Redox regulation in skeletal muscle during contractile activity and aging.

Skeletal muscle has the ability to adapt and remodel after functional, mechanical, and metabolic stresses by activation of different adaptation mechanisms that induce gene expression, biochemical changes, and structural remodeling. Skeletal muscle cells continuously generate reactive oxygen and nitrogen species (RONS), which can act as mediators in cellular signaling pathways that regulate the adaptation mechanisms. There is strong evidence that indicates that RONS are generated in skeletal muscle cells during contractile activity and this induces the activation of transcription factors which modulate gene expression of antioxidant and protective proteins. Thus, it has been proposed that RONS act as signals that modulate the adaptation mechanisms in skeletal muscle and other cells. Structural and functional changes occur in skeletal muscle during aging and are characterized by a reduction of muscle mass and force (sarcopenia). The causes are known, however, there is considerable support for an involvement of RONS in the process of aging and sarcopenia. Several studies indicate that adaptive responses of skeletal muscle that are activated and regulated by RONS are disrupted during aging. This reduction of skeletal muscle adaptation to contractile activity during aging might be responsible for the loss of muscle mass and function and the progressive deterioration of this organ. In summary, there is sufficient evidence that indicates that cellular redox regulation in skeletal muscle is crucial in the physiology and pathology of skeletal muscle. However, new methodologies and experimental models are required for understanding the complex biology of RONS in the cell. This will provide future interventions that mitigate pathologies and aging of skeletal muscle.

Heat shock factor activation in human muscles following a demanding intermittent exercise protocol is attenuated with hyperthermia.

AIM: The present study investigated whether increased activation of heat shock factors (HSF) following exercise relates primarily to the increased muscle temperature or to exercise in general. METHODS: Six subjects completed 40 min of intermittent cycling (15s:15s exercise:recovery at 300 +/- 22 W) at an ambient temperature of either 20.0 +/- 1.3 or 40.3 +/- 0.7 degrees C. Muscle biopsies were taken prior to and immediately following the exercise protocol with samples analysed for HSF DNA binding by electrophoretic mobility shift assay. RESULTS: Exercise at 40 degrees C resulted in significantly increased oesophageal (39.3 +/- 0.2 degrees C) and muscle temperature (40.0 +/- 0.2 degrees C) at the end of the exercise protocol compared with 20 degrees C (oesophageal, 38.1 +/- 0.1 degrees C; muscle, 38.9 +/- 0.2 degrees C). However, an increased DNA binding of HSF was not evident following exercise at 40 degrees C (reduced by 21 +/- 22%) whereas it increased by 29 +/- 51% following exercise at 20 degrees C. CONCLUSION: It appears that increased temperature is not the major factor responsible for activation of HSF DNA binding.

Genetic modification of the manganese superoxide dismutase/glutathione peroxidase 1 pathway influences intracellular ROS generation in quiescent, but not contracting, skeletal muscle cells.

Increased amounts of reactive oxygen species (ROS) are generated by skeletal muscle during contractile activity, but their intracellular source is unclear. The oxidation of 2',7'-dichlorodihydrofluorescein (DCFH) was examined as an intracellular probe for reactive oxygen species in skeletal muscle myotubes derived from muscles of wild-type mice and mice that were heterozygous knockout for manganese superoxide dismutase (Sod2(+/-)), homozygous knockout for glutathione peroxidase 1 (GPx1(-/-)), or MnSOD transgenic overexpressors (Sod2-Tg). Myoblasts were stimulated to fuse and loaded with DCFH 5-7 days later. Intracellular DCF epifluorescence was measured and myotubes were electrically stimulated to contract for 15 min. Quiescent myotubes with decreased MnSOD or GPx1 showed a significant increase in the rate of DCFH oxidation whereas those with increased MnSOD did not differ from wild type. Following contractions, myotubes from all groups showed an equivalent increase in DCF fluorescence. Thus the oxidation of DCFH in quiescent skeletal muscle myotubes is influenced by the content of enzymes that regulate mitochondrial superoxide and hydrogen peroxide content. In contrast, the increase in DCFH oxidation following contractions was unaffected by reduced or enhanced MnSOD or absent GPx1, indicating that reactive oxygen species produced by contractions were predominantly generated by nonmitochondrial sources.

Effects of aging and cyclosporin treatment on the hepatobiliary efflux of glutathione.

The aim of this study was to investigate the effects of cyclosporin (CyA) treatment on biliary glutathione efflux in rats of different ages (1, 2, 4, and 24 months). CyA treatment reduced the liver content of total glutathione in 1-, 2- and 24 month old rats (-30%, -43% and -30%, respectively). By contrast, oxidized glutathione (GSSG) concentration in liver tended to increase, although non significantly, in the rats aged 4 and 24 month (+36% and +28%, respectively). The oxidized-to-reduced glutathione ratio was significantly increased in 2-, 4- and 24 month old animals (+23%, +36% and >100%, respectively). Regarding biliary glutathione, our data indicate that efflux rates of total glutathione in control (untreated) rats increased to a maximum at 4 months, and decreased (-56%) in 24 month old rats, although values were still higher than those from young animals. CyA treatment significantly reduced biliary glutathione secretion except in 24 month old rats (-98%, -66% and -32%, at 1, 2 and 4 month, respectively). In addition, following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates into bile were significantly reduced by the drug only in 1- and 2 month old rats (-29% and -55%, respectively) and even tended to increase, although non significantly, in oldest animals. Our data indicate that inhibition of biliary glutathione efflux by CyA was greater in younger rats and support the view that increased intrabiliary catabolism of the tripeptide and inhibition of its canalicular transport could contribute to the decline in biliary glutathione secretion induced by the drug.

Effects of aging on the susceptibility to the toxic effects of cyclosporin A in rats. Changes in liver glutathione and antioxidant enzymes.

Free radicals are involved in aging and cyclosporin A-induced toxicity. The age-related changes in the liver oxidative status of glutathione, lipid peroxidation, and the activity of the enzymatic antioxidant defense system, as well as the influence of aging on the susceptibility to the hepatotoxic effects of cyclosporin (CyA) were investigated in rats of different ages (1, 2, 4, and 24 months). The hepatic content of reduced glutathione (GSH) increased with aging, peaked at 4 months, and decreased in senescent rats. By contrast, glutathione disulfide (GSSG) and thiobarbituric acid-reactive substances (TBARS) concentrations and superoxide dismutase, catalase, and glutathione peroxidase activities were higher in the oldest than in the youngest rats. CyA treatment, besides inducing the well-known cholestatic syndrome, increased liver GSSG and TBARS contents and the GSSG/GSH molar ratio, and altered the nonenzymatic and enzymatic antioxidant defense systems. The CyA-induced cholestasis and hepatic depletion of GSH, and the increases in the GSSG/GSH ratio, and in GSSG and TBARS concentrations were higher in the older than the mature rats. Moreover, superoxide dismutase and catalase activities were found to be significantly decreased only in treated senescent rats. The higher CyA-induced oxidative stress, lipoperoxidation, and decreases in the antioxidant defense systems in the aged animals render them more susceptible to the hepatotoxic effects of cyclosporin.

Glutathione metabolism in cyclosporine A-treated rats: dose- and time-related changes in liver and kidney.

1. We investigated the simultaneous effects of cyclosporine A (CsA) treatment in rats on glutathione metabolism, oxidative status and their interorgan relationship in the liver and kidney. 2. Reduced and oxidized glutathione (GSH and GSSG, respectively), lipid peroxidation and the activity of several enzymes of the glutathione cycle were evaluated in adult Wistar rats treated daily (i.p.) with saline, CsA vehicle (olive oil) or CsA (10 and 20mg/kg per day) for either 1 or 4 weeks (short- and long-term treatments, respectively). 3. Cyclosporine A treatment elicited a significant depletion in liver GSH content and a decrease in the GSH/GSSG ratio that was unrelated to either the time of treatment or the dose used; these effects were already evident after 1 week of treatment. Renal GSH levels remained unaffected or increased, while those of GSSG increased markedly in all CsA-treated rats, leading to decreases in the GSH/GSSG ratio, except in rats treated in the short term with the lower dose of CsA. These changes in the GSH/GSSG ratio were time and dose dependent. Short-term CsA treatment using the higher dose and long-term treatment with both doses of CsA progressively enhanced lipid peroxidation, which was reflected by increased levels of thiobarbituric acid-reactive substances in both hepatic and renal homogenates. Hepatic gamma-glutamylcysteine synthetase activity was increased after long-term treatment with both doses of CsA, whereas the activity of GSH hepatic peroxidase and GSH transferase was not significantly modified in any of the experimental groups. In contrast, renal gamma-glutamyl transpeptidase activity decreased in a progressive fashion, with the magnitude of this decrease being dose and time dependent. The plasma levels of total glutathione increased only in rats treated in the long term, regardless of the dose of CsA used, and remained unaltered in animals treated in the short term. 4. In summary, the data collected indicate that CsA treatment alters the interorgan homeostasis of glutathione and the oxidative status of the rat liver and kidney, which is associated with increases in lipid peroxidation in both organs, and also induces modifications in the activity of some enzyme related to the glutathione cycle.

Role of S-adenosylmethionine on the hepatobiliary homeostasis of glutathione during cyclosporine A treatment.

The effects of cyclosporine A (CyA) treatment on the hepatic content and biliary output of reduced (GSH) and oxidized (GSSG) glutathione and lipid peroxidation in the liver, and the ability of S-adenosylmethionine (SAMe) to antagonize the CyA-induced alterations were studied in male Wistar rats. To evaluate the efficacy of SAMe, three CyA and SAMe protocols were used: cotreatment with SAMe plus CyA, pretreatment with SAMe before starting cotreatment, and post-treatment with SAMe after beginning treatment with CyA alone. CyA treatment for one and four weeks depleted liver GSH, decreased the GSH/GSSG ratio and significantly reduced GSH and GSSG biliary concentrations and secretion rates. Additionally, long-term treatment enhanced lipid peroxidation. By contrast, when the rats were treated with CyA plus SAMe using any of the administration protocols, SAMe was seen to be efficient in antagonizing the GSH hepatic depletion, the changes in hepatic GSH/GSSG ratio and the increase induced by CyA in lipid peroxidation. Furthermore, SAMe also abolished the effects of CyA on the biliary secretion rates of GSH and GSSG. The efficacy of SAMe was similar, regardless of the administration protocols used. In conclusion, our results clearly demonstrate that SAMe is good for preventing, antagonizing and reversing the CyA-induced alterations in the hepatobiliary homeostasis of glutathione.

[Presentation of Burkitt's lymphoma in nasal sinus]. / Presentación nasosinusal del linfoma de Burkitt.

Burkitt' lymphoma is a malignant, non-Hodgkin's lymphoma of high grade that present two clinical from the african or endemic form affects near the middle of children of central africa and the american or sporadic form, that was first described in North American and the clinical setting was similar to endemic form. In our geographic area is an unusual entity. We present a clinical case of marrocan child that the first symptom was nasosinusal.

Role of alpha2-adrenoceptors on the hyperglycaemic and insulin secretory effects derived from alpha1- and beta-adrenoceptor stimulation in the rabbit.

1. In conscious fasted rabbits the insulin secretory response induced by the intravenous infusion of the alpha1-adrenoceptor agonist, amidephrine (10 microg kg(-1) min(-1)) was blocked by the simultaneous administration of clonidine (2 microg kg(-1) min(-1) i.v.). 2. The excitatory effect of amidephrine (10 microg kg(-1) min(-1)) on insulin secretion was similarly suppressed by the concomitant infusion of the selective alpha2-adrenoceptor agonist UK14304 (1 microg kg(-1) min(-1)). Both, the increase in blood glucose and the inhibition of insulin secretion found with UK14304 when infused alone were antagonized in rabbits previously treated with the very selective alpha2-adrenoceptor antagonist 2-methoxyidazoxan (1.5 microg kg(-1) min(-1)). 3. The combined administration of amidephrine (3 microg kg(-1) min(-1)) and isoprenaline (0.3 microg kg(-1) min(-1)) evoked a potentiated increase in insulin plasma levels in the face of a weak hyperglycaemia, an established reduction in blood pressure and tachycardia. 4. The potentiated insulin secretory response derived from alpha1- and beta-adrenoceptor stimulation was blunted by clonidine administration. In its presence a sustained hyperglycaemic response was found. 5. The increase in plasma lactate levels resulting from dual adrenoceptor stimulation (amidephrine: 10 microg kg(-1) min(-1) + salbutamol: 0.3 microg kg(-1) min(-1)) was smaller than the expected should addition or potentiation occurred. 6. Our results point to a possible physiological role played by alpha2-adrenoceptors on insulin secretion, since their stimulation by the endogenous catecholamines could lead to inhibition of insulin release, masking any potentiated response that otherwise should have appeared from alpha1- and beta-adrenoceptor stimulation.

Comparative effects of calcium channel blockers and indomethacin on insulin secretion and blood pressure increase derived from alpha 1-adrenoceptor stimulation in the rabbit.

1. In conscious, fasted rabbits the intravenous infusion of the alpha 1-adrenoceptor agonist, amidephrine (3 and 10 micrograms kg-1 min-1) induced a dose related increase in insulin plasma levels. This effect was accompanied by a minor hypo- or hyperglycaemic response, depending on the dose of agonist infused. 2. A dose related increase in mean arterial pressure and reduction in heart rate were also found after amidephrine administration. 3. The insulin secretory response to amidephrine was not prevented in rabbits previously treated with atropine (5.26 micrograms kg-1 min-1). However, in the presence of muscarinic receptor blockade the bradycardic effect of amidephrine was either suppressed or attenuated. 4. Pretreatment with the calcium channel antagonist elgodipine (35 ng kg-1 min-1) or with indomethacin (0.66 mg kg-1 min-1) clearly blocked the effect of amidephrine on insulin secretion. 5. The haemodynamic changes induced by amidephrine were preserved in the presence of either verapamil (0.17 microgram kg-1 min-1) or indomethacin, whereas the hypertensive response was antagonized by elgodipine. 6. Our results suggest that the metabolic and haemodynamic changes mediated by amidephrine are two independent effects, insulin secretion requiring the presence of extracellular calcium and the synthesis of arachidonic acid metabolites.

[Neuroendocrine tumor of the submaxillary gland. Apropos of a case]. / Tumor neuroendocrino de glándula submaxilar. A propósito de un caso.

A case is presented of primary neuroendocrine tumour of the submaxillary gland. Study for metastases was negative, but in a few months a pancreatic tumour appeared, and the patient deceased. We make a bibliographical revision of the subject, which shows the rarity of the localization of small cell tumours in this area.

[Nasosinusal inverted papilloma]. / Papilomas invertidos nasosinusales.

Inverted papilloma is a papillar lesion of the nasal cavity and paranasal sinuses that arise from the Schneiderian membrane. This tumor has a high rate of local recurrence. We present a review of 10 cases of inverted papilloma of the nose and paranasal sinuses. A review of the literature is done.

[Verrucous carcinoma of the larynx]. / Carcinoma verrucoso de laringe.

From 1981-1984, we have diagnosed and treated 5 cases verrucous carcinoma of the larynx. The clinical findings, histopathology, and management of verrucous carcinoma of the larynx are discussed.

[Review of 156 myringoplasties]. / Revisión de 156 miringoplastias.

We report the anatomical and functional results of 156 myringoplasty; 134 with onlay surgical technique and 22 with underlay technique. We comment the climatologic of our area and its relation with the surgical failures.

[Aberrant internal carotid artery in the middle ear]. / Carótida interna aberrante en oído medio.

An aberrant internal carotid artery in the middle ear is rare. We present a new case with a red mass behind the eardrum. The diagnosis must be established by radiology and angiography. The consequences of injury and surgical intervention are serious. The purpose of this paper is to review the literature on the subject of vascular anomalies of the middle ear and to discuss the diagnosis and management of this lesion.