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A review of the literature suggests that the effects of nitric oxide (NO) on skeletal muscles fibers can be classified in
two groups. In the first, the effects of NO are direct, due to nitrosation or metal nitrosylation of target proteins: depression
of isometric force, shortening velocity of loaded or unloaded contractions, glycolysis and mitochondrial respiration. The
effect on calcium release channels varies, being inhibitory at low and stimulatory at high NO concentrations. The general
consequence of the direct effects of NO is to ‘brake’ the contraction and its associated metabolism. In the second group,
the effects of NO are mediated by cGMP: increase of the shortening velocity of loaded or unloaded contractions, maximal mechanical
power, initial rate of force development, frequency of tetanic fusion, glucose uptake, glycolysis and mitochondrial respiration;
decreases of half relaxation time of tetanus and twitch, twitch time-to-peak, force maintained during unfused tetanus and
of stimulus-associated calcium release. There is negligible effect on maximal force of isometric twitch and tetanus. The general
consequence of cGMP-mediated effects of NO is to improve mechanical and metabolic muscle power, similar to a transformation
of slow-twitch to fast-twitch muscle, an effect that we may summarize as a ‘slow-to-fast’ shift. 相似文献
4.
Endothelium-derived nitric oxide and vascular physiology and pathology 总被引:13,自引:0,他引:13
J.-F. Arnal A.-T. Dinh-Xuan M. Pueyo B. Darblade J. Rami 《Cellular and molecular life sciences : CMLS》1999,55(8-9):1078-1087
In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine
is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later
as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by
one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively,
the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its
activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine,
thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca2+. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise
mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal
caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory
role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be
responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be
promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty
streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally,
a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS
enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology
of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis. 相似文献
5.
Molecular basis of autosomal-dominant polycystic kidney disease 总被引:5,自引:0,他引:5
Gallagher AR Hidaka S Gretz N Witzgall R 《Cellular and molecular life sciences : CMLS》2002,59(4):682-693
Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery
that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1
and polycystin-2, the proteins encoded by these two genes. While polycystin-1 may mediate the contact among cells or between
cells and the extracellular matrix, a lot of evidence suggests that polycystin-2 represents an endoplasmic reticulum-bound
cation channel. Cyst development has been compared to the growth of benign tumors and this view is highlighted by the model
that a somatic mutation in addition to the germline mutation is responsible for cystogenesis (two-hit model of cyst formation).
Since in vitro polycystin-1 and polycystin-2 interact through their COOH termini, the two proteins possibly act in a common
pathway, which controls the width of renal tubules. The loss of one protein may lead to a disruption of this pathway and to
the uncontrolled expansion of tubules. Our increasing knowledge of the molecular events in ADPKD has also started to be useful
in designing novel diagnostic and therapeutic strategies.
Received 12 September 2001; received after revision 7 November 2001; accepted 7 November 2001 相似文献
6.
Negative regulators of cytokine signal transduction 总被引:20,自引:0,他引:20
D. J. Hilton 《Cellular and molecular life sciences : CMLS》1999,55(12):1568-1577
7.
Arginase expression in peritoneal macrophages and increase in circulating polyamine levels in mice infected with Schistosoma mansoni 总被引:5,自引:0,他引:5
Abdallahi OM Bensalem H Augier R Diagana M De Reggi M Gharib B 《Cellular and molecular life sciences : CMLS》2001,58(9):1350-1357
We investigated the nitric oxide (NO) synthase and arginase pathways in resident peritoneal macrophages of mice infected
with the tropical parasite Schistosoma mansoni. The two enzymes may have opposite effects, insofar as NO may be involved in the killing of the parasite whereas arginase
may stimulate parasite growth via polyamine synthesis. We determined the effects of the infection on the expression and activity
of the two enzymes in macrophages, before and after cytokine activation. Cells from infected mice expressed the hepatic type
I arginase, whereas in control cells, the enzyme was expressed only after cytokine activation, as were NO synthase II and
type II arginase in both groups of cells. Moreover, we found that in infected mice, arginase expression in macrophages was
associated with a ten fold increase in the concentration of circulating ornithine-derived polyamines. This may be of pathological
importance, since parasitic helminths are though to be dependent on their hosts for the uptake and interconversion of polyamines.
Received 13 March 2001; received after revision 4 May 2001; accepted 7 June 2001 相似文献
8.
F. E. Weber J. H. Dyer F. López García M. Werder T. Szyperski K. Wüthrich H. Hauser 《Cellular and molecular life sciences : CMLS》1998,54(7):751-759
The preform of the rabbit sterol carrier protein 2 (pre-rSCP2) was cloned, the uniformly 15N-labelled protein expressed in Escherichia coli and studied by three-dimensional 15N-resolved nuclear magnetic resonance spectroscopy. In spite of its low solubility in aqueous solution of only ∼0.3 mM, sequential
15N and 1H backbone resonance assignments were obtained for 105 out of the 143 residues. From comparison of the sequential and medium-range
nuclear Overhauser effects (NOEs) in the two proteins, all regular secondary structures previously determined in mature human
SCP2 (hSCP2) [Szyperski et al. (1993) FEBS Lett. 335: 18–26] were also identified in pre-rSCP2. Near-identity of the backbone 15N and 1H chemical shifts and 1 : 1 correspondence of 24 long-range NOEs to backbone amide groups in the two proteins show that the
residues 21 – 143 adopt the same globular fold in pre-rSCP2 and mature hSCP2. The N-terminal 20-residue leader peptide of pre-rSCP2 is flexibly disordered in solution and does not observably affect the conformation of the polypeptide segment 21 – 143.
Received 11 May 1998; accepted 15 May 1998 相似文献
9.
Morphine 6 glucuronide stimulates nitric oxide release in mussel neural tissues: evidence for a morphine 6 glucuronide opiate receptor subtype 总被引:1,自引:0,他引:1
Mantione K Zhu W Rialas C Casares F Cadet P Franklin AL Tonnesen J Stefano GB 《Cellular and molecular life sciences : CMLS》2002,59(3):570-574
We have previously demonstrated that Mytilus edulis pedal ganglia contain opiate alkaloids, i.e., morphine and morphine 6 glucuronide (M6G), as well as mu opiate receptor subtype
fragments exhibiting high sequence similarity to those found in mammals. Now we demonstrate that M6G stimulates pedal ganglia
constitutive nitric oxide (NO) synthase (cNOS)-derived NO release at identical concentrations and to similar peak levels as
morphine. However, the classic opiate antagonist, naloxone, only blocked the ability of morphine to stimulate cNOS-derived
NO release and not that of M6G. CTOP, a mu-specific antagonist, blocked the ability of M6G to induce cNOS-derived NO release
as well as that of morphine, suggesting that a novel mu opiate receptor was present and selective toward M6G. In examining
a receptor displacement analysis, both opiate alkaloids displaced [3H]-dihydromorphine binding to the mu opiate receptor subtype. However, morphine exhibited a twofold higher affinity, again
suggesting that a novel mu opiate receptor may be present.
Received 1 November 2001; received after revision 1 February 2002; accepted 1 February 2002 相似文献
10.
The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease 总被引:16,自引:0,他引:16
Nijtmans LG Artal SM Grivell LA Coates PJ 《Cellular and molecular life sciences : CMLS》2002,59(1):143-155
Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the
PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins,
Phb1p and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type
of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both
Phb1p and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them
against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence
homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence
proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with
the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation,
immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless,
because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes.
Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as
proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect
their true function more accurately.
Received 21 May 2001; received after revision 2 July 2001; accepted 24 July 2001 相似文献
11.
H. F. Rosenberg 《Cellular and molecular life sciences : CMLS》1998,54(8):795-803
The eosinophil ribonucleases, eosinophil-derived neurotoxin (EDN/RNase 2) and eosinophil cationic protein (ECP/RNase 3) are
two closely related proteins with intriguing functional and evolutionary properties. While both EDN and ECP maintain the structural
and catalytic residues typical of the RNase A superfamily, the role of ribonuclease activity in the physiologic function of
these proteins remains unclear. The biochemistry and physiology of EDN, ECP and the recently discovered ribonuclease k6 (RNase
6) will be reviewed in this chapter. 相似文献
12.
J. L. Boucher C. Moali J. P. Tenu 《Cellular and molecular life sciences : CMLS》1999,55(8-9):1015-1028
Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission,
control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine
to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and
an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated
by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between
the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and arginases for L-arginine utilization,
and by potent inhibition of arginase activity by Nω-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway. 相似文献
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The suppressors of cytokine signalling (SOCS) 总被引:10,自引:0,他引:10
14.
The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen 总被引:1,自引:1,他引:0
The life of aerobes is dependent on iron and oxygen for efficient bioenergetics. Due to potential risks associated with iron/oxygen
chemistry, iron acquisition, concentration, storage, utilization, and efflux are tightly regulated in the cell. A central
role in regulating iron/oxygen chemistry in animals is played by mRNA translation or turnover via the iron responsive element
(IRE)/iron regulatory protein (IRP) system. The IRE family is composed of three-dimensional RNA structures located in 3′ or
5′ untranslated regions of mRNA. To date, there are 11 different IRE mRNAs in the family, regulated through translation initiation
or mRNA stability. Iron or oxidant stimuli induce a set of graded responses related to mRNA-specific IRE substructures, indicated
by differential responses to iron in vivo and binding IRPs in vitro. Molecular effects of phosphorylation, iron and oxygen remain to be added to the structural information of the IRE-RNA and
IRP repressor in the regulatory complex.
Received 21 April 2007; received after revision 13 July 2007; accepted 2 August 2007 相似文献
15.
N. Miosge T. Sasaki M.-L. Chu R. Herken R. Timpl 《Cellular and molecular life sciences : CMLS》1998,54(6):606-613
The microfibrillar proteins fibulin-1 and fibulin-2 were previously identified as prominent components of the endocardial
cushion tissue (ECT) during heart development and shown to persist in adult valves and septa. Immunogold staining has now
been used to compare their localization in embryonic (days 9–11) and adult mouse heart with that of fibronectin and the chondroitin
sulphate proteoglycan versican. All four proteins were deposited in the ECT, which consists of a hyaluronan-rich, mainly unstructured
matrix, but were barely detectable in myocardial basement membranes or within endocardial cells. Digestion with hyaluronate
lyase selectively released the fibulins and versican but not fibronectin from the ECT. Yet neither of the two fibulins bound
to hyluronan in solid-phase assays, in contrast to versican. In the adult heart valve, all four proteins could be detected
close to cross-striated collagen fibrils or microfibrils, but only versican was lost upon exposure to hyaluronate lyase. The
data indicate that fibulins are associated with the hyaluronan-matrix of ECT through a bridge of versican, but that this association
changes upon valve development to another supramolecular, presumably microfibrillar organization based on fibronectin and/or
fibrillins.
Received 3 April 1998; accepted 8 April 1998 相似文献
16.
Generation of the serine proteinase plasmin from the extracellular zymogen plasminogen can be catalyzed by either of two
other serine proteinases, the urokinase- and tissue-type plasminogen activators (uPA and tPA). The plasminogen activation
system also includes the serpins PAI-1 and PAI-2, and the uPA receptor (uPAR). Many findings, gathered over several decades,
strongly suggest an important and causal role for uPA-catalyzed plasmin generation in cancer cell invasion through the extracellular
matrix. Recent evidence suggests that the uPA system is also involved in cancer cell-directed tissue remodeling. Moreover,
the system also supports cell migration and invasion by plasmin-independent mechanisms, including multiple interactions between
uPA, uPAR, PAI-1, extracellular matrix proteins, integrins, endocytosis receptors, and growth factors. These interactions
seem to allow temporal and spatial reorganizations of the system during cell migration and a selective degradation of extracellular
matrix proteins during invasion. The increased knowledge about the plasminogen activation system may allow utilization of
its components as targets for anti-invasive therapy. 相似文献
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18.
H.-O. Ito T. Ueda Y. Hashimoto T. Imoto T. Koga 《Cellular and molecular life sciences : CMLS》1997,53(1):51-60
We previously generated a monoclonal antibody (mAb) against a putative pathogenic epitope on native type II collagen (CII)
for the induction of collagen-induced arthritis in mice (mAb1), and an anti-idiotypic mAb which appears to possess the internal
image of the CII epitope (mAb2). In the present study, the structural basis of the antigen/mAb1 and mAb1/mAb2 interactions
was examined. When partially SH-reduced mAb1 was analysed on Western blots, only fragments containing both heavy (H) and light
(L) chains were recognized by mAb2. When mAb2 was partially SH-reduced, only fragments containing both H and L chains were
recognized by mAb1. H and L chains were separated from mAb1 in a reduced, denatured condition, and each chain and a mixture
of the two were refolded. mAb2 reacted specifically to the renatured whole IgG molecule of mAb1, but not to the refolded L
or to H chains. Recombinant single chain Fv (scFv) generated from mAb1 and mAb2 had properties of the original mAbs, whereas
genetical
ly constructed chimeric scFvs, consisting of VH from mAb1 and an irrelevant VL , or VL of mAb1 and an irrelevant VH , did not react either to CII or to mAb2. Thus, interactions among CII, mAb1 and mAb2 appear to depend on quaternary structures
containing different protein subunits. These observations support the internal image property of the mAb2. In addition, this
dependency on quaternary structure for recognition of proteins may also be relevant to other protein-protein interactions.
Received 29 July 1996; received after revision 13 September 1996; accepted 18 October 1996 相似文献
19.
Jean-Luc Dreyer 《Cellular and molecular life sciences : CMLS》1982,38(5):521-529
Summary Iron-sulfur clusters in proteins are now recognized as among the main types of electron-transferring groups in biological
systems, besides heme and flavins. Recent developments have brought forth a better understanding about the ways the protein
environment modulates the potential of the cluster by placing the cluster in a more or less hydrophobic surrounding. Refinement
in models, extensive studies on the kinetics of electron transfer (e.g. by measurement of the electronic spin lattice relaxation
time) and the introduction of novel spectroscopic methods (EXAFS, magnetic CD and others) in the elucidation of structures
in various systems are among the main developments. Other advances include EPR studies of the spatial orientation of Fe−S
centers in complex membraneous systems (e.g. in mitochondria) and the recent elucidation of the nature of center X in photosystem
I by M?ssbauer-spectroscopy. M?ssbauer studies have also been described on a number of Fe−S proteins (nitrogenase, aconitase,
some ferredoxins, etc.) and revealed the existence of novel structures that enlarged the number of known basic units of Fe−S
centers. These advances include: 1. the discovery of a novel non-heme Fe-protein (called desulforedoxin) of the rebredoxin
type, 2. the elucidation of the nitrogenase Fe−S centers and the nitrogenase cofactor and 3. the discovery of a three-iron
cluster in several enzymes and some ferredoxins. The latter 3-Fe cluster seems capable of being converted into a classical
4-Fe cluster under appropriate conditions, a phenomenon that plays a role in activation-deactivation of some enzymes (e.g.
aconitase). It is now recognized that some iron-sulfur clusters may be involved in systems devoided of any oxydation-reduction
reaction and may act as sensors of the surrounding redox potential, triggering the activation/deactivation of an enzyme (cf.
e.g. aconitase). 相似文献
20.
B. Thébaud J.-F. Arnal J. C. Mercier A.-T. Dinh-Xuan 《Cellular and molecular life sciences : CMLS》1999,55(8-9):1103-1112
Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The
rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated
lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood
flow is increased. Inhaled NO has been succesfully applied to treat persistent pulmonary hypertension of the newborn, reducing
the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound
hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to
be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary
vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient
improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established.
NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory
tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased
in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased
in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation
of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous
NO. 相似文献