共查询到20条相似文献,搜索用时 0 毫秒
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NADPH oxidases are a family of oxidases that utilize molecular oxygen to generate hydrogen peroxide and superoxide, thus indicating physiological functions of these highly reactive and short-lived species. The regulation of these NADPH oxidases (nox) enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. While the complexity of the nox family (Nox1-5, Duox1, 2) is daunting, the complexity also allows for targeting of NADPH oxidases in disease states. In this review, we discuss which inflammatory and malignant disorders can be targeted by nox inhibitors, as well as clinical experience in the use of such inhibitors. 相似文献
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Altenhöfer S Kleikers PW Radermacher KA Scheurer P Rob Hermans JJ Schiffers P Ho H Wingler K Schmidt HH 《Cellular and molecular life sciences : CMLS》2012,69(14):2327-2343
Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis. 相似文献
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Kai Song Hao Wu H. N. Ashiqur Rahman Yunzhou Dong Aiyun Wen Megan L. Brophy Scott Wong Sukyoung Kwak Diane R. Bielenberg Hong Chen 《Cellular and molecular life sciences : CMLS》2017,74(3):393-398
VEGF-driven tumor angiogenesis has been validated as a central target in several tumor types deserving of continuous and further considerations to improve the efficacy and selectivity of the current therapeutic paradigms. Epsins, a family of endocytic clathrin adaptors, have been implicated in regulating endothelial cell VEGFR2 signaling, where its inactivation leads to nonproductive leaky neo-angiogenesis and, therefore, impedes tumor development and progression. Targeting endothelial epsins is of special significance due to its lack of affecting other angiogenic-signaling pathways or disrupting normal quiescent vessels, suggesting a selective modulation of tumor angiogenesis. This review highlights seminal findings on the critical role of endothelial epsins in tumor angiogenesis and their underlying molecular events, as well as strategies to prohibit the normal function of endogenous endothelial epsins that capitalize on these newly understood mechanisms. 相似文献
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Bencherif M Lippiello PM Lucas R Marrero MB 《Cellular and molecular life sciences : CMLS》2011,68(6):931-949
In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis,
psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated
inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial
changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines
such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting
alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines.
This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7
receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach
could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory
components. 相似文献
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P.-E. Chabrier C. Demerlé-Pallardy M. Auguet 《Cellular and molecular life sciences : CMLS》1999,55(8-9):1029-1035
Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases. 相似文献
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Chi Chiu Wang Ellen Billett Astrid Borchert Hartmut Kuhn Christoph Ufer 《Cellular and molecular life sciences : CMLS》2013,70(4):599-630
Monoamine oxidases (MAOs) are flavoproteins of the outer mitochondrial membrane that catalyze the oxidative deamination of biogenic and xenobiotic amines. In mammals there are two isoforms (MAO-A and MAO-B) that can be distinguished on the basis of their substrate specificity and their sensitivity towards specific inhibitors. Both isoforms are expressed in most tissues, but their expression in the central nervous system and their ability to metabolize monoaminergic neurotransmitters have focused MAO research on the functionality of the mature brain. MAO activities have been related to neurodegenerative diseases as well as to neurological and psychiatric disorders. More recently evidence has been accumulating indicating that MAO isoforms are expressed not only in adult mammals, but also before birth, and that defective MAO expression induces developmental abnormalities in particular of the brain. This review is aimed at summarizing and critically evaluating the new findings on the developmental functions of MAO isoforms during embryogenesis. 相似文献
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The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical
receptor by the appropriate agonists, the cognate G proteins undergo a cycle of activation and deactivation; the α-subunits and the βγ-dimers interact sequentially with several reaction partners (receptor, guanine nucleotides and effectors as well as regulatory
proteins) by exposing appropriate binding sites. For most of these domains, low molecular weight ligands have been identified
that either activate or inhibit signal transduction. These ligands include short peptides derived from receptors, G protein
subunits and effectors, mastoparan and related insect venoms, modified guanine nucleotides, suramin analogues and amphiphilic
cations. Because compounds that act on G proteins may be endowed with new forms of selectivity, we propose that G protein
subunits may therefore be considered as potential drug targets.
Received 18 September 1998; received after revision 6 November 1998; accepted 11 November 1998 相似文献
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Telomeres and telomerase as targets for cancer therapy 总被引:3,自引:0,他引:3
Telomeres are protective structures located at the ends of all eukaryotic chromosomes. Telomere shortening upon cell division
restricts the proliferative capacity of most normal human cells due to the lack of telomerase, an enzyme synthesizing telomeric
DNA de novo. Since most tumor cells are reliant on the activity of telomerase to maintain the stability of predominantly short individual
telomeres, inhibition of this enzyme presents an attractive approach for a mechanism-based anticancer therapy. Here, we review
advances and obstacles in targeting telomerase and telomeres and discuss potential applications of such approaches for the
clinic.
Received 9 November 2006; received after revision 8 December 2006; accepted 17 January 2007 相似文献
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From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing 总被引:6,自引:1,他引:5
Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed. 相似文献
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The type I copper center in multicopper oxidases is constructed from 1Cys2His and weakly coordinating 1Met or the non-coordinating 1Phe/1Leu, and it exhibits spectral properties and an alkaline transition similar to those of the blue copper center in blue copper proteins. Since the type I copper center in multicopper oxidases is deeply buried inside the protein molecule, electron transfers to and from type I copper are performed through specific pathways: the hydrogen bond between an amino acid located at the substrate binding site and a His residue coordinating type I copper, and the His-Cys-His sequence connecting the type I copper center and the trinuclear copper center comprised of a type II copper and a pair of type III coppers. The intramolecular electron transfer rates can be tuned by mutating the fourth ligand of type I copper. Further, mutation at the Cys ligand gives a vacant type I copper center and traps the reaction intermediate during the four-electron reduction of dioxygen. 相似文献
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D.B. Moody 《Cellular and molecular life sciences : CMLS》2001,58(10):1461-1474
T cells are well known to recognize peptide antigens presented by major histocompatibility (MHC) class I or class II molecules. More recently, the CD1 family of antigen-presenting molecules has been shown to present both mammalian and microbial glycolipid antigens for specific recognition by T cells. Human CD1c proteins mediate T cell recognition of polyisoprenyl glycolipids, evolutionarily conserved phosphoglycolipids, which function in glycan synthesis pathways. This family of antigenic molecules is particularly attractive for the study of the molecular features that control T cell recognition of self and foreign glycolipids because natural polyisoprenols from mammals, fungi, protozoa, mycobacteria and eubacteria differ in structure. Moreover, these naturally occurring structural differences can influence their recognition by CD1c-restricted T cells. This review of the structural diversity and evolutionary relationships of polyisoprenoid glycolipids emphasizes those features of polyisoprenyl glycolipid biosynthesis that are relevant to their functions as targets of CD1-mediated T cell responses. Received 16 March 2001; received after revision 19 April 2001; accepted 23 April 2001 相似文献
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Alina Sesarman Gestur Vidarsson Cassian Sitaru 《Cellular and molecular life sciences : CMLS》2010,67(15):2533-2550
Therapy approaches based on lowering levels of pathogenic autoantibodies represent rational, effective, and safe treatment
modalities of autoimmune diseases. The neonatal Fc receptor (FcRn) is a major factor regulating the serum levels of IgG antibodies.
While FcRn-mediated half-life extension is beneficial for IgG antibody responses against pathogens, it also prolongs the serum
half-life of IgG autoantibodies and thus promotes tissue damage in autoimmune diseases. In the present review article, we
examine current evidence on the relevance of FcRn in maintaining high autoantibody levels and discuss FcRn-targeted therapeutic
approaches. Further investigation of the FcRn-IgG interaction will not only provide mechanistic insights into the receptor
function, but should also greatly facilitate the design of therapeutics combining optimal pharmacokinetic properties with
the appropriate antibody effector functions in autoimmune diseases. 相似文献