Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three fractions of rat adenosine-3',5'-monophosphate-dependent protein kinase were isolated, partially purified in buffer concentration gradient at normal state and after long-term physical loading and studied. It is found that first two fractions of protein kinases at normal state and after intensive muscular work have similar activities with and without cAMP, apparent Km values for ATP and total histone and half-maximal stimulation by cyclic AMP, but they differed from the third fraction. There are differences in some kinetic parameters and in the cyclic AMP stimulated activities between protein kinases after physical loading. The data obtained suggest the existence of at least two kinases in rat skeletal muscle. The isoenzymes differ in their activities during fatigue.
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PMID:[Several properties of 3':5'-AMP-dependent skeletal muscle protein kinases in normal rats and following physical exertion to fatigue]. 21 65

We have investigated the effect of systemic treatment with drugs that affect the cAMP cascade on the sensory response and sensory fatigue in an identified mechanosensory neuron of Drosophila. Forskolin, an activator of adenylate cyclase, decreases the sensory response of the neuron. H7, an inhibitor of protein kinase, inhibits sensory fatigue. Octopaminergic ligands facilitate sensory fatigue. These results, together with our previous neurogenetic analysis of sensory fatigue in Drosophila (Corfas and Dudai 1990), corroborate the hypothesis that the cAMP cascade is involved in the generation and modulation of sensory fatigue.
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PMID:Pharmacological evidence for the involvement of the cAMP cascade in sensory fatigue in Drosophila. 217 30

The present work aimed to determine the role played by protein kinase-C (PKC) in the alpha 1-adrenoceptor-induced activation of hepatic metabolism. The following observations indicate that activation of PKC is a condition necessary for alpha 1-adrenoceptor activation of hepatic functions, but not sufficient to mimic the receptor-mediated effects in the absence of external physiological stimuli. 1) alpha 1-Adrenoceptor activation promoted the translocation of PKC from the cytosol to its active form in the plasma membrane. 2) Activation of PKC by the phorbol ester 12-myristate 13-acetate or exogenous diacylglycerols or by elevation of endogenous levels of diacylglycerols by inhibiting diacylglycerol kinase mimicked the alpha 1-adrenoceptor-mediated actions. However, the time course and magnitude of the nonreceptor responses differ from those mediated by alpha 1-adrenoceptor activation. In addition, nonreceptor-mediated activation of PKC decreased the alpha 1-adrenoceptor responsiveness. 3) Inhibition of PKC by either H-7 [1-(5-isoquinolinilsulfonyl)2-methylpiperazine] or staurosporine inhibited all of the alpha 1-adrenoceptor-induced responses, except gluconeogenesis. The vasopressin effects were not inhibited by H-7, indicating that PKC activation is a distinct feature of the hepatic alpha 1-adrenoceptor activation that is not shared by all the Ca(2+)-mobilizing agonists. The diacylglycerol-PKC branch of the alpha 1-adrenoceptor signaling pathway seems to control the sustained phase of stimulation of hepatic functions. In these studies we have also observed that phorbol 12-myristate 13-acetate produces a concentration-dependent inhibition of hepatic respiration. However, decreased energy availability does not seem to be the cause of its action to decrease alpha 1-adrenoceptor responsiveness.
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PMID:Role of protein kinase-C in the alpha 1-adrenoceptor-mediated responses of perfused rat liver. 840 60

Six subjects performed isometric contraction (66% maximal force) to fatigue with the knee extensor muscles. Biopsies were taken from the quadriceps femoris muscle at rest, at fatigue and 1 min after termination of contraction. In three of the subjects recovery from contraction occurred in the presence of an intact circulation (non-occluded, NON) to the thigh, whereas in the other three the circulation during recovery was occluded (OCC). Glycogen synthase fractional activity (GSF) decreased in all subjects from (mean +/- SE) 0.53 +/- 0.06 at rest to 0.37 +/- 0.04 at fatigue (P < 0.001). In the OCC group GSF returned to the pre-exercise value within 1 min after termination of contraction (0.59 +/- 0.07 at rest vs. 0.57 +/- 0.04 at 1 min post-exercise), whereas in the NON group GSF increased to a higher extent (0.48 +/- 0.09 at rest vs. 0.70 +/- 0.06 at 1 min post-exercise). The increase in GSF during the 1-min recovery was almost three-fold higher in the NON group (0.15 +/- 0.02 vs. 0.38 +/- 0.03). Cyclic AMP-dependent protein kinase (cAMP-PK) (assayed at 0/100 microM and 0.2/100 microM cAMP) did not change at fatigue or during recovery in either group. Glycogen synthase phosphatase (GSP) increased at fatigue by approximately 30% (P < 0.05 vs. rest). It is concluded that isometric contraction mediated inactivation of GS (i.e. phosphorylation of GS) is due to activation of a protein kinase(s) but not cAMP-PK. The rapid activation of GS in the NON group demonstrates that a humoral factor(s), possibly insulin and/or oxygen, is responsible for this phenomenon.
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PMID:Regulation of glycogen synthase in human muscle during isometric contraction and recovery. 845 44

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
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PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

The rapid activation of glycogen synthase in human skeletal muscle during recovery from isometric contraction is dependent on an intact circulation, which suggests the requirement of an activating humoral factor. To determine whether the activating factor is insulin, muscle biopsies were obtained from subjects at rest, at fatigue, 3 min postexercise with an intact circulation, and 3 min postexercise during which circulation to the muscle was occluded. Two inositol phosphoglycan mediators of insulin action were isolated from the biopsies, and bioactivity was measured by determining the effects of the isolated mediators on the activities of purified cyclic AMP-dependent protein kinase, pyruvate dehydrogenase phosphatase and glycogen synthase phosphatase in vitro. Bioactivity was not altered by any condition compared with rest. These data suggest that changes in inositol phosphoglycans are not responsible for the circulation-dependent activation of glycogen synthase during recovery from exercise.
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PMID:No change in insulin mediators in human skeletal muscle during isometric contraction or recovery. 893 13

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-gamma (PLC-gamma) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-gamma. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-gamma, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.
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PMID:Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. 1049 6

Although protein kinases are known to play a role in modulating a variety of intracellular functions, the direct effect of inhibition of these enzymes on skeletal muscle force production has not been studied. The purpose of the present study was to examine this issue by determining the effects produced on diaphragm force generation by two protein kinase inhibitors: (a) H7, an inhibitor of both cAMP-dependent protein kinase (PKA) and of protein kinase C, and (b) H89, a selective inhibitor of PKA. Experiments (n=15) were performed using isolated, arterially perfused, electrically stimulated rat diaphragms. Perfusate temperature was adjusted to maintain muscle temperature at 27 degrees C and arterial pressure was kept at 150 Torr. Animals were divided into three groups: (a) a control group perfused with Krebs-Henselheit solution equilibrated with 95% O(2)/5% CO(2), (b) a group in which H7 (2 microM) was added to the perfusate, and (c) a group perfused with solution containing H89 (4 microM). In all three groups, we assessed diaphragm twitch kinetics, force-frequency relationships and in vitro fatiguability. We found that both H7 and H89 administration slowed twitch relaxation, augmented force generation in response to low frequency stimulation, and increased the rate of development of fatigue. Specifically, for control, H7 and H89 groups, respectively, we found: (a) 1/2 relaxation time averaged 64+/-2 S.E.M., 87+/-6 and 90+/-2 ms, P<0. 003, (b) force production during 10-Hz stimulation averaged 12.6+/-1. 1, 20.1+/-2.3, and 20.3+/-2.1 N/cm(2), P<0.035, and (c) force fell to 14.3+/-2.0, 9.5+/-0.5 and 8.7+/-0.2% of its initial value after 20 min of fatiguing stimulation, P<0.035. These data show that it is possible to produce large increases in low frequency skeletal muscle force generation by directly inhibiting PKA. We speculate that it may be possible to pharmacologically augment respiratory muscle force and pressure generation in clinical medicine by administration of PKA inhibitors.
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PMID:Effects of protein kinase A inhibition on rat diaphragm force generation. 1077 42

GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors. Fourteen patients (13 evaluable for safety) received escalating doses of GEM231 at 20-360 mg/m2 (2.5-9 mg/kg). Tumor histologies included non-small cell lung cancer, renal cell cancer, sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13 microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II fever and fatigue at doses > or = 240 mg/m2. There was no treatment-related complement activation or thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses > or =160 mg/m2. Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative reversible transaminase elevation (three of three patients at 360 mg/m2 and three of six patients at 240 mg/m2 during weeks 3-10). One patient with colon cancer had stabilization of a previously rising carcinoembryonic antigen. Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested.
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PMID:A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors. 1077 49

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.
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PMID:The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. 1112 11


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