Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular-genetic tests clinically available in Japan are mainly for the analysis of microbial nucleic acids. Genetic tests targeting the human genome have been limited to research purposes, although a few tests are available for clinical use. In April 2006, reimbursement was readjusted and four molecular-genetic tests were added to those with national insurance coverage: Major bcr-abl mRNA nucleic acid amplification assay, genetic analysis of progressive muscular dystrophy, genetic analysis of rearranged immunoglobulin gene, and genetic analysis of malignant tumor. Under Japan's healthcare system, only laboratory tests catalogued in the reimbursement can be clinically applied. Otherwise, the costs won't be reimbursed. Since most molecular-genetic tests are not given insurance reimbursement points, the costs are charged to the patients themselves. This is one of the reasons why molecular-genetic tests are not used in clinics. Other reasons are that such tests are based on the home-brew method, and that standardized assay methods are not available. I reviewed and discussed the following issues: the present status of medicine based on genomic information in Japan, and the significance of the standardization of molecular-genetic testing in clinical application. I also introduced the JMCoE (Japan Molecular Center of Excellence) program for the promotion of molecular-genetic testing in clinics.
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PMID:[Personalized medicine based on genomic information: the present status in terms of clinical application]. 1854 88

Skeletal muscle atrophy/wasting is a serious complication of a wide range of diseases and conditions such as aging, disuse, AIDS, chronic obstructive pulmonary disease, space travel, muscular dystrophy, chronic heart failure, sepsis, and cancer. Emerging evidence suggests that nuclear factor-kappa B (NF-kappaB) is one of the most important signaling pathways linked to the loss of skeletal muscle mass in various physiological and pathophysiological conditions. Activation of NF-kappaB in skeletal muscle leads to degradation of specific muscle proteins, induces inflammation and fibrosis, and blocks the regeneration of myofibers after injury/atrophy. Recent studies employing genetic mouse models have provided strong evidence that NF-kappaB can serve as an important molecular target for the prevention of skeletal muscle loss. In this article, we have outlined the current understanding regarding the role of NF-kappaB in skeletal muscle with particular reference to different models of muscle wasting and the development of novel therapy.
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PMID:Nuclear factor-kappa B signaling in skeletal muscle atrophy. 1857 72

Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were systematically mapped to tissues they affect from disease-relevant literature in PubMed to create a disease-tissue covariation matrix of high-confidence associations of >1,000 diseases to 73 tissues. By retrieving >2,000 known disease genes, and generating 1,500 disease-associated protein complexes, we analyzed the differential expression of a gene or complex involved in a particular disease in the tissues affected by the disease, compared with nonaffected tissues. When this analysis is scaled to all diseases in our dataset, there is a significant tendency for disease genes and complexes to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also identified complexes in Parkinson disease, cardiomyopathies, and muscular dystrophy syndromes that are similarly tissue specific. Our method represents a conceptual scaffold for organism-spanning analyses and reveals an extensive list of tissue-specific draft molecular pathways, both known and unexpected, that might be disrupted in disease.
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PMID:A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes. 1910 45

Growth hormone (GH) exercises its growth effects by stimulating insulin-like growth factor I (IGF-I) synthesis in the liver (endocrine IGF-I) and by inducing chondrocyte differentiation/replication and local production of IGF-I (paracrine/autocrine IGF-I). Injectable recombinant human (rh)IGF-I (mecasermin) has been available for nearly 20 years for treatment of the rare instances of GH insensitivity caused by GH receptor defects or GH-inhibiting antibodies. Full restoration of normal growth, as occurs with rhGH replacement of GH deficiency, is not seen, presumably because only the endocrine deficiency is addressed. RhIGF-I has also been effective as an insulin-sensitizing agent in severe insulin-resistant conditions. Although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications. Promotion of rhIGF-I for treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH. Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity. The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals. Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies. The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis-a concern for long-term therapy. It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.
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PMID:Mecasermin (recombinant human insulin-like growth factor I). 1919 69

The dynamics of gene expression are regulated by histone acetylases (HATs) and histone deacetylases (HDACs) that control the acetylation state of lysine side chains of the histone proteins of chromatin. The catalytic activity of these two enzymes remodels chromatin to control gene expression without altering gene sequence. Treatment of cancer has been the primary target for the clinical development of HDAC inhibitors, culminating in approval for the first HDAC inhibitor for the treatment of cutaneous T cell lymphoma. Beyond cancer, HDAC inhibition has potential for the treatment of many other diseases. The HDAC inhibitors phenylbutyric acid, valproic acid, and suberoylanilide hydroxamic acid (SAHA) have been shown to correct errant gene expression, ameliorate the progression of disease, and restore absent synthetic or metabolic activities for a diverse group of non-cancer disorders. These benefits have been found in patients with sickle cell anemia, HIV, and cystic fibrosis. In vitro and in vivo models of spinal muscular atrophy, muscular dystrophy, and neurodegenerative, and inflammatory disorders also show response to HDAC inhibitors. This review examines the application of HDAC inhibition as a treatment for a wide-range of non-cancer disorders, many of which are rare diseases that urgently need therapy. Inhibition of the HDACs has general potential as a pharmacological epigenetic approach for gene therapy.
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PMID:Inhibition of histone deacetylases: a pharmacological approach to the treatment of non-cancer disorders. 1935 90

Although the mitochondrial permeability transition pore (mPTP) was first discovered almost 30 years ago [1], it did not attract significant research attention until the 1990's when several studies implicated mPTP in apoptosis [2]. Today, the dogma suggests that opening of mPTP is detrimental to the cell and mPTP activation is widely thought to contribute to disease in cancer, neurodegenerative diseases, stroke, muscular dystrophy, and cardiac reperfusion injury [3]. Multiple factors including Ca(2+), OH(-), P(i), cyclophilin D, reactive oxygen and nitrogen species (ROS and RNS) trigger mPTP opening [4]. However, whether mPTP activation feeds back to alter mitochondrial ROS generation remains unclear. We recently demonstrated that under normal conditions, individual mitochondria undergo spontaneous transient bursts of quantal superoxide generation, termed "superoxide flashes" [5]. Superoxide flashes are observed in all cell types investigated to date and are triggered by a surprising functional coupling between mPTP activation and electron transport chain (ETC) dependent superoxide production. Additionally, reoxgenation following anoxia leads to uncontrolled superoxide flash genesis in cardiomyocytes. This positive feedback mechanism for mPTP/ETC-dependent ROS generation may drive localized redox signaling in individual mitochondria under physiological conditions, and when left unchecked, contribute to global cellular oxidative stress under pathological conditions in cardiac disease. The mPTP activity-dependent cell life and death determination imposes new challenges and opportunities in the pursuit of therapeutic agents for treating diseases in which oxidative stress has been implicated such as cardiac ischemia-reperfusion injury.
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PMID:Superoxide flashes: illuminating new insights into cardiac ischemia/reperfusion injury. 1964 73

In recent years, it has become clear that balanced regulation of reactive oxygen species is of critical significance for cell-fate determination as well as for stem cell development, function, and survival. Although many questions regarding intracellular redox status regulation of stem cell fate remain, we review here what is known regarding the impact of cell-fate signaling as shown with a variety of human cancer cells and more recently on cancer-initiating cells and on the regenerative capacity of skeletal muscle and hematopoietic tissue and their stem cells. We also discuss the role of altered intracellular redox status as a potential primary pathogenic mechanism in muscular dystrophy and hematopoietic pathologies. Studies discussed here illustrate how understanding altered redox regulation of stem cell behavior may contribute to the development of novel stem cell therapies.
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PMID:Oxidative stress regulation of stem and progenitor cells. 1965 Jun 89

Defects in nuclear morphology often correlate with the onset of disease, including cancer, progeria, cardiomyopathy, and muscular dystrophy. However, the mechanism by which a cell controls its nuclear shape is unknown. Here, we use adhesive micropatterned surfaces to control the overall shape of fibroblasts and find that the shape of the nucleus is tightly regulated by the underlying cell adhesion geometry. We found that this regulation occurs through a dome-like actin cap that covers the top of the nucleus. This cap is composed of contractile actin filament bundles containing phosphorylated myosin, which form a highly organized, dynamic, and oriented structure in a wide variety of cells. The perinuclear actin cap is specifically disorganized or eliminated by inhibition of actomyosin contractility and rupture of the LINC complexes, which connect the nucleus to the actin cap. The organization of this actin cap and its nuclear shape-determining function are disrupted in cells from mouse models of accelerated aging (progeria) and muscular dystrophy with distorted nuclei caused by alterations of A-type lamins. These results highlight the interplay between cell shape, nuclear shape, and cell adhesion mediated by the perinuclear actin cap.
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PMID:A perinuclear actin cap regulates nuclear shape. 1985 Aug 71

Altered expression of proteins in the dystrophin-associated glycoprotein complex results in muscular dystrophy and has more recently been implicated in a number of forms of cancer. Here we show that loss of either of two members of this complex, dystrophin in mdx mice or alpha sarcoglycan in Sgca(-/-) mice, results in the spontaneous development of muscle-derived embryonal rhabdomyosarcoma (RMS) after 1 year of age. Many mdx and Sgca(-/-) tumors showed increased expression of insulin-like growth factor 2, retinoblastoma protein, and phosphorylated Akt and decreased expression of phosphatase and tensin homolog gene, much as is found in a human RMS. Further, all mdx and Sgca(-/-) RMS analyzed had increased expression of p53 and murine double minute (mdm)2 protein and contained missense p53 mutations previously identified in human cancers. The mdx RMS also contained missense mutations in Mdm2 or alternatively spliced Mdm2 transcripts that lacked an exon encoding a portion of the p53-binding domain. No Pax3:Fkhr or Pax7:Fkhr translocation mRNA products were evident in any tumor. Expression of natively glycosylated alpha dystroglycan and alpha sarcoglycan was reduced in mdx RMS, whereas dystrophin expression was absent in almost all human RMS, both for embryonal and alveolar RMS subtypes. These studies show that absence of members of the dystrophin-associated glycoprotein complex constitutes a permissive environment for spontaneous development of embryonal RMS associated with mutation of p53 and mutation or altered splicing of Mdm2.
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PMID:Mice lacking dystrophin or alpha sarcoglycan spontaneously develop embryonal rhabdomyosarcoma with cancer-associated p53 mutations and alternatively spliced or mutant Mdm2 transcripts. 2001 82

The cathepsins are a family of lysosomal cysteine proteases that are abundant in living cells and play important roles in intracellular proteolysis. Cathepsins are necessary for cell survival, and disruption of regulation of the activity of these enzymes causes serious diseases including allergy, atherosclerosis, muscular dystrophy, Alzheimer's disease and cancer. Therefore, the design of inhibitors for cathepsins is important in development of therapeutic agents. This review will focus on the features of the tertiary structure and substrate-binding specificity of cathepsins B, L, S and K, based on X-ray crystal structures of their complexes with inhibitors. To illustrate an approach to drug design, an example of structure-based design of a cathepsin B-specific inhibitor is described.
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PMID:Development of cathepsin inhibitors and structure-based design of cathepsin B-specific inhibitor. 2033 81


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