P) (66%) were observed in dystrophic mdx/utrn-/- muscle compared to wild type. Significant decreases in GSK-3-(P) (57%) and p38-(P)(2.9-fold) were also observed. Most of these signaling events were similar in dystrophic mice over-expressing the alpha7 integrin. However, a further increase in p70S6K-(P) (18-fold) and decrease in GSK-3-(P)(3.7-fold) were detected in alpha7BX2- mdx/utrn-/- compared to wild type mice and these changes were significant compared to mdx/utrn-/- mice. CONCLUSION: The alpha7beta1 integrin confers a protective effect in dystrophic mice and increased p70S6K activity appears important to this.
5) Sildenafil Ameliorates Cardiomyopathy in mdx Mice
Candace M. Parchen1, Justin M. Percival2, Dao-Fu Dai3, Heidi N Gray1, Stanley C. Froehner2, Joseph A. Beavo1. 1Pharmacology, 2Physiology and Biophysics, 3Pathology, University of Washington, Seattle, WA
Duchenne muscular dystrophy (DMD) is the most prevalent type of muscular dystrophy and is the result of an X-linked mutation in the dystrophin gene. The progression of skeletal muscle damage is rapid in DMD patients and cardiomyopathy soon follows. We have investigated whether or not sildenafil citrate, a phosphodiesterase 5 (PDE5) inhibitor, can be used to ameliorate the age-related cardiac dysfunction in dystrophin-null (mdx) mice, a mouse model of DMD. Using echocardiography, we show that chronic sildenafil treatment improves several functional deficits in the cardiac performance of aged mdx mice. Collagen VI levels are also lower in the hearts of sildenafil-treated mdx mice, suggesting a remodeling of the extracellular matrix. This is the first study to report a cardioprotective effect of PDE5 inhibition in aged mdx mice. Overall, the data suggest that PDE5 inhibitors could be a useful treatment for the cardiomyopathy suffered by DMD patients.
6) Blastocyst Injection of Wild Type Embryonic Stem Cells Induces Global Corrections in Mdx Mice
Joseph M Vitale, Elizabeth Stillwell, Farah Khadim, Genie Elson, Aneela Altaf, Joel Schneider, Ghassan Yehia, Diego Fraidenraich. Cell Biology & Molecular Medicine, University of Medicine & Dentistry of New Jersey, Newark, NJ
Duchenne muscular dystrophy (DMD) is an incurable neuromuscular degenerative disease, caused by a mutation in the dystrophin gene. Mdx mice recapitulate DMD features. Here we show that injection of wild-type (WT) embryonic stem cells (ESCs) into mdx blastocysts produces mice with improved pathology. A small fraction of WT ESCs incorporates into the mdx mouse nonuniformly to upregulate protein levels of dystrophin in the skeletal muscle. The chimeric muscle shows reduced regeneration and restores dystrobrevin, a dystrophin-related protein, in areas with high and with low dystrophin content. WT ESC injection also normalizes the amount of fat, a tissue that does not express dystrophin. ESC injection without dystrophin does not prevent the appearance of phenotypes in the skeletal muscle or in the fat. Thus, dystrophin supplied by the ESCs reverses disease in mdx mice globally.
7) Murine mammary tumor growth is blunted in dystrophin deficient mdx mice
Mary Pat Meaney, Robert W. Grange, Young H. Ju. Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA
Breast cancer (BC) is the second leading cause of cancer death in women in the US. Changes to the dystrophin glycoprotein complex (DGC), a multi-protein structure that likely plays mechanical and signaling roles, have been reported in BC cells. For example, expression of α- and β-dystroglycan appears to be inversely related to tumor stage. However, systemic absence of the DGC, as seen in the mdx mouse model of Duchenne muscular dystrophy, does not appear to induce spontaneous mammary tumor formation, indicating that presence of the DGC may be necessary for breast cancer initiation. We therefore hypothesized that breast tumor growth would be altered in mdx mice compared to wild type (C57BL/6) mice. We injected E0771 murine mammary adenocarcinoma cells into mdx and C57BL/6 mice. After 3 weeks of tumor growth, blood, skeletal muscles and tumors were collected and analyzed. Growth of E0771 tumors and serum content of migration and invasion chemokine markers, RANTES and MCP-1, was dramatically blunted in mdx mice. The dystrophin protein was not detectable in E0771 cells or tumors, suggesting that its expression, like that of other DGC components, may be suppressed or altered in this cancer cell line. The exact mechanism(s) of tumor inhibition in mdx mice is not presently known; however, our results suggest a mechanism for suppressing BC growth and progression may depend on the absence of one or more proteins in the DGC.
USA - a laminina 111 já tinha sido descrita como potencial tratamento da distrofia muscular congênita (artigo que incluí no dia 31/12/08); na pesquisa atual os mesmos autores descrevem o benefício da injeção de laminina 111 em camundongos com distrofia muscular tipo Duchenne. Os animais foram tratados antes de apresentar os sintomas da doença e a droga foi testada também em células de pacientes com Duchenne. O artigo na íntegra não está disponível no momento. O vídeo da reportagem pode ser visto aqui .
Resultados iniciais com a terapia gênica na distrofia muscular tipo cinturas (18/04/09)
USA - estes são os resultados iniciais de um protocolo de estudo em pacientes com distrofia tipo cinturas que receberam uma injeção de um vetor viral contendo o gene alfa sarcoglicano; a injeção foi feita no músculo extensor digital breve e o mesmo músculo do outro membro recebeu uma solução salina. Os resultados mostraram um expressão do gene 4 a 5 vezes superior ao lado controle com recuperação das alterações do músculo, sem efeitos colaterais. os pesquisadores prosseguirão o estudo com outros pacientes. Não há ainda programação para tratamento por via sistêmica para correção do defeito genético em todos os músculos. O resumo em inglês pode ser lido abaixo:
LGMD 2D gene therapy restores alpha-sarcoglycan and associated proteins
Jerry R. Mendell, Louise R. Rodino-Klapac, Xiomara Rosales-Quintero, Janaiah Kota, Brian D. Coley, Gloria Galloway, Josepha M. Craenen, Sarah Lewis , Vinod Malik, Christopher Shilling, Barry J. Byrne, Thomas Conlon, Katherine J Campbell, William G. Bremer , Laurence Viollet, Ph.D. , Christopher M. Walker, Zarife Sahenk, K. Reed Clark
Objectives: Alpha-sarcoglycan deficiency is a severe form of muscular dystrophy (LGMD2D) without treatment. Gene replacement represents a strategy for correcting the underlying defect. Questions related to this approach were addressed in this clinical trial, particularly the need for immunotherapy, and persistence of gene expression.
Methods: A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis (EDB) muscle was conducted. Control sides received saline. A three-day course of methylprednisolone accompanied gene transfer without further immune suppression.
Results: No adverse events were encountered. SGCA gene expression increased 4-5 fold over control sides when examined at 6 weeks (two subjects) and 3 months (one subject). The full sarcoglycan complex was restored in all subjects and muscle fiber size was increased in the 3-month subject. AAV1 neutralizing antibodies were seen as early as 2 weeks. Neither CD4+ nor CD8+ cells were increased over contralateral sides. Scattered foci of inflammation could be found but showed features of programmed cell death. ELISpot showed no IFN- response to -SG or AAV1 capsid peptide pools with the exception of a minimal capsid response in one subject. Restimulation to detect low frequency capsid specific T cells by ELISpot assays was negative. Results of the first three subjects successfully achieved study aims precluding the need for additional enrollment.
Interpretation: The finding of this gene replacement study in LGMD2D has important implications for muscular dystrophy. Sustained gene expression was seen, but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials.
Inibição da prostaglandina D sintetase diminui a necrose muscular (10/04/09)
Japão - músculos de pacientes com distrofia muscular de Duchenne apresentam expressão da prostaglandina D sintetase. Nesta pesquisa em camundongos normais e camundongos com distrofia muscular os autores utilizaram a droga HQL-79, que inibe a prostaglandina D sintetase. Os autores observaram redução da inflamação e consequentemente da necrose muscular e também aumento de força nos camundongos com distrofia muscular. O resumo em inglês pode ser lido abaixo:
(Am. J. Pathol., Apr 2009) Inhibition of prostaglandin D synthase suppresses muscular necrosis
Duchenne muscular dystrophy is a fatal muscle wasting disease that is characterized by a deficiency in the protein dystrophin. Previously, we reported that the expression of hematopoietic prostaglandin D synthase (HPGDS) appeared in necrotic muscle fibers from patients with either Duchenne muscular dystrophy or polymyositis. HPGDS is responsible for the production of the inflammatory mediator, prostaglandin D2. In this paper, we validated the hypothesis that HPGDS has a role in the etiology of muscular necrosis. We investigated the expression of HPGDS/ prostaglandin D2 signaling using two different mouse models of muscle necrosis, that is, bupivacaine-induced muscle necrosis and the mdx mouse, which has a genetic muscular dystrophy . We treated each mouse model with the HPGDS-specific inhibitor, HQL-79, and measured both necrotic muscle volume and selected cytokine mRNA levels. We confirmed that HPGDS expression was induced in necrotic muscle fibers in both bupivacaine-injected muscle and mdx mice. After administration of HQL-79, necrotic muscle volume was significantly decreased in both mouse models. Additionally, mRNA levels of both CD11b and transforming growth factor 1 were significantly lower in HQL-79-treated mdx mice than in vehicle-treated animals. We also demonstrated that HQL-79 suppressed prostaglandin D2 production and improved muscle strength in the mdx mouse. Our results show that HPGDS augments inflammation, which is followed by muscle injury. Furthermore, the inhibition of HPGDS ameliorates muscle necrosis even in cases of genetic muscular dystrophy .
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