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181.
Liver X receptors in cardiovascular and metabolic disease 总被引:5,自引:0,他引:5
Liver X receptors (LXRs) α and β are nuclear oxysterol receptors and metabolic sensors initially found to regulate cholesterol
metabolism and lipid biosynthesis. Recent studies have elucidated the importance of LXR in the development of cardiovascular
diseases and metabolic disorders. LXR agonists prevent development of atherosclerosis by modulation of metabolic as well as
inflammatory gene expression in rodent models. Moreover, LXR activation inhibits hepatic gluconeogenesis and lowers serum
glucose levels, indicating possible application of LXR activation in the treatment of diabetes mellitus. However, first-generation
LXR agonists elevate hepatic and serum trigylceride levels, making subtype-specific agonists and selective LXR modulators
rather than unselective LXR agonists a potential pharmacological strategy. This review summarizes the multiple physiological
and pathophysiological implications of LXRs and observations that identify LXRs as potential targets for therapeutic interventions
in human cardiovascular and metabolic disease.
Received 30 August 2005; received after revision 10 October 2005; accepted 4 November 2005 相似文献
182.
Gandhi TK Zhong J Mathivanan S Karthick L Chandrika KN Mohan SS Sharma S Pinkert S Nagaraju S Periaswamy B Mishra G Nandakumar K Shen B Deshpande N Nayak R Sarker M Boeke JD Parmigiani G Schultz J Bader JS Pandey A 《Nature genetics》2006,38(3):285-293
We present the first analysis of the human proteome with regard to interactions between proteins. We also compare the human interactome with the available interaction datasets from yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans) and fly (Drosophila melanogaster). Of >70,000 binary interactions, only 42 were common to human, worm and fly, and only 16 were common to all four datasets. An additional 36 interactions were common to fly and worm but were not observed in humans, although a coimmunoprecipitation assay showed that 9 of the interactions do occur in humans. A re-examination of the connectivity of essential genes in yeast and humans indicated that the available data do not support the presumption that the number of interaction partners can accurately predict whether a gene is essential. Finally, we found that proteins encoded by genes mutated in inherited genetic disorders are likely to interact with proteins known to cause similar disorders, suggesting the existence of disease subnetworks. The human interaction map constructed from our analysis should facilitate an integrative systems biology approach to elucidating the cellular networks that contribute to health and disease states. 相似文献
183.
Amundadottir LT Sulem P Gudmundsson J Helgason A Baker A Agnarsson BA Sigurdsson A Benediktsdottir KR Cazier JB Sainz J Jakobsdottir M Kostic J Magnusdottir DN Ghosh S Agnarsson K Birgisdottir B Le Roux L Olafsdottir A Blondal T Andresdottir M Gretarsdottir OS Bergthorsson JT Gudbjartsson D Gylfason A Thorleifsson G Manolescu A Kristjansson K Geirsson G Isaksson H Douglas J Johansson JE Bälter K Wiklund F Montie JE Yu X Suarez BK Ober C Cooney KA Gronberg H Catalona WJ Einarsson GV 《Nature genetics》2006,38(6):652-658
With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry. 相似文献
184.
Gilbert SL Zhang L Forster ML Anderson JR Iwase T Soliven B Donahue LR Sweet HO Bronson RT Davisson MT Wollmann RL Lahn BT 《Nature genetics》2006,38(2):245-250
Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases. 相似文献
185.
Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor 总被引:2,自引:0,他引:2
Takahashi C Contreras B Iwanaga T Takegami Y Bakker A Bronson RT Noda M Loda M Hunt JL Ewen ME 《Nature genetics》2006,38(1):118-123
Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression. 相似文献
186.
Scorpio A Blank TE Day WA Chabot DJ 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2237-2248
Anthrax has been a major cause of death in grazing animals and an occasional cause of death in humans for thousands of years. Since the late 1800s there has been an exceptional international history of anthrax vaccine development. Due to animal vaccinations, the rate of infection has dropped dramatically. Anthrax vaccines have progressed from uncharacterized whole-cell vaccines in 1881, to pXO2-negative spores in the 1930s, to culture filtrates absorbed to aluminum hydroxide in 1970, and likely to recombinant protective antigen in the near future. Each of these refinements has increased safety without significant loss of efficacy. The threat of genetically engineered, antibiotic and vaccine resistant strains of Bacillus anthracis is fueling hypothesis-driven research and global techniques--including genomics, proteomics and transposon site hybridization--to facilitate the discovery of novel vaccine targets. This review highlights historical achievements and new developments in anthrax vaccine research. 相似文献
187.
Niimura N Arai S Kurihara K Chatake T Tanaka I Bau R 《Cellular and molecular life sciences : CMLS》2006,63(3):285-300
Neutron diffraction provides an experimental method of directly locating hydrogen atoms in proteins, a technique complimentary to ultra-high-resolution [1, 2] X-ray diffraction. Three different types of neutron diffractometers for biological macromolecules have been constructed in Japan, France and the United States, and they have been used to determine the crystal structures of proteins up to resolution limits of 1.5-2.5 A. Results relating to hydrogen positions and hydration patterns in proteins have been obtained from these studies. Examples include the geometrical details of hydrogen bonds, H/D exchange in proteins and oligonucleotides, the role of hydrogen atoms in enzymatic activity and thermostability, and the dynamical behavior of hydration structures, all of which have been extracted from these structural results and reviewed. Other techniques, such as the growth of large single crystals, the preparation of fully deuterated proteins, the use of cryogenic techniques, and a data base of hydrogen and hydration in proteins, will be described. 相似文献
188.
189.
Galanin – 25 years with a multitalented neuropeptide 总被引:1,自引:0,他引:1
Galanin, a neuropeptide widely expressed in the central and peripheral nervous systems and in the endocrine system, has been shown to regulate numerous physiological and pathological processes through interactions with three G-protein-coupled receptors, GalR1 through GalR3. Over the past decade, some of the receptor subtype-specific effects have been elucidated through pharmacological studies using subtype selective ligands, as well as through molecular approaches involving knockout animals. In the present review, we summarize the current data which constitute the basis of targeting GalR1, GalR2 and GalR3 for the treatment of various human diseases and pathological conditions, including seizure, Alzheimer's disease, mood disorders, anxiety, alcohol intake in addiction, metabolic diseases, pain and solid tumors. 相似文献