Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the orientation of the myosin regulatory light chain (RLC) in single muscle fibres were measured using polarised fluorescence from acetamidotetramethylrhodamine (ATR). Mutants of chicken skeletal RLC containing single cysteine residues at positions 2, 73, 94, 126 and 155 were labelled with either the 5 or 6-isomer of iodo-ATR, giving ten different probes. The labelled RLCs were exchanged into demembranated fibres from rabbit psoas muscle without significant effect on active force generation. Fluorescence polarisation measurements showed that nine out of the ten probe dipoles were more perpendicular to the fibre axis in the absence of ATP (in rigor) than in either relaxation or active contraction. The orientational distribution of the RLC region of the myosin head in active contraction is closer to the relaxed than to the rigor orientation, and is not equivalent to a linear combination of the relaxed and rigor orientations. Rapid length steps were applied to the fibres to synchronise the motions of myosin heads attached to actin. In active contraction the fluorescence polarisation changed both during the step, indicating elastic distortion of the RLC region of the myosin head, and during the subsequent rapid force recovery that is thought to signal the working stroke. The peak change in fluorescence polarisation produced by an active release of 5 nm per half sarcomere indicates an axial tilt of less than 5 degrees for all ten probes, if all the myosin heads in the fibre respond to the length step. This tilting was towards the rigor orientation for all ten probes, and could be explained by 14% of the heads moving to the rigor orientation. An active stretch tilted the heads away from the rigor conformation by a similar extent.
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PMID:Orientation changes of fluorescent probes at five sites on the myosin regulatory light chain during contraction of single skeletal muscle fibres. 964 45

The anticoagulant transmembrane glycoprotein thrombomodulin (TM) is expressed at the luminal surface of vascular endothelial cells. Recently, we showed that TM antigen and TM mRNA are expressed in brain microvessels in several species and that brain capillaries have the capability to activate protein C. The activation of protein C in brain microcirculation was greatly impaired by major stroke risk factors in rats due to downregulation of TM. In this study, a partial sequence of TM was determined from TM mRNA from brain capillaries examined in brain capillaries of the rat, a species that provides a useful model to investigate stroke mechanisms in relation to brain hemostasis. The predicted deduced amino acid sequences for rat TM were compared with other TM sequences. Particularly high homology (77-100%) among functional domains of the protein, i.e., the epidermal growth factor repeats (EGFRs) 1-6 and the transmembrane region, was observed between mice and rats. Somewhat less degree of homology was observed for bovine and human EGFRs 1-6, while the homology of the transmembrane region was 92-96%. All cysteine residues were conserved among the TM sequences, and specific amino acids previously suggested to be essential for activation of protein C by thrombin TM were highly conserved. We conclude that the highly conserved mRNA and protein sequences may reflect a similar anticoagulant role of TM in brain endothelial and systemic vascular endothelial cells across different species.
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PMID:Rat brain capillary thrombomodulin: structure and function. 985 12

The gaseous signal molecule, nitric oxide (NO*), is generated enzymatically by NO synthase (NOS) from L-arginine. Overproduction of NO contributes to cell and tissue damage as sequelae of infection and stroke. Strategies to suppress NO synthesis rely heavily on guanidino-substituted L-arginine analogs (L-NAME, L-NA, L-NMMA, L-NIO) as competitive inhibitors of NOS, which are often used in high doses to compete with millimolar concentrations of intracellular arginine. We show that these analogs are also a source for non-enzymatically produced NO. Enzyme-independent NO release occurs in the presence of NADPH, glutathione, L-cysteine, dithiothreitol and ascorbate. This non-enzymatic synthesis of NO can produce potentially toxic, micromolar concentrations of NO and can oppose the effects of NOS inhibition. NO production driven by NOS inhibitors was demonstrated ex vivo in the central nervous and peripheral tissues of gastropod molluscs Aplysia and Pleurobranchaea using electron paramagnetic resonance and spin-trapping techniques. These results have important implications for therapeutic regulation of NO homeostasis.
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PMID:Non-enzymatic production of nitric oxide (NO) from NO synthase inhibitors. 991 69

This overviews recent understanding of the mechanisms of apoptosis on ischemia-induced neuronal cell death. Apoptosis is a prominent feature of the developing nervous system. Several lines of evidence suggest that apoptosis is also an important mechanism of cell death in adult brain in acute or chronic diseases such as stroke and Alzheimer's disease. In animal models of stroke, markers of apoptosis such as cytoplasmic and nuclear condensation and DNA fragmentation appear in neurons. A variety of physiological and pathological stimuli can activate signal-transduction pathways that result in the sequential proteolytic activation of caspase family members. The activation of caspases can be inhibited by several molecules, including peptide aldehydes (caspase-1 and or caspase-3 inhibitors) and crmA that target the active-site cysteine of caspase family members, Bcl-2, IAP (inhibitor of apoptosis protein) and NAIP (neuronal apoptosis inhibitory protein). Once activated, caspase-1 protease can activate the caspase family members and hydrolyze a discrete set of cellular targets. Poly (ADP-ribose)polymerase (PARP), which appears to facilitate apoptosis, was recognized as a substrate of activated caspase-3. These results suggest that caspase family, bcl-2 family, IAP family and substrates such PARP contribute to mechanisms of cell death in ischemic brain injury. Inhibition of the caspase family, particularly by non-peptide inhibitors that cross the blood-brain barrier and easily penetrate neurons and glia, could provide novel treatments for stroke and other forms of brain and spinal cord injury in humans.
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PMID:[Involvement of caspase on apoptosis in ischemia-induced neuronal cell death: usefulness of caspase inhibitors for stroke therapy]. 1020 84

In recent years, numerous clinical trials were undertaken in order to elucidate the active principle of garlic (Allium sativum L., Alliaceae). The most prominent effect of garlic preparations is a contribution to the prevention of stroke and arteriosclerosis. Allicin[(2-propenyl)-2-propenethiosulfinate] and other sulfur containing compounds were suggested as active compounds. The extremely unstable allicin itself is liberated from the more stable alliin [S-(+)-2-propenyl-L-cysteine sulfoxide] by the enzyme alliinase (EC 4.4.1.4) if fresh garlic is crunched or garlic powder is moistened. Therefore, an active enzyme is required in alliin containing remedies like those prepared from garlic powder. In order to investigate enzyme stability, alliinase was isolated from garlic powder. The partially purified enzyme could be stabilized over several months by addition of sodium chloride, sucrose, and pyridoxal-5'-phosphate. Alliinase may also be freeze-dried. This allows combinations of synthetic alliin and purified alliinase as components of an acid resistant tablet or capsule. In the intestine, the pro-drug alliin would be enzymatically converted to allicin. In clinical trials, highly dosed preparations of this kind should yield a precise information about the physiological effects of allicin. In addition, alliin-homologues substances which bear a modified alkyl side chain and do not occur in nature may be tested.
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PMID:Stabilization and pharmaceutical use of alliinase. 1023 40

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) begins with migraine with aura in approximately one-third of the patients. More severe symptoms of recurrent strokes usually appear at 30-50 years of age. However, well before the first stroke, CADASIL may be diagnosed on the basis of characteristic hyperintensities in T2-weighted magnetic resonance images. Multiple lacunar infarcts located mainly in the basal ganglia and frontal white matter lead to a cognitive decline and finally to dementia. These infarcts result from a thickening and fibrosis of the walls of the small and medium-sized penetrating arteries with consequent obliteration and/or thrombosis. Although the symptoms are almost exclusively neurological, the arteriopathy is generalized. Thus, basophilic, periodic acid-Schiff-positive and, in electron microscopy, osmiophilic material accumulates between degenerating smooth muscle cells. This occurs even in dermal arteries, which renders skin a useful target for diagnostic biopsy. Presently, no specific therapy is available. CADASIL is caused by missense point mutations in the Notch3 gene, which encodes a transmembrane receptor protein. Each gene defect leads to either a gain or loss of a cysteine residue in the extracellular, N-terminal domain of the molecule, which most probably results in conformational alteration. The function of Notch3 in adults and the pathogenesis of CADASIL are still unknown.
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PMID:CADASIL: hereditary disease of arteries causing brain infarcts and dementia. 1047 42

Homocysteine (HC) at concentrations of from 0.05 to 1.0 mM caused dose-dependent loss of [Mg2+]i in cultured cerebral vascular smooth muscle cells (VSMC), whereas cysteine and methionine (its metabolic products) failed to interfere with changes in [Mg2+]i. HC, methionine and cysteine did not produce any changes in [Ca2+]i. Lowering [Mg2+]o to 0.3 mM resulted in elevation of [Ca2+]i and loss of [Mg2+]i. Depletion of [Mg2+]i, induced by HC, was potentiated by low Mg2+. Preincubation of these cells with vitamin B6, vitamin B12, folic acid, alone, did not alter [Ca2+]i or [Mg2+]i. Likewise, concomitant addition of vitamin B6, vitamin B12, or folic acid, together with HC (1 mM) did not change the reduction in [Mg2+]i induced by HC. However, concomitant addition of HC and the three vitamins inhibited completely the loss of [Mg2+]i. Exposure of these cells to each vitamin, alone, or combination of the three vitamins failed to interfere with reduction in [Mg2+]i induced by low [Mg2+]i, but it did suppress the rise in [Ca2+]i. Interestingly, in the presence of low [Mg2+]o, the vitamin combination did not retard depletion of [Mg2+]i. The present findings are compatible with the hypothesis that an increased serum HC concentration causes abnormal metabolism of Mg2+ in cerebral VSMC, thus priming these cells for HC-induced atherogenesis, cerebral vasospasm and stroke. Our results suggest the need for the three B-vitamins, together with normal physiological levels of Mg2+, in order to prevent [Mg2+]i depletion and occlusive cerebral vascular diseases induced by homocysteinemia.
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PMID:Extracellular magnesium regulates effects of vitamin B6, B12 and folate on homocysteinemia-induced depletion of intracellular free magnesium ions in canine cerebral vascular smooth muscle cells: possible relationship to [Ca2+]i, atherogenesis and stroke. 1055 43

Active cellular suicide by apoptosis plays important roles in animal development, tissue homeostasis and a wide variety of diseases, including cancer, AIDS, stroke and many neurodegenerative disorders. A central step in the execution of apoptosis is the activation of an unusual class of cysteine proteases, termed caspases, that are widely expressed as inactive zymogens. Originally, the mechanisms for regulating the caspase-based cell death programme seemed to be different in Caenorhabditis elegans, mammals and insects. However, recent results suggest that these apparent differences in the control of cell death reflect our incomplete knowledge, rather than genuine mechanistic differences between different organisms.
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PMID:Death by design: mechanism and control of apoptosis. 1061 82

Caspase-9 is a member of caspase family of cysteine proteases that have been implicated in apoptosis and cytokine processing. When cells receive apoptotic stimuli, mitochondria releases cytochrome c which then binds to Apaf-1, the mammalian Ced-4 homologue, together with dATP. The resultant complex recruits Caspase-9 leading to its activation. Activated Caspase-9 cleaves downstream caspases such as Caspase-3, -6 and -7 initiating the caspase cascade. The majority of homozygous Caspase-9 null mice die perinatally with a markedly enlarged and malformed cerebrum caused by a reduction of apoptosis during early brain development. Thus, Caspase-9 function is essential for apoptosis during normal development of the central nervous system. These data suggest that inhibition of Caspase-9 activity would render opportunity to treat patients suffering from neurological diseases such as stroke, neurodegenerative diseases or brain injury caused by hypoxia.
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PMID:Caspase-9. 1068 48

Mutations in Notch3 cause CADASIL (cerebral autosomal dominant adult onset arteriopathy), which leads to stroke and dementia in humans. CADASIL arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits. Patients carry highly stereotyped mutations that lead to an odd number of cysteine residues within EGF-like repeats of the Notch3 receptor extracellular domain. Such mutations may alter the processing or the trafficking of this receptor, or may favor its oligomerization. In this study, we examined the Notch3 expression pattern in normal tissues and investigated the consequences of mutations on Notch3 expression in transfected cells and CADASIL brains. In normal tissues, Notch3 expression is restricted to vascular smooth muscle cells. Notch3 undergoes a proteolytic cleavage leading to a 210-kDa extracellular fragment and a 97-kDa intracellular fragment. In CADASIL brains, we found evidence of a dramatic and selective accumulation of the 210-kDa Notch3 cleavage product. Notch3 accumulates at the cytoplasmic membrane of vascular smooth muscle cells, in close vicinity to but not within the granular osmiophilic material. These results strongly suggest that CADASIL mutations specifically impair the clearance of the Notch3 ectodomain, but not the cytosolic domain, from the cell surface.
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PMID:The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. 1071 25


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