Abstract:
:Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein-mediated drug clearance. In contrast, docetaxel (Taxotere), a closely related antineoplastic agent, did not activate SXR and displayed superior pharmacokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. We also found that ET-743, a potent antineoplastic agent, suppressed MDR1 transcription by acting as an inhibitor of SXR. These findings demonstrate how the molecular activities of SXR can be manipulated to control drug clearance.
journal_name
Nat Medjournal_title
Nature medicineauthors
Synold TW,Dussault I,Forman BMdoi
10.1038/87912keywords:
subject
Has Abstractpub_date
2001-05-01 00:00:00pages
584-90issue
5eissn
1078-8956issn
1546-170Xpii
87912journal_volume
7pub_type
杂志文章相关文献
NATURE MEDICINE文献大全abstract::Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ec...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2850
更新日期:2012-08-01 00:00:00
abstract::HIV-specific mucosal and cellular immunity was analyzed in heterosexual couples discordant for HIV status in serum and in HIV-unexposed controls. HIV-specific IgA but not IgG was present in urine and vaginal wash samples from HIV-exposed seronegative individuals (ESN), whereas both IgA and IgG were observed in their H...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1197-1250
更新日期:1997-11-01 00:00:00
abstract::Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated de...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4062
更新日期:2016-04-01 00:00:00
abstract::Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1750
更新日期:2008-05-01 00:00:00
abstract::The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-1072-4
更新日期:2020-11-01 00:00:00
abstract::The mechanisms responsible for the persistence of HIV-1 after many years of suppressive antiretroviral therapy (ART) have been only partially elucidated. Most of the studies investigating HIV-1 persistence have been performed with blood, although it is well known that germinal centers (GCs) within lymph nodes (LNs) se...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4113
更新日期:2016-07-01 00:00:00
abstract::Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM)....
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4431
更新日期:2017-12-01 00:00:00
abstract::Infection with Plasmodium falciparum during pregnancy leads to the accumulation of parasite-infected erythrocytes in the placenta, and is associated with excess perinatal mortality, premature delivery and intrauterine growth retardation in the infant, as well as increased maternal mortality and morbidity. P. falciparu...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/71582
更新日期:2000-01-01 00:00:00
abstract::Cyclooxygenase (COX) has two isoforms. Generally, COX 1 is constitutively expressed in most tissues, where it maintains physiological processes; inducible COX 2 is considered a pro-inflammatory enzyme and a chief target for the treatment of inflammatory diseases. Here we present evidence that COX 2 may have anti-infla...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/9550
更新日期:1999-06-01 00:00:00
abstract::The pathogenic bacterium Neisseria meningitidis is an important cause of septicemia and meningitis, especially in childhood. The establishment and maintenance of bacteremic infection is a pre-requisite for all the pathological sequelae of meningococcal infection. To further understand the genetic basis of this essenti...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/81380
更新日期:2000-11-01 00:00:00
abstract::Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers gr...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.1891
更新日期:2008-12-01 00:00:00
abstract::Neutrophil extracellular traps (NETs) are released as neutrophils die in vitro in a process requiring hours, leaving a temporal gap that invasive microbes may exploit. Neutrophils capable of migration and phagocytosis while undergoing NETosis have not been documented. During Gram-positive skin infections, we directly ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2847
更新日期:2012-09-01 00:00:00
abstract::Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalities in mice with targeted deletion of the gene for neuronal nitric oxide synthase which model the clinical disorders. The mice possess hypertrophic dilated bladders and dysfunctional urinary outlets which do not relax in r...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0597-571
更新日期:1997-05-01 00:00:00
abstract::The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. T...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/nm1087
更新日期:2004-08-01 00:00:00
abstract::In the version of this article originally published, Dimitry G. Sayenko's affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the autho...
journal_title:Nature medicine
pub_type: 已发布勘误
doi:10.1038/s41591-018-0248-7
更新日期:2018-12-01 00:00:00
abstract::Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. Despite the rapid increase in the number of individu...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1693
更新日期:2008-01-01 00:00:00
abstract::By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show h...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3958
更新日期:2015-10-01 00:00:00
abstract::A high-fat diet increases the risk of colon, breast and prostate cancer. The molecular mechanism by which dietary lipids promote tumorigenesis is unknown. Their effects may be mediated at least in part by the peroxisome proliferator-activated receptors (PPARs). These ligand-activated nuclear receptors modulate gene ex...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/2042
更新日期:1998-09-01 00:00:00
abstract::Evolutionary patterns of virus replication and distribution in lymphoid tissue during the early phases of HIV infection have not been delineated. Lymph node (LN) biopsies were excised from patients at different times after the estimated time of primary infection. Within 3 months of the acute viral syndrome, HIV was mo...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0398-341
更新日期:1998-03-01 00:00:00
abstract::The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0302-282
更新日期:2002-03-01 00:00:00
abstract::Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therape...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2377
更新日期:2011-06-26 00:00:00
abstract::The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1641
更新日期:2007-10-01 00:00:00
abstract::We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ pop...
journal_title:Nature medicine
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1038/s41591-018-0053-3
更新日期:2018-06-01 00:00:00
abstract::One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotrop...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3776
更新日期:2015-03-01 00:00:00
abstract::Technologies are needed to map and image biological barriers in vivo that limit solid tumor delivery and, ultimately, the effectiveness of imaging and therapeutic agents. Here we integrate proteomic and imaging analyses of caveolae at the blood-tumor interface to discover an active transendothelial portal to infiltrat...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3623
更新日期:2014-09-01 00:00:00
abstract::We have designed short peptides composed of two functional domains, one a tumor blood vessel 'homing' motif and the other a programmed cell death-inducing sequence, and synthesized them by simple peptide chemistry. The 'homing' domain was designed to guide the peptide to targeted cells and allow its internalization. T...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/12469
更新日期:1999-09-01 00:00:00
abstract::We evaluated the ability of neonatal porcine islets to engraft and restore glucose control in pancreatectomized rhesus macaques. Although porcine islets transplanted into nonimmunosuppressed macaques were rapidly rejected by a process consistent with cellular rejection, recipients treated with a CD28-CD154 costimulati...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1375
更新日期:2006-03-01 00:00:00
abstract::Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes whose products are specifically dedicated to protect cellular functions against stress. One of the best known ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1097-1150
更新日期:1997-10-01 00:00:00
abstract::Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing h...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm903
更新日期:2003-08-01 00:00:00
abstract::Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We show that two pathogen recognition receptors, Toll-like receptor 2 (TLR2) and dectin-1, recognizing the same microbial stimulus, stimulate distinc...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.1925
更新日期:2009-04-01 00:00:00