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)

The shock syndrome has been classically considered as a consequence of both decreased tissue perfusion and O2 supply; however, in some types of shock like septic or traumatic ones, regional blood flows may be increased. A decade ago, mitochondrial alterations consistent with uncoupling of oxidative phosphorylation were reported in either endotoxemic or hemorrhagic experimental shock or in humans. Recently, the discovery of nitric oxide (NO) and its increase in the shock state, has opened new perspectives in the understanding of this problem. Nitric oxide produces vasodilatation and, at the same time, increases the mitochondrial production of O2 active species like superoxide anion. Both radicals react to form a strong oxidant that is able to nitrate the phenolic rings of proteins: peroxynitrite. This effect leads to the impairment of the activities of different mitochondrial enzymes like succinate dehydrogenase and ATPase and the mitochondrial function and finally, to decreased energy levels and to multiorgan failure. The increase in NO release is due to the effects of circulating peptides and of increased adhesion of neutrophils to the endothelium and to the positive effects of inflammatory mediators like TNF-alpha and cytokines on inducible NOS (iNOS) expression in endothelium and tissues. It is suggested that the shock state is the consequence of an imbalance between NO and O2 and their metabolites.
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PMID:[Shock: concepts for a definition]. 981 94

Extraocular muscles (EOMs) are specialized skeletal muscles that are constantly active, generate low levels of force for cross sectional area, have rapid contractile speeds, and are highly fatigue resistant. The neuronal isoform of nitric oxide synthase (nNOS) is concentrated at the sarcolemma of fast-twitch muscles fibers, and nitric oxide (NO) modulates contractility. This study evaluated nNOS expression in EOM and the effect of NO modulation on lateral rectus muscle's contractility. nNOS activity was highest in EOM compared with diaphragm, extensor digitorum longus, and soleus. Neuronal NOS was concentrated to the sarcolemma of orbital and global singly innervated fibers, but not evident in the multi-innervated fibers. The NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor), increased submaximal tetanic and peak twitch forces. The NO donors S-nitroso-N-acetylcysteine (SNAC) and spermineNONOate reduced submaximal tetanic and peak twitch forces. The effect of NO on the contractile force of lateral rectus muscle is greater than previously observed on other skeletal muscle. NO appears more important in modulating contraction of EOM compared with other skeletal muscles, which could be important for the EOM's specialized role in generation of eye movements.
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PMID:Nitric oxide synthase expression and effects of nitric oxide modulation on contractility of rat extraocular muscle. 1148 Dec 24

The distribution of Fos-immunoreactive (Fos-ir) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-reactive neurons in the rat lumbar spinal cord was examined following muscle fatigue caused by intermittent high-rate (100 s(-1)) electrical stimulation of the triceps surae muscle or the ventral root L5 (VRL5) for 30 min. Following both types of stimulation, the fatigue-related c-fos gene expression was more extensive in the L2-L5 segments on the stimulated side, and the majority of Fos-ir neurons were concentrated in the dorsal horn. After direct muscle stimulation, the highest number of Fos-ir neurons were detected in two regions: layer 5, and superficial layers (1 and 2(o)), although many labeled cells were also found in layers 3, 4, 6, and 7. In response to VRL5 stimulation, the maximal density of Fos-ir neurons was detected in the middle and lateral parts of layers 1 and 2(o), the zone of termination of high-threshold muscle afferents(.) Statistically significant prevalence of Fos-ir cell number was also found in layers 5 and 7 on the stimulated side. A few Fos-ir neurons were detected in the ventral horn (layer 8 and area 10) on both sides. The lamellar distribution of NADPH-d-reactive neurons was similar over all experimental groups of animals. In the L3-L6 segments, such reactive cells were arranged in two distinct regions: dorsal horn (layers 2(i), 3, and 5) and area 10; in the L1 and L2 segments, an additional cluster of NADPH-d positive cells was found in the intermediolateral cell column (IML). Double-labeled cells were not detected. We suggest that c-fos expression in response to muscle fatigue reveals activity of functionally different types of spinal neurons which could operate together with NOS-containing cells in pre-motoneuronal networks to modulate the motoneuron output.
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PMID:c-fos Expression and NADPH-d reactivity in spinal neurons after fatiguing stimulation of hindlimb muscles in the rat. 1174 76

The influence of NO on the efficiency of oxygen usage by a skeletal muscle under fatigue of dog's gastrocnemius muscle was investigated. In control experiments was shown, that 10 short-term (30") electrical stimulation (8 Hz, 5 ms, 20 V) with 5" interval resulted in significant reduction of the muscle contraction force (more than 40%) and increased considerably oxygen cost of muscle gastrocnemius work (more than 130%) compared to the initial parameters. The registered depression of the muscle contraction force testified to development of gastrocnemius muscle fatigue, accompanied by mitochondrial factor (MF) appearance in blood from femoralis vein, which, as shown by us earlier, is a marker of the mPTP opening. Injection of L-NMMA, a NOS inhibitor (2.7 mg/kg, i.a.) resulted in pronounced fall (more than 1.5 times) of the initial force parameters, in comparison with the control experiments. Under these conditions the magnitude of oxygen cost of gastrocnemius muscle work exceeded control parameters considerably. The development of gastrocnemius muscle fatigue under L-NMMA action was accompanied, as well as in the control condition by the mPTP opening. The preliminary injection of sodium nitroprusside, a NO donor (0.2 mg/kg, i.v.) prevented a fall of muscle contractions force and considerable inhibition of oxygen usage efficiency by gastrocnemius muscle under conditions similar to control. Furthemore, gastrocnemius muscle fatigue was not developed, and MF concentration in blood from femoralis vein was much lower, than in the control experiments, that testified to absence of the mPTP opening. Apparently, preliminary short-term (30") electrical stimulation (8 Hz, 5 ms, 20 V) with 2' interval, created the precondition effect and raised the level of authentic NO. Under these conditions, as well as under preliminary injection of the NO donor, we did not register the marked inhibition of oxygen usage efficiency and development of gastrocnemius muscle fatigue. At the same time, MF in blood from v. femoralis was practically absent, that testify to absence of the mPTP opening. Thus, NO in physiological concentration by inhibition of mPTP opening, can prevent decrease of oxygen usage efficiency and development of the working skeletal muscle fatigue.
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PMID:[Effect of nitric oxide on the efficiency of oxygen consumption by the working skeletal muscle in fatigue]. 1580 Nov 98

Caffeine (Caf) is largely used to delay fatigue, improving physical activity. However, its role remains elusive, and there are no hemodynamic or immunohistochemical data regarding its effects on skeletal muscle. We studied the hemodynamic and NOS expression of Bax/Bcl2 in skeletal muscle after single Caf administration. Thirty-two male rats were divided into six groups: the first was iv-injected with Caf (16mg/kg), the second with Caf+L-NAME, the third with Caf+L-arg, the fourth with Caf+L-NAME+L-arg, fifth with saline. Mean arterial blood pressure (MAP) was monitored for 30', then the animals were killed. The sixth group was injected with Caf and killed after 2h. The quadriceps were isolated and processed by immunohistochemistry. We found that Caf increased MAP temporarily, while Caf+L-NAME increased it for a longer period. In untreated muscle, all NOS isoforms was expressed with different intensity and localisation, and Bcl2 was strongly expressed among the myofibrils. In Caf and Caf+L-NAME treated animals, NOS expression was lost; Bcl2 expression decreased among myofibrils but increased inside the subsarcolemma. The L-arg administration reversed these Caf and L-NAME effects. Two hours after Caf, NOS expression increased. We concluded that improved physical performance could be related to Caf's ability to interfere with the endogenous muscular synthesis of NO.
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PMID:Acute caffeine administration decreased NOS and Bcl2 expression in rat skeletal muscles. 1723 87

Caffeine is the most frequently ingested neuroactive drug in the world and it is largely used to delay fatigue and improve physical activity. Caffeine can modulate NO synthesis in cells and may influence muscular function by modifying the cellular cycle life-death. There is little data concerning the relationship between caffeine in the heart, NOS expression and apoptosis and no data regarding the acute effect of high doses of caffeine in the in vivo myocardium. We therefore studied hemodynamic NOS and Bax/Bcl2 expression in the rat myocardium after a single cafffeine administration. Thirty-two male rats were divided into six groups: the first was iv-injected with caffeine (16 mg/kg), the second with caffeine + L-NAME (30 mg/kg), the third with caffeine + L-arg (0.5 g/kg), the fourth with caffeine + L-NAME + L-arg and finally the fifth with saline. Mean arterial blood pressure (MAP) was monitored for 30 min, then the animals were killed. The sixth group was injected with caffeine and killed after 2 h. The hearts were isolated and processed by immunohistochemistry. We found that caffeine increased MAP temporarily while caffeine + L-NAME increased it for a longer period. In the control myocardium, all NOS isoforms were expressed. The Bcl2 were strongly expressed inside the perinuclear cytoplasm whereas Bax was very faintly detectable in the peripheral cytoplasm. In caffeine and caffeine + L-NAME treated animals, NOS expression disappeared. Bax and Bcl2 expression did not vary. The l-arg administration reversed these caffeine and L-NAME effects on NOS expression. Two hours after caffeine, NOS expression increased and Bax and Bcl2 expression did not vary, although Bcl2 was mainly expressed in the peripheral cytoplasm. We conclude that improved caffeine-induced physical performance could also be related to caffeine's ability to interfere with endogenous myocardial NO synthesis. Furthermore, we suggest that myocardial cell plays an effective anti-apoptotic role against acute caffeine administration.
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PMID:Effects of acute caffeine administration on NOS and Bax/Bcl2 expression in the myocardium of rat. 1808 18

NOS is a key enzyme in the production of NO, a molecule that directly regulates vasorelaxation and blood supply. Diverse forms of muscle disease have been clinically associated with unusual fatigue after exercise. The localization of neuronal NOS (nNOS) at the plasma membrane of muscle has recently been shown to prevent muscle fatigue after exercise. In this issue of the JCI, Lai et al. show that dystrophin--the structural protein missing in individuals with Duchenne muscular dystrophy--anchors nNOS to the sarcolemma through a direct interaction with dystrophin spectrin-like repeats 16 and 17 (see the related article, doi:10.1172/JCI36612). Furthermore, in another recently reported study of mouse models of muscular dystrophy, phosphodiesterase 5A inhibitors were used to treat the downstream ischemia that is associated with nNOS mislocalization. Collectively, these findings significantly advance our understanding of exercise-induced muscle fatigue and its role in muscle disease.
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PMID:NO more muscle fatigue. 1922 8

Signaling via the neuronal NOS (nNOS) splice variant nNOSmu is essential for skeletal muscle health and is commonly reduced in neuromuscular disease. nNOSmu is thought to be the predominant source of NO in skeletal muscle. Here we demonstrate the existence of what we believe to be a novel signaling pathway, mediated by the nNOS splice variant nNOSbeta, localized at the Golgi complex in mouse skeletal muscle cells. In contrast to muscles lacking nNOSmu alone, muscles missing both nNOSmu and nNOSbeta were severely myopathic, exhibiting structural defects in the microtubule cytoskeleton, Golgi complex, and mitochondria. Skeletal muscles lacking both nNOSmu and nNOSbeta were smaller in mass, intrinsically weak, highly susceptible to fatigue, and exhibited marked postexercise weakness. Our data indicate that nNOSbeta is a critical regulator of the structural and functional integrity of skeletal muscle and demonstrate the existence of 2 functionally distinct nNOS microdomains in skeletal muscle, created by the differential targeting of nNOSmu to the sarcolemma and nNOSbeta to the Golgi. We have previously shown that sarcolemmal nNOSmu matches the blood supply to the metabolic demands of active muscle. We now demonstrate that nNOSbeta simultaneously modulates the ability of skeletal muscle to maintain force production during and after exercise. We conclude therefore that nNOS splice variants are critical regulators of skeletal muscle exercise performance.
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PMID:Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle. 2012 30

A 47-year-old man was admitted to our hospital in June 2009 because of fatigue and blast cells in peripheral blood. Bone marrow examination showed that 67% leukemic cells were positive for myeloperoxidase (MPO) and negative for esterase stain. Flow cytometric analysis (FCM) revealed the expressions of CD2, cyCD3, CD5, TdT, CD13 on the blasts. Chromosome analysis of the bone marrow cells demonstrated 46, XY in 18 of the 20 analyzed cells, 46,XY,t(1;11)(q21;p15) in 1 of the 20 analyzed cells, and 47,XY,+11 in 1 of the 20 analyzed cells. The patient was diagnosed as having mixed phenotype acute leukemia, T/myeloid, NOS, according to the WHO classification. He received induction chemotherapy for ALL, but could not achieve complete remission (CR). After initial treatment, residual leukemic cells with CD13, CD33 and MPO were detected by FCM; therefore, he received re-induction chemotherapy for AML, and achieved CR. Acute leukemia of ambiguous lineage is a relatively rare subtype in acute leukemia and standard chemotherapy has not been established. It was suggested that the selection of chemotherapy based on the results of FCM was successful in our patient.
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PMID:[Successful selection of chemotherapy based on cell surface antigens in a patient with mixed phenotype acute leukemia]. 2053 55

Romidepsin (depsipeptide or FK228) is a histone deacetylase inhibitor, one of a new class of agents active in T-cell lymphoma. A phase 2 trial was conducted in cutaneous (CTCL) and peripheral (PTCL) T-cell lymphoma. Major and durable responses in CTCL supported the approval of romidepsin for CTCL. Forty-seven patients with PTCL of various subtypes including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma were enrolled. All patients had received prior therapy with a median of 3 previous treatments (range 1-11); 18 (38%) had undergone stem-cell transplant. All patients were evaluated for toxicity; 2 patients discovered to be ineligible were excluded from response assessment. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. Complete responses were observed in 8 and partial responses in 9 of 45 patients, for an overall response rate of 38% (95% confidence interval 24%-53%). The median duration of overall response was 8.9 months (range 2-74). Responses were observed in various subtypes, with 6 responses among the 18 patients with prior stem-cell transplant. The histone deacetylase inhibitor romidepsin has single agent clinical activity associated with durable responses in patients with relapsed PTCL.
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PMID:Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. 2163 14


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