Ingenuity Network-Assisted Transcription Profiling: Identification of a New Pharmacologic Mechanism for MK886

Mayburd, Anatoly L.; Martlínez, Alfredo; Sackett, Daniel; Liu, Huaitian; Shih, Joanna H.; Tauler, Jordy; Avis, Ingalill; Mulshine, James L.

doi:10.1158/1078-0432.ccr-05-2149

Cited by 79 publications

(58 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that fasttwitch muscle had about two times more proteins susceptible to carbonylation, with over 20 of these proteins showing significant increases in carbonylation with age in fast-twitch muscle. Subsequent analysis using Ingenuity Pathway Analysis (IPA) (Mayburd et al, 2006), revealed that these carbonylated proteins belong to pathways and functional classes in muscle already known to be impaired in aging skeletal muscle. Moreover, proteins susceptible to carbonylation having a role in two functions, cellular function/maintenance and cell death, were significantly represented in the fast-twitch muscle, but not in the slowtwitch muscle.…”

Section: Carbonylation and Aging Skeletal Musclementioning

confidence: 99%

Age-related muscle dysfunction

Thompson

2009

Experimental Gerontology

198

170

View full text Add to dashboard Cite

Aging is associated with a progressive decline of muscle mass, strength, and quality, a condition described as sarcopenia of aging. Despite the significance of skeletal muscle atrophy, the mechanisms responsible for the deterioration of muscle performance are only partially understood. The purpose of this review is to highlight cellular, molecular and biochemical changes that contribute to age-related muscle weakness. Keywordsactin; myosin; aged muscle; enzymatic activity; oxidative modifications SarcopeniaAging is associated with a progressive decline of muscle mass, strength, and quality, a condition described as sarcopenia. These age-related changes are observed in healthy, active adults who are 50 years and older (Hughes et al., 2002). The prevalence of sarcopenia in older adults under the age of 70 years is about 25% and increases to 40% in adults 80 years or older (Baumgartner et al., 1998). Sarcopenia represents a risk factor for frailty, loss of independence, and physical disability (Roubenoff, 2000). Loss of mobility resulting from muscle loss predicts major physical disability and mortality, and is associated with poor quality of life, social needs, and health care needs (Fried and Guralnik, 1997). The economic impact of sarcopenia and its detrimental correlates are immense (Janssen et al., 2004). Thus, understanding the mechanisms leading to muscle dysfunction (e.g., weakness) at advanced age represents a high public health priority. The purpose of this article is to highlight cellular, molecular, and biochemical changes that contribute to age-related muscle dysfunction. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Muscle physiology-short reviewFor skeletal muscle, the control of force has to be accurate and precise with the contractile machinery being switched on and off rapidly to allow for complex coordinated movements. Action potentials initiated at the neuromuscular junction propagate along the length of the fiber and the transverse tubules. As the wave of depolarization passes down the transverse tubules there is an interaction with the sarcoplasmic reticulum that results in the release of calcium, initiating the interaction of actin and myosin and muscle contraction. This process is known as excitation-contraction coupling. Thus, age-related structural changes or chemical modifications in proteins that affect excitation-contraction coupling are likely to influence muscle function.The basic contractile unit of muscle, the myofibril, consists of a linear array of sarcomeres, which contains interdigitating myosin and actin fila...

show abstract

Section: Carbonylation and Aging Skeletal Musclementioning

confidence: 99%

Age-related muscle dysfunction

Thompson

2009

Experimental Gerontology

198

170

View full text Add to dashboard Cite

show abstract

“…This approach has been successfully used to analyze changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (17) and other systems (18,19). In this study, we applied this knowledge-based approach analysis, and for the first time, we demonstrate the interactions and network of signaling elicited by anabolic and catabolic treatment regimens of PTH peptides.…”

Section: Pthmentioning

confidence: 99%

Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis

Li¹,

Líu²,

Qin³

et al. 2007

Journal of Biological Chemistry

165

148

View full text Add to dashboard Cite

Parathyroid hormone (PTH) stimulates bone formation when injected daily but causes severe bone loss with continuous infusion. The mechanism of its paradoxical effects is still elusive. In this study, we compared changes in the gene expression profile in bone induced by intermittent or continuous treatment with three different PTH peptides, PTH-(1-34), -(1-31), and -(3-34), in Sprague-Dawley female rats. PTH-(1-34) regulated numerous genes (ϳ1,000), but differentially, in both regimes. PTH-(1-31) regulated a similar number of genes in the intermittent regimen but fewer in the continuous regimen, consistent with its less potent catabolic effect. PTH-(3-34) regulated very few genes in both regimes, which suggests the protein kinase C pathway plays a limited role in mediating the dual effects of PTH, whereas the cAMPdependent protein kinase A pathway appears to predominate. In the intermittent treatment, many genes encoding signaling mediators, transcription factors, cytokines, and proteases/ protease inhibitors are regulated rapidly and cyclically with each PTH injection; genes associated with skeletal development show a slowly accruing pattern of expression. With continuous treatment, some genes are regulated from 6 h, and the mRNA levels are sustained with a longer infusion, whereas others show a kinetic decrease and then increase later. Significant up-regulation of genes stimulating osteoclastogenesis in the anabolic regime suggests a provocative and paradoxical theme for the anabolic effect of PTH that a full anabolic response requires a transient up-regulation of genes classically associated with a resorptive response. Ingenuity pathway analysis was performed on the microarray data. A novel signaling network was established that is differentially regulated in the two PTH treatment regimes. Key regulators are suggested to be AREG, CCL2, WNT4, and cAMP-responsive element modulator. PTH,2 administered intermittently, stimulates bone formation in contrast to antiresorptive agents, which reduce bone resorption. Concerns with the limited improvement of antiresorptive treatments in severe osteoporosis led to a search for alternative anabolic agents (1). Teraparatide, recombinant human parathyroid hormone consisting of the first 34 of the 84 amino acids of human parathyroid hormone, has been shown to reduce significantly the risk of both vertebral and nonvertebral fractures in postmenopausal women and to significantly increase bone mineral density (2). It has become the only anabolic agent currently approved for the treatment of osteoporosis in the United States.Bone is a highly specialized form of connective tissue and dynamic organ in all higher vertebrates; it undergoes continuous regeneration. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion, with coupling of osteoclastic resorption and osteoblastic formation (3). This physiological process is coordinated and tightly regulated by local and endocrine factors to ensure that there is a balance between bone formation and ...

show abstract

“…There are a number of resources in the world that allow reconstruction of such associative gene networks, for example, MetaCore [27], Ingenuity [28] and ANDSystem [29,30]. In particular, using the developed by us ANDSystem tool, the following studies were performed: analysis of proteomic data on Helicobacter pylori infection [31]; analysis of the urine proteomic profile in control and under the influence of space flight factors [32]; analysis of tissue-specific gene knockout effect and the search for potential drug targets [33]; analysis of hepatitis C virus life cycle gene networks [34]; analysis of comorbid relations of bronchial asthma and tuberculosis [35], preeclampsia, diabetes and obesity [36], glaucoma [37]; search for novel candidate genes of susceptibility to tuberculosis [38].…”

Section: Introductionmentioning

confidence: 99%

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks

et al. 2018

View full text Add to dashboard Cite

Background: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or~22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. Results: Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension -713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system.

show abstract

Ingenuity Network-Assisted Transcription Profiling: Identification of a New Pharmacologic Mechanism for MK886

Cited by 79 publications

References 33 publications

Age-related muscle dysfunction

Age-related muscle dysfunction

Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks

Contact Info

Product

Resources

About