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Important Therapeutic Implications (important + therapeutic_implication)
Selected AbstractsRole of histone and transcription factor acetylation in diabetes pathogenesisDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2005Steven G. Gray Abstract Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed $100 billion annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The ,Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications. Copyright © 2005 John Wiley & Sons, Ltd. [source] Endothelial cell-specific molecule 2 (ECSM2) modulates actin remodeling and epidermal growth factor receptor signalingGENES TO CELLS, Issue 3 2009Fanxin Ma Endothelial cell-specific molecules (ECSMs) play a pivotal role in the pathogenesis of many angiogenesis-related diseases. Since its initial discovery, the exact function of human ECSM2 has not been defined. In this study, by database mining, we identified a number of hypothetical proteins across species exhibiting substantial sequence homology to the human ECSM2. We showed that ECSM2 is preferentially expressed in endothelial cells and blood vessels. Their characteristic structures and unique expression patterns suggest that ECSM2 is an evolutionarily conserved gene and may have important functions. We further explored the potential roles of human ECSM2 at the molecular and cellular level. Using a reconstitution mammalian cell system, we demonstrated that ECSM2 mainly resides at the cell membrane, is critically involved in cell-shape changes and actin cytoskeletal rearrangement, and suppresses tyrosine phosphorylation signaling. More importantly, we uncovered that ECSM2 can cross-talk with epidermal growth factor receptor (EGFR) to attenuate the EGF-induced cell migration, possibly via inhibiting the Shc-Ras-ERK (MAP kinase) pathway. Given the importance of growth factor and receptor tyrosine kinase-mediated signaling and cell migration in angiogenesis-related diseases, our findings regarding the inhibitory effects of ECSM2 on EGF-mediated signaling and cell motility may have important therapeutic implications. [source] Oxidative damage is a potential cause of cone cell death in retinitis pigmentosaJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005JiKui Shen Retinitis pigmentosa (RP) is a prevalent cause of blindness caused by a large number of different mutations in many different genes. The mutations result in rod photoreceptor cell death, but it is unknown why cones die. In this study, we tested the hypothesis that cones die from oxidative damage by performing immunohistochemical staining for biomarkers of oxidative damage in a transgenic pig model of RP. The presence of acrolein- and 4-hydroxynonenal-adducts on proteins is a specific indicator that lipid peroxidation has occurred, and there was strong immunofluorescent staining for both in cone inner segments (IS) of two 10-month-old transgenic pigs in which almost all rods had died, compared to faint staining in two 10-month-old control pig retinas. In 22- and 24-month-old transgenic pigs in which all rods and many cones had died, staining was strong in cone axons and some cell bodies as well as IS indicating progression in oxidative damage between 10 and 22 months. Biomarkers for oxidative damage to proteins and DNA also showed progressive oxidative damage to those macromolecules in cones during the course of RP. These data support the hypothesis that the death of rods results in decreased oxygen consumption and hyperoxia in the outer retina resulting in gradual cone cell death from oxidative damage. This hypothesis has important therapeutic implications and deserves rapid evaluation. © 2005 Wiley-Liss, Inc. [source] Prevalence of viral infection detected by PCR and RT-PCR in patients with acute exacerbation of COPD: A systematic reviewRESPIROLOGY, Issue 3 2010Anant MOHAN ABSTRACT Background and objective: Viruses are important aetiological agents of acute exacerbation of COPD (AECOPD). Their reported prevalence varies from region to region. This systematic review calculated the prevalence of respiratory viral infections in AECOPD. Methods: A systematic search was performed using Medline, and references of relevant articles and conference proceedings were hand searched. Articles for review were selected based on the following criteria: (i) prospective or cross-sectional study, (ii) original research, (iii) viral detection used the highly sensitive techniques of PCR and/or Reverse Transcriptase PCR (RT-PCR), (iv) viral prevalence in AECOPD defined, and (v) full paper available in English. We assessed the study quality and extracted data independently and in duplicate using a pre-defined data extraction form. Weighted mean prevalence (WMP) was calculated and a forest plot was constructed to show the dispersion. Results: Eight studies met the inclusion criteria. The WMP of respiratory viral infection in AECOPD was 34.1% (95% CI: 23.9,44.4). picornavirus was the most commonly detected virus with WMP 17.3% (95% CI: 7.2,27.3), followed by influenza; 7.4% (95% CI: 2.9,12.0), respiratory syncytial virus; 5.3% (95% CI: 1.6,9.0), corona viruses; 3.1% (95% CI: 0.4,5.8), parainfluenza; 2.6% (95% CI: 0.4,4.8), adenovirus; 1.1% (95% CI: ,1.1 to 3.3), and human metapneumovirus; 0.7% (95% CI: ,0.3 to 1.8). Maximum WMP was observed in studies from Europe followed by the USA, Australia and Asia. Picorna was the most common virus detected in Western countries whereas influenza was most common in Asia. Conclusions: This systematic review demonstrated that viruses are strongly associated with AECOPD, with the highest detection rates of viruses being in Europe. The geographical epidemiology of viruses may have important therapeutic implications for management of AECOPD. [source] The expanding realm of heterologous immunity: friend or foe?CELLULAR MICROBIOLOGY, Issue 2 2006Kathleen R. Page Summary Antecedent or current infections can alter the immunopathologic outcome of a subsequent unrelated infection. Immunomodulation by co-infecting pathogens has been referred to as ,heterologous immunity' and has been postulated to play a role in host susceptibility to disease, tolerance to organ transplant, and autoimmune disease. The effect of various infections on heterologous immune responses has been well studied in the context of shared epitopes and cross-reactive T cells. It has been shown that prior infections can modulate protective immunity and immunopathology by forming a pool of memory T cells that can cross-react with antigens from heterologous organisms or through the generation of a network of regulatory cells and cytokines. While it is not feasible to alter a host's history of prior infection, understanding heterologous immune responses in the context of simultaneous unrelated infections could have important therapeutic implications. Here, we outline key evidence from animal and human studies demonstrating the effect of heterologous immunity on the outcome of disease. We briefly review the role of T cells, but expand our discussion to explore other immune mechanisms that may modulate the response to concurrent active infections. In particular, we underscore the role of the innate immune system, polarized responses and regulatory mechanisms on heterologous immune responses. [source] | |||||||||||||