出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/03/30 12:00:15」(JST)[Wiki en表示]
- Systems pharmacology identifies drug targets for Stargardt disease-associated retinal degeneration.
- Chen Y, Palczewska G, Mustafi D, Golczak M, Dong Z, Sawada O, Maeda T, Maeda A, Palczewski K.AbstractA systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.
- The Journal of clinical investigation.J Clin Invest.2013 Dec 2;123(12):5119-34. doi: 10.1172/JCI69076. Epub 2013 Nov 15.
- A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease
- PMID 24231350
- Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha.
- Hamamura K1, Tanjung N, Yokota H.Author information 1Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, SL155, 723 West Michigan Street, Indianapolis, IN, 46202, USA, firstname.lastname@example.org.AbstractIn response to various stresses including viral infection, nutrient deprivation, and stress to the endoplasmic reticulum, eukaryotic translation initiation factor 2 alpha (eIF2α) is phosphorylated to cope with stress induced apoptosis. Although bone cells are sensitive to environmental stresses that alter the phosphorylation level of eIF2α, little is known about the role of eIF2α mediated signaling during the development of bone-resorbing osteoclasts. Using two chemical agents (salubrinal and guanabenz) that selectively inhibit de-phosphorylation of eIF2α, we evaluated the effects of phosphorylation of eIF2α on osteoclastogenesis of RAW264.7 pre-osteoclasts as well as development of MC3T3 E1 osteoblast-like cells. The result showed that salubrinal and guanabenz stimulated matrix deposition of osteoblasts through upregulation of activating transcription factor 4 (ATF4). The result also revealed that these agents reduced expression of the nuclear factor of activated T cells c1 (NFATc1) and inhibited differentiation of RAW264.7 cells to multi-nucleated osteoclasts. Partial silencing of eIF2α with RNA interference reduced suppression of salubrinal/guanabenz-driven downregulation of NFATc1. Collectively, we demonstrated that the elevated phosphorylation level of eIF2α not only stimulates osteoblastogenesis but also inhibit osteoclastogenesis through regulation of ATF4 and NFATc1. The results suggest that eIF2α-mediated signaling might provide a novel therapeutic target for preventing bone loss in osteoporosis.
- Journal of bone and mineral metabolism.J Bone Miner Metab.2013 Nov;31(6):618-28. doi: 10.1007/s00774-013-0450-0. Epub 2013 Mar 28.
- In response to various stresses including viral infection, nutrient deprivation, and stress to the endoplasmic reticulum, eukaryotic translation initiation factor 2 alpha (eIF2α) is phosphorylated to cope with stress induced apoptosis. Although bone cells are sensitive to environmental stresses tha
- PMID 23536193
- Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo.
- Vaccaro A1, Patten SA, Aggad D, Julien C, Maios C, Kabashi E, Drapeau P, Parker JA.Author information 1CRCHUM, Université de Montréal, Montréal, QC, Canada.AbstractC. elegans and D. rerio expressing mutant TAR DNA Binding Protein 43 (TDP-43) are powerful in vivo animal models for the genetics and pharmacology of amyotrophic lateral sclerosis (ALS). Using these small-animal models of ALS, we previously identified methylene blue (MB) as a potent suppressor of TDP-43 toxicity. Consequently here we investigated how MB might exert its neuroprotective properties and found that it acts through reduction of the endoplasmic reticulum (ER) stress response. We tested other compounds known to be active in the ER unfolded protein response in worms and zebrafish expressing mutant human TDP-43 (mTDP-43). We identified three compounds: salubrinal, guanabenz and a new structurally related compound phenazine, which also reduced paralysis, neurodegeneration and oxidative stress in our mTDP-43 models. Using C. elegans genetics, we showed that all four compounds act as potent suppressors of mTDP-43 toxicity through reduction of the ER stress response. Interestingly, these compounds operate through different branches of the ER unfolded protein pathway to achieve a common neuroprotective action. Our results indicate that protein-folding homeostasis in the ER is an important target for therapeutic development in ALS and other TDP-43-related neurodegenerative diseases.
- Neurobiology of disease.Neurobiol Dis.2013 Jul;55:64-75. doi: 10.1016/j.nbd.2013.03.015. Epub 2013 Apr 5.
- C. elegans and D. rerio expressing mutant TAR DNA Binding Protein 43 (TDP-43) are powerful in vivo animal models for the genetics and pharmacology of amyotrophic lateral sclerosis (ALS). Using these small-animal models of ALS, we previously identified methylene blue (MB) as a potent suppressor of TD
- PMID 23567652
- Therapeutic effects of evening administration of guanabenz and clonidine on morning hypertension : evaluation using home-based blood pressure measurements
- HASHIMOTO J
- J Hypertens 21, 805-811, 2003
- NAID 30018867129
- Interactions of Ligands at Angiotensin II-Receptors and Imidazoline Receptors
- Wethmar Uta,Raasch Walter,Dendorfer Andreas [他],DOMINIAK Peter
- The Japanese journal of pharmacology 85(2), 167-174, 2001-02-01
- … Antazoline, cimetidine, clonidine, efaroxan, guanabenz, guanethidine, idazoxan, moxonidine and rilmenidine up to a concentration of 100 μM failed to displace the specific binding of [125I]Sar1,Ile8 angiotensin II at the AT1-receptor characterized by losartan (IC50 = 26 ± 12 nM) in liver homogenate. …
- NAID 10007119963
- Positive Inotropic Effects of Imidazoline Derivatives Are Not Mediated via Imidazoline Binding Sites but α_1-Adrenergic Receptors
- Raasch Walter,Chun K. R. Julian,Dendorfer Andreas [他],DOMINIAK Peter
- The Japanese journal of pharmacology 84(1), 1-6, 2000-09-01
- … of 0.5μM was calculated and since competition studies with guanabenz(K<SUB>i</SUB>=0.1μM), clonidine(K<SUB>i</SUB>=58.1μM)and moxonidine(K<SUB>i</SUB>=129μM)confirmed the specificity of the I<SUB>2</SUB>−binding. …
- NAID 10008184906
- Guanabenz official prescribing information for healthcare professionals. Includes: indications, dosage, adverse reactions, pharmacology and more. ... In other controlled clinical trials at the starting dose of 16 mg/day in 476 patients ...
- Easy to read patient leaflet for guanabenz. Includes indications, proper use, special instructions, precautions, and possible side effects. ... If OVERDOSE is suspected: Contact 1-800-222-1222 (the American Association of Poison ...