Abstract:
:Bile formation is an osmotic process driven by the vectorial transport of actively transferred biliary components across the basolateral (sinusoidal) and apical (canalicular) hepatocyte membranes, the latter being the rate-limiting step of the overall blood-to-bile transfer. The ATP-binding cassette (ABC) superfamily of membrane transporters comprises novel ATP-dependent carriers that mediate canalicular transfer of several endogenous and exogenous substrates, and therefore play a key role in bile formation. Gene expression, as well as the balance between vesicular targeting and internalization of these transporters to/from the canalicular membrane are highly regulated processes. This balance is affected in several models of hepatocellular cholestasis, and these alterations may either initiate or perpetuate the cholestatic manifestations. This review describes the regulation of the normal activity of hepatocellular ABC transporters, focusing on the involvement of transcription factors and signaling pathways in the regulation of carrier synthesis, dynamic localization and phosphorylation status. Its alteration in different experimental models of cholestasis, such as those induced by estrogens, lipopolysaccharide (endotoxin), monohydroxylated bile salts and oxidative stress, is also reviewed. Finally, several experimental therapeutic approaches based upon the administration of compounds known/thought to induce carrier synthesis (e.g., protein synthesis inducers), to counteract etiological factors responsible for the cholestatic disease (e.g., corticoids in lipopolysaccharide-induced cholestasis) or to stimulate exocytic insertion of canalicular transporters (e.g., cAMP, silymarin or tauroursodeoxycholate) are described with respect to their ability to prevent cholestatic alterations; the role of signaling molecules as putative downstream mediators of their effects are also discussed.
journal_name
Curr Med Chemjournal_title
Current medicinal chemistryauthors
Crocenzi FA,Mottino AD,Roma MGdoi
10.2174/0929867043455918subject
Has Abstractpub_date
2004-02-01 00:00:00pages
501-24issue
4eissn
0929-8673issn
1875-533Xjournal_volume
11pub_type
杂志文章,评审abstract::In the last decade much attention has been paid to the development of metabolically non-reversible dimeric or hybrid compounds, which combine two structural units of one or two lead compounds of interest for the treatment of Alzheimer's disease. As a consequence of their capability to simultaneously interact with two ...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986706775527974
更新日期:2006-01-01 00:00:00
abstract::Over the last century, many studies have demonstrated that low-density lipoprotein (LDL) is a key risk factor of cardiovascular diseases (CVD) related to atherosclerosis. Thus, for these CVD patients, LDL lowering agents are commonly used in the clinic to reduce the risk for CVD. LDL, upon modification, will develop d...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867325666180316121015
更新日期:2019-01-01 00:00:00
abstract::Serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists. Among 5-HTRs, the 5-HT(1A) subtype is the best studied and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867023371030
更新日期:2002-02-01 00:00:00
abstract::Trypanosomatids are a group of flagellated unicellular eukaryotes, causing serious human diseases including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.) and Leishmaniasis (Leishmania spp.). The second messenger cAMP is involved in numerous and fundamental processes in these parasites...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867326666190620093029
更新日期:2019-01-01 00:00:00
abstract::Drug repositioning, an innovative therapeutic application of an old drug, has received much attention as a particularly costeffective strategy in drug R&D Recent work has indicated that repositioning can be promoted by utilizing a wide range of information sources, including medicinal chemical, target, mechanism, main...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:
更新日期:2013-01-01 00:00:00
abstract::Recent advances have identified the podocyte as a key target in glomerular injury. The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity for proteins in the kidney. Podocyte injury or loss leads to proteinuria. Apoptosis has been shown to contribute to renal cell loss, inclu...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986708784911542
更新日期:2008-01-01 00:00:00
abstract::Whilst knowledge of basic biology, diagnosis and prognosis of glioblastoma (GB - WHO grade IV) are steadily improving, advancements of therapy are discouragingly slow, with the only significant novelty during last ten years represented by introduction of temozolomide in chemotherapy. In order to analyze the current st...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867322666150530210700
更新日期:2015-01-01 00:00:00
abstract::Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras. The mechanism of action of FTS is well understood. It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane. This agent...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867311320100002
更新日期:2013-01-01 00:00:00
abstract:BACKGROUND:Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, with an incidence of 3.19 cases per 100,000 person years and remarkably poor prognosis showing a 5-year survival rate of 4-5%, and only a 26-33% survival rate at 2 years in clinical trials. OBJECTIVE:In this paper, we review the...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867324666170516123206
更新日期:2017-01-01 00:00:00
abstract::Four different types of small RNAs functionally associated with gene silencing have been discovered in animals including small interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs). Experimental evidence suggests that miRNAs regulate the expression of more than 30% of protein-coding genes. ...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986710794182980
更新日期:2010-01-01 00:00:00
abstract::Fullerenes as a unique class of carbon allotropes have been studied extensively for their distinctive material properties and potential technological applications, including those in biology and medicine. Since a major focus in the latter has been on drug development and formulation, in this paper we highlight some re...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/092986711795656225
更新日期:2011-01-01 00:00:00
abstract::The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors, a set of three receptor sub-types encoded by distinct genes, function as lipid sensors to regulate a broad range of genes in many metabolically active tissues. Synthetic PPAR agonists have exhibited therapeutic benefits in treating diab...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867033368295
更新日期:2003-02-01 00:00:00
abstract::Atrial fibrillation is the most common disorder of cardiac rhythm. In spite of diagnosis simplicity, patients with atrial fibrillation are difficult to treat. In the recent years with the description of the phenomenon called remodelling, it has been possible to better define the principle mechanisms responsible for in...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867054020954
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND:Nitric oxide (NO) plays important regulatory roles in a plethora of biological functions and thus holds tremendous potential to be exploited for clinical uses. However, the chemistries in the molecular design of nano-nitric oxide delivery systems is currently lacking. OBJECTIVE:The overarching aim of this r...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867324666170407141222
更新日期:2018-01-01 00:00:00
abstract::Antimitotics binding at the colchicine site of tubulin are important antitumour and vascular disrupting agents. Pyridines and azines are privileged scaffolds in medicinal chemistry and in recent years many colchicine site ligands (CSL) have incorporated them into their structures with the aim of improving their pharma...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986732311160420104823
更新日期:2016-01-01 00:00:00
abstract::Leukoaraiosis (LA), one of the most frequent causes of cognitive disturbances, is presumed to involve vascular demyelinization and cerebral small-vessel diseases. Although it has been suggested that the development of LA is associated with cerebral circulatory disturbances, the pathomechanism of this circulatory probl...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986707780362907
更新日期:2007-01-01 00:00:00
abstract::Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease,...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867311320100001
更新日期:2013-01-01 00:00:00
abstract::It is well recognised that increased levels of high density lipoprotein (HDL) protect against atherosclerosis and correlate with improved prognosis for vascular disease associated events. While many of the atheroprotective effects of HDL are ascribed to the ability to remove cholesterol from the vasculature through th...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986709787458425
更新日期:2009-01-01 00:00:00
abstract::Drug-loaded nanoparticles have shown great potential in the study of carriers for disease-targeting drug delivery. Drug-loaded nanoparticles are excellent in keeping the drug in the systemic circulation for a prolonged period of time, introducing targeting molecules to improve targeting efficiency and to reduce side e...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986712800784694
更新日期:2012-01-01 00:00:00
abstract::Cancer is the world's second leading cause of death after heart diseases, and involves abnormal cell growth at a primary site and the potential to spread to other parts of the body. Tumors are highly heterogeneous and consist of subgroups of cells with distinct characteristics. Of these, the cancer stem cells (CSC) ni...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867327666200320155053
更新日期:2020-03-20 00:00:00
abstract::A BRAF somatic mutation at residue 600 of the BRAF protein (BRAFV600E) is highly prevalent in papillary thyroid carcinomas (PTC). This mutation occurs in approximately 44% (from 29% to 83%) of PTC depending on the different studies. BRAFV600E is almost always found in PTC with a papillary or a mixed follicular/papilla...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986710791111189
更新日期:2010-01-01 00:00:00
abstract::Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated Low-Density Lipoprotein Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients exhibit a scarce responsiveness or e...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986712803341485
更新日期:2012-01-01 00:00:00
abstract::Atrial fibrillation (AF) and chronic kidney disease (CKD) are disorders with increasing prevalence. The presence of CKD increases the risk of incident AF and vice versa, and the presence of AF may accelerate CKD progression. Nearly a third of patients with established CKD also have AF, whilst half of AF patients may h...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867323666160210130109
更新日期:2016-01-01 00:00:00
abstract::Cervical spondylotic myelopathy (CSM) is a very common and debilitating disease; however, its underlying pathocellular process remains uncertain. Attempts have been made to reproduce CSM in experimental animal models in order to deepen the knowledge on the molecular pathobiology of this disease. The up-to-date observa...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986710790820598
更新日期:2010-01-01 00:00:00
abstract::For many years the spotlight in drug discovery has been on a relatively small number of validated therapeutic target classes, such as G-protein coupled receptors and enzymes such as protein kinases, with well characterized enzymatic and cellular activities. However, with recent progress in genomics and proteomics, pro...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867311320240003
更新日期:2013-01-01 00:00:00
abstract::ATP binding cassette (ABC) transporters are involved in drug absorption, distribution and elimination. They also mediate multidrug resistance in cancer cells. Isoflavones, such as genistein (GNT), belong to a class of naturally-occurring compounds found at high concentrations in commonly consumed soya based-foods and ...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867323666160406120711
更新日期:2016-01-01 00:00:00
abstract::In healthy individuals, natural and adaptive immune responses are able to control virus entry into the host. In particular, CD8(+)-mediated cytotoxicity, sustained by the intervention of CD4+ cells, represents the major key event leading to virus eradication. On the other hand, viruses are able to evade from host immu...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986706775476106
更新日期:2006-01-01 00:00:00
abstract::The use of antisense oligonucleotides as therapeutic agents has generated considerable enthusiasm in the research and medical community. Antisense oligonucleotides as therapeutic agents were proposed as far back as in the 1970s when the antisense strategy was initially developed. Nonetheless, it has taken almost a qua...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/0929867054864859
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND:Numerous studies have demonstrated that halogenated agents elicit myocardial conditioning effects when adminis-tered perioperatively in cardiac surgery. Recent evidence has been published of the benefits of maintaining exposure to halogenated agents during the early postoperative period. The enzymatic mechan...
journal_title:Current medicinal chemistry
pub_type: 杂志文章
doi:10.2174/0929867327999201001202607
更新日期:2020-10-01 00:00:00
abstract::Since its discovery in 1995 adiponectin has garnered considerable interest from the academic, clinical and biotech communities due to its proposed salutary anti-inflammatory, anti-diabetic, anti-atherogenic and cardioprotective properties. As a result our appreciation of adiponectin's structure and the importance of p...
journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/092986712803833155
更新日期:2012-01-01 00:00:00