Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders.

Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

Reduction of high-fat diet-induced liver proinflammatory state by eicosapentaenoic acid plus hydroxytyrosol supplementation: involvement of resolvins RvE1/2 and RvD1/2.

High-fat diet (HFD)-fed mice show obesity with development of liver steatosis and a proinflammatory state without establishing an inflammatory reaction. The aim of this work was to assess the hypothesis that eicosapentaenoic acid (EPA) plus hydroxytyrosol (HT) supplementation prevents the inflammatory reaction through enhancement in the hepatic resolvin content in HFD-fed mice. Male C57BL/6J mice were fed an HFD or a control diet and supplemented with EPA (50 mg/kg/day) and HT (5 mg/kg/day) or their respective vehicles for 12 weeks. Measurements include liver levels of EPA, DHA and palmitate (gas chromatography), liver resolvins and triglyceride (TG) and serum aspartate transaminase (AST) (specific kits) and hepatic and serum inflammatory markers (quantitative polymerase chain reaction and enzyme-linked immunosorbent assay). Compared to CD, HFD induced body weight gain, liver steatosis and TG accumulation, with up-regulation of proinflammatory markers in the absence of histological inflammation or serum AST changes; these results were accompanied by higher hepatic levels of resolvins RvE1, RvE2, RvD1 and RvD2, with decreases in EPA and DHA contents. EPA+HT supplementation in HFD feeding synergistically reduced the steatosis score over individual treatments and increased the hepatic levels of EPA, DHA and resolvins, with attenuation of proinflammatory markers. Lack of progression of HFD-induced proinflammatory state into overt inflammation is associated with resolvin up-regulation, which is further increased by EPA+HT supplementation eliciting steatosis attenuation. These findings point to the importance of combined protocols in hepatoprotection due to the involvement of cross-talk mechanisms, which increase effectiveness and diminish dosages, avoiding undesirable effects.

A combined docosahexaenoic acid-thyroid hormone protocol upregulates rat liver ß-Klotho expression and downstream components of FGF21 signaling as a potential novel approach to metabolic stress conditions.

Liver preconditioning by a docosahexaenoic acid (DHA) and triiodothyronine (T3) combined protocol underlies peroxisome-proliferator activated receptor α (PPARα)-fibroblast growth factor 21 (FGF21) upregulation, the study of the regulatory mechanisms involved being the aim of this work. Combined DHA (daily doses of 300 mg kg-1 for 3 days)-T3 (0.05 mg kg-1 at the fourth day) administration elicited higher levels of liver DHA and serum T3, with enhanced hepatic nuclear/cytosolic PPARα ratios, upregulation of FGF21 and ß-Klotho expression, and a small reduction in that of FGF receptor 1 (FGFR1), compared with the respective controls. Concomitantly, the components of the FGF21 cascade extracellular-signal-regulated kinase 1/2 (ERK1/2), FGF receptor substrate 2α (FRS2α), cFos, ribosomal S6 kinase 1 (RSK1), liver kinase B1 (LKB1), and AMP-activated protein kinase (AMPK) were activated. The upregulation of liver PPARα-FGF21-AMPK signaling by the combined DHA-T3 protocol resulted in values significantly higher than those elicited by the addition of the data obtained for DHA and T3 alone. It is concluded that combined DHA-T3 supplementation achieves synergistic effects on liver PPARα-FGF21-AMPK signaling, which may result in significant metabolic changes associated with energy expenditure that are of importance in the treatment of obesity and other metabolic disorders.

Señales de alarma precoces del trastorno del espectro autista en personas con síndrome de Down / Early warning signs of autism spectrum disorder in people with Down syndrome

Introducción. En la población general, el diagnóstico de trastornos del espectro autista (TEA) se realiza generalmente en una etapa temprana, mejorándose así el pronóstico. En las personas con síndrome de Down (SD), la falta de instrumentos específicos y adaptados para el diagnóstico, y la falta de experiencia de los profesionales, hace que el diagnóstico de TEA suela pasar desapercibido. Objetivo. Identificar señales de alarma «tempranas» de un posible diagnóstico de TEA en niños con SD en los primeros años de vida (de 0 a 4 años). Métodos. Estudio retrospectivo de cohortes: niños con SD y TEA (SD-TEA) y niños con SD y sin TEA (SD-noTEA) emparejados por sexo y edad. Se identificaron las siguientes señales de alarma tempranas: 1) ausencia de sonrisa social; 2) falta atención compartida; 3) falta de búsqueda de consuelo/protección; 4) ausencia de queja; 5) poco interés por el otro; 6) no señala; 7) no imita; 8) ausencia de balbuceo, vocalización; 9) expresión facial inapropiada; 10) rituales verbales o acciones repetitivas; 11) manierismos manos/dedos; 12) estereotipias; 13) interés sensorial, y 14) no integración de la mirada y la conducta. Seis investigadores, quienes no participaron en la identificación de las señales de alarma tempranas, seleccionaron aquellas que orientarían a un diagnóstico de TEA (análisis cualitativo). Se solicitó a los padres videos de las personas con SD en «actividad» entre los 0 y 4 años. Los mismos investigadores, cegados al diagnóstico de TEA y tras visualizar los videos, puntuaron las señales de alarma tempranas en 3 categorías: presencia/ausencia/no evaluable (análisis cuantitativo). Resultados. Durante el año 2013, se obtuvieron 12 videos de 12 personas con SD: 6 del grupo SD-TEA y 6 del grupo SD-noTEA. El análisis cualitativo identificó como señales de alarma temprana relacionadas con el diagnóstico de TEA: «no integración de la mirada», «no imita», «rituales verbales o acciones repetitivas» y «estereotipias»; y el análisis cuantitativo identificó: «falta de atención compartida» y «falta de interés por el otro». Conclusión. Ciertas «señales de alarma» pueden orientar hacia un diagnóstico de TEA en los primeros años de vida en niños con SD (AU)

Introduction. In general population, the current trend is to make the diagnosis of Autism Spectrum Disorders (ASD) at an early stage, which it is crucial to improve the prognosis. In contrast, in Down syndrome (DS) population, the ASD diagnosis is frequently delayed, having negative consequences on the overall development of the children who suffer. Objective. To identify «early warning signals» for the detection of the ASD in DS in the first years of life (0 to 4 years). Methods. Retrospective cohort study: SD with an ASD diagnosis (SD-ASD) and healthy-DS (SD-noASD) matched by sex and age. Early warning signals were identified and selected from different questionnaires for ASD of general population: 1. Lack of social smile; 2. Shared care foul; 3. Lack of finding comfort/protection; 4. Lack of complaint; 5. Little interest for the others; 6. No pointing; 7. Non-imitation; 8. Lack of babbling/vocalization; 9. Inappropriate facial expression; 10. Presence of rituals as repetitive actions or repetitive sentences; 11. Mannerisms hands/fingers; 12. Stereotypes; 13. Lack of interest sensory; and 14. Non-integration of the look. Six investigators, who did not participate in the identification of the «early warning signals», selected those that would guide a diagnosis of ASD (qualitative analysis). Parents were asked for videos of people with DS in «activity» between 0 and 4 years. The same investigators, blinded to the diagnosis of ASD and after watching the videos, scored the «early warning signals» in three categories: presence / absence / non-evaluable (quantitative analysis). Results. During the year 2013, 12 videos of 12 people with SD were obtained: 6 from SD-ASD group and 6 from the SD-noASD group. The qualitative analysis identified as early warning signals related to the diagnosis of ASD: «non-integration of the look», «non-imitation», «presence of rituals as repetitive actions or repetitive sentences» and «stereotypies», and the quantitative analysis: «shared care foul» and «little interest for the others». Conclusion. Certain «warning signals» may lead to a diagnosis of ASD in the first years of life in children with DS (AU)

Thyroid hormone activates rat liver adenosine 5,-monophosphate-activated protein kinase: relation to CaMKKb, TAK1 and LKB1 expression and energy status.

AMP-activated protein kinase (AMPK) is a sensor of energy status supporting cellular energy homeostasis that may represent the metabolic basis for 3,3,,5-triiodo-L-thyronine (T3) liver preconditioning. Functionally transient hyperthyroid state induced by T3 (single dose of 0.1 mg/kg) in fed rats led to upregulation of mRNA expression (RT-PCR) and protein phosphorylation (Western blot) of hepatic AMPK at 8 to 36 h after treatment. AMPK Thr 172 phosphorylation induced by T3 is associated with enhanced mRNA expression of the upstream kinases Ca2+ -calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) and transforming growth-factor-beta-activated kinase-1 (TAK1), with increased protein levels of CaMKKbeta and higher TAK1 phosphorylation, without changes in those of the liver kinase B1 (LKB1) signaling pathway. Liver contents of AMP and ADP were augmented by 291 percent and 44 percent by T3 compared to control values (p less than 0.05), respectively, whereas those of ATP decreased by 64% (p less than 0.05), with no significant changes in the total content of adenine nucleotides (AMP + ADP + ATP) at 24 h after T3 administration. Consequently, hepatic ATP/ADP content ratios exhibited 64 percent diminution (p less than 0.05) and those of AMP/ATP increased by 425 percent (p less than 0.05) in T3-treated rats over controls. It is concluded that in vivoT3 administration triggers liver AMPK upregulation in association with significant enhancements in AMPK mRNA expression, AMPK phosphorylation coupled to CaMKKbeta and TAK1 activation, and in AMP/ATP ratios, which may promote enhanced AMPK activity to support T3-induced energy consuming processes such as those of liver preconditioning.

Molecular mechanisms of steatosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease and is considered the hepatic manifestation of the metabolic syndrome associated with diabetes mellitus type 2. The prevalence of NAFLD in the general population reaches 15-20%. It is also estimated that nonalcoholic steatohepatitis (NASH) affects 3% of the population. NAFLD refers to a wide spectrum of liver damage, which ranges from simple steatosis or intracellular triglyceride accumulation, to inflammation (NASH), fibrosis and cirrhosis. The mechanisms involved in the accumulation of triglycerides in the liver and subsequent hepatocellular damage are multifactorial and are not completely understood. However, metabolic changes such as insulin resistance (IR) are developed, being a common factor in the retention of fatty acids (FA) within the hepatocytes with oxidation and production of free radicals at the mitochondrial level, which are capable of causing lipid peroxidation, cytokine production, and necrosis. In addition, there are alterations in the hepatic bioavailability of long chain n-3 polyunsaturated fatty acids, conditions that alter the expression of a series of transcriptional factors involved in lipolytic and lipogenic processes in the liver. A greater knowledge of the etiopathogenic mechanisms of NAFLD is fundamental for the development of future effective therapeutic strategies. The pathophysiological fundamentals of liver steatosis are analyzed in this study.

Variables relacionadas con la calidad de atención de la consulta nutricional y percepción del éxito en el tratamiento para el control del peso corporal / Variables related to the quality of care nutritional consulting and perception

Objetivo: Determinar la asociación entre variables relacionadas con la calidad de la consulta nutricional y la percepción del paciente en el éxito del tratamiento para el control del peso corporal en un grupo de mujeres mayores de 20 años, habitantes de la Ciudad Autónoma de Buenos Aires o del Gran Buenos Aires. Metodología: Diseño observacional, transversal de correlación. Muestreo aleatorio simple de 97 mujeres que concurrieron por lo menos una vez a una consulta nutricional llevada a cabo por un Licenciado en Nutrición. Se realizó encuesta estructurada y voluntaria analizando como variable dependiente la percepción del éxito del tratamiento nutricional y como variables independientes, tres variables relacionadas con la calidad de la atención, como la escucha del profesional (buena, regular o mala), indicaciones adecuadas a gustos, hábitos y tolerancias digestivas y tipo de material entregado en la consulta. Resultados: Del total de la muestra estudiada el 61,9% percibió como exitoso a su último tratamiento para el control del peso corporal. Para la mayoría el ámbito físico donde se desarrolló la consulta fue adecuado (95,9%), siendo suficiente el tiempo destinado a la misma (89,7%), con buena escucha llevada a cabo por el profesional (75,3%). La percepción del éxito fue asociada significativamente con una buena escucha del profesional en la consulta (p: 0,0001) y con el manejo de indicaciones adecuadas a los gustos y hábitos de las pacientes (p: 0,002). No se observó asociación entre las indicaciones adecuadas a la tolerancia digestiva y el tipo de material empleado con la percepción de éxito en la consulta nutricional. Conclusiones: La percepción del éxito en el tratamiento nutricional fue asociada significativamente con una buena escucha por parte del profesional en la consulta e indicaciones adecuadas en cuanto a sus gustos y hábitos alimentarios.

Delayed ischemic preconditioning protects against liver ischemia-reperfusion injury in vivo.

OBJECTIVES: Ischemic preconditioning (IP) affords resistance to liver ischemia-reperfusion (IR) injury, providing an early phase of protection. Development of delayed IP against IR injury was assessed using partial IR in rat liver. METHODS: The IP manuver (10 minutes of ischemia and up to 72 hours of reperfusion) was induced before 1 hour of ischemia and 20 hours of reperfusion. At the end of the reperfusion period, blood and liver samples were analyzed for serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), haptoglobin and tumor necrosis factor-alpha (TNF-alpha) levels, hepatic histology, protein carbonyl and glutathione (GSH) contents as well as nuclear factor-kappaB (NF-kappaB), and activating protein-1 (AP-1) DNA binding. RESULTS: The IP manuver significantly increased protein carbonyl/GSH ratios (275%), serum ALT (42%), and AST (58%); these changes normalized after 12 hours. Serum AST, ALT, and LDH levels were significantly increased by IR (4-, 5.6-, and 7.0-fold, respectively), with significant changes in liver histology, protein carbonyl/GSH ratio (481% enhancement), and serum TNF-alpha (6.1-fold increase). Delayed IP in IR animals reduced serum AST (66%), ALT (57%), and LDH (90%) and liver GSH depletion (89%), with normalization of protein carbonyl content, serum TNF-alpha levels, and liver histology. Enhanced AP-1/NF-kappaB DNA binding ratios and diminished haptoglobin expression induced by IR were normalized by IP. CONCLUSION: These data support that delayed IP suppresses IR-induced liver injury, oxidative stress, and TNF-alpha response, which coincide with recovery of IR-altered signaling functions represented by normal AP-1/NF-kappaB DNA binding ratios and acute phase responses.

Kupffer-cell activity is essential for thyroid hormone rat liver preconditioning.

We studied the role of Kupffer cell functioning in T3 liver preconditioning against ischemia-reperfusion (IR) injury using the macrophage inactivator gadolinium chloride (GdCl3) previous to T3 treatment. Male Sprague-Dawley rats given a single i.p. dose of 0.1 mg T3/kg were subjected to 1 h ischemia followed by 20 h reperfusion, in groups of animals pretreated with 10 mg GdCl3/kg i.v. 72 h before T(3) or with the respective vehicles. IR resulted in significant enhancement of serum aspartate aminotransferase (3.3-fold increase) and tumor necrosis factor-alpha (93% increase) levels, development of liver damage, and diminished nuclear factor-kappaB DNA binding over control values. These changes, which were suppressed by the T3 administration prior to IR, persisted in animals given GdCl3 before T3 treatment, under conditions of complete elimination of ED2+ Kupffer cells achieved in a time window of 72 h. It is concluded that Kupffer cell functioning is essential for T3 liver preconditioning, assessed in a warm IR injury model by hepatic macrophage inactivation.

Terapia hormonal sustitutiva: beneficios y riesgos / Hormonal replacement therapy: benefits and risks

La terapia hormonal sustitutiva utilizada en mujeres en estado de deprivación hormonal, especialmente estrogénica, ha sido utilizada desde los años sesenta con una baja incidencia de aceptación. Es de importancia prioritaria conocer sus beneficios y los riesgos que puede ocasionar antes de determinar sus indicaciones o desaconsejar su uso. En los últimos años la confusión ha crecido en torno a la misma, a ello ha contribuido la existencia de multitud de fármacos, de variadas vías de administración, de diferentes pautas y formas, así como de distintos tiempos de duración del tratamiento. Ante estas situaciones confusas y ante la falta de evidencias claras sobre los beneficios y los riesgos el facultativo sanitario en quien recae la responsabilidad de su asistencia se encuentra sin elementos claros para decidir. Lo que sí está claro es la existencia de una sintomatología vasomotora presente en alrededor del 80% de mujeres en edad posmenopáusica, que afecta en diferentes grados la calidad de vida y que demanda una solución terapéutica de los sanitarios

The hormonal replacement therapy, main estrogens therapy, used for treat the climacteric and vasomotor symptoms, was used from the sixty decade but with a low observance and acceptance. It's important know the effects, benefits, advantage and the risks of hormone therapy in healthy postmenopausal women before its indications and prohibition of use. In the last few years grew the reports and confuse about the risks of this therapy. The different drugs, dose, oral or transdermal administration, the efficacy and safety and duration of therapy was not clear. It there was not practical recommendations for the clinician. The hormone therapy its necessary in the vasomotor symptoms in highly symptomatic menopausal patients and in the prevention and treatment of urogenital and vaginal atrophy. The recommendations on its use and management are examined in light of current evidence

Sexualidad en la mujer climatérica / No disponible

No disponible

beta 2-glycoprotein I (apolipoprotein H) modulates uptake and endocytosis associated chemiluminescence in rat Kupffer cells.

beta 2-Glycoprotein I (beta 2 GPI) is known to influence macrophage uptake of particles with phosphatidylserine containing surfaces, as apoptotic thymocytes and unilamellar vesicles in vitro. Nevertheless, effects upon macrophage activation induced by this interaction are still unknown. beta 2 GPI influence upon the reactive species production by Kupffer cells was evaluated in order to investigate whether beta 2 GPI modulates the macrophage response to negatively charged surfaces. Chemiluminescence of isolated non-parenchymal rat liver cells was measured after phagocytosis of opsonized zymosan or phorbolymristate acetate (PMA) stimulation, in the presence and absence of large unilamellar vesicles (LUVs) containing 25 mol% phosphatidylserine (PS) or 50 mol% cardiolipin (CL) and complementary molar ratio of phosphatidylcholine (PC). beta 2 GPI decreased by 50% the chemiluminescence response induced by opsonized zymosan, with a 66% reduction of the initial light emission rate. PMA stimulated Kupffer cell chemiluminescence was insensitive to human or rat beta 2 GPI. Albumin (500 micrograms/ml) showed no effect upon chemiluminescence. beta 2 GPI increased PS/PC LUV uptake and degradation by Kupffer cells in a concentration-dependent manner, without leakage of the internal contents of the LUVs, as shown by fluorescence intensity enhancement. LUVs opsonized with antiphospholipid antibodies (aPL) from syphilitic patients increased light emission by Kupffer cells. Addition of beta 2 GPI to the assay reduced chemiluminescence due to opsonization with purified IgG antibodies from systemic lupus erythematosus (SLE or syphilis (Sy) patient sera. A marked net increase in chemiluminescence is observed in the presence of Sy aPL antibodies, whereas a decrease was found when SLE aPL were added to the assay, in the presence or absence of beta 2 GPI. At a concentration of 125 micrograms/ml, beta 2 GPI significantly reduced Kupffer cell Candida albicans phagocytosis index and killing score by 50 and 10%, respectively. The present data strongly suggest that particle uptake in the presence of beta 2 GPI is coupled to an inhibition of reactive species production by liver macrophages during the respiratory burst, supporting the role of beta 2 GPI as a mediator of senescent cell removal.

Influence of C-phycocyanin on hepatocellular parameters related to liver oxidative stress and Kupffer cell functioning.

OBJECTIVES: Kupffer cells, liver macrophages involved in immunomodulation, phagocytosis, and biochemical attack, can induce cytotoxicity and inflammation when their activity is exacerbated. The aim of this study was to evaluate the effects of C-phycocyanin on Kupffer cell functioning considering its antioxidant and anti-inflammatory properties. MATERIALS AND METHODS: Actions of C-phycocyanin on colloidal carbon phagocytosis, carbon-induced respiratory burst activity, and sinusoidal lactate dehydrogenase (LDH) release were studied in isolated perfused mouse liver. The influence of C-phycocyanin on tumor necrosis factor-a (TNF-alpha) and nitrite levels in serum and liver nitric oxide synthase (NOS) activity was assessed in rats subjected to thyroid hormone (T3) administration, a condition known to underlie hepatic oxidative stress comprising an increased Kupffer cell activity. RESULTS: C-phycocyanin elicited a concentration-dependent inhibition of carbon phagocytosis and carbon-induced O2 uptake (IC50 = 0.2 mg/ml) by perfused livers, with a 52% diminution in the carbon-induced sinusoidal release of LDH being found at a concentration of 0.25 mg/ml. Thyroid calorigenesis induced an 82-fold increase in serum TNF-alpha levels, an effect that was suppressed by pretreatment with C-phycocyanin, the antioxidant alpha-tocopherol, and by the Kupffer cell inactivator gadolinium chloride. C-phycocyanin also suppressed the T3-induced increases in serum nitrite levels (234%) and in the activity of hepatic NOS (75%). CONCLUSIONS: C-phycocyanin significantly decreases Kupffer cell phagocytosis and the associated respiratory burst activity, effects that may contribute to the abolition of oxidative stress-induced TNF-alpha response and NO production by hyperthyroid state.

Ablación endometrial: ¿cuál es la mejor alternativa? / Endometrial ablation: which is the best choice?

Aproximadamente un 20 por ciento de mujeres en edad fértil pueden presentar menorragia. Los tratamientos médicos están indicados en mujeres que no desean cirugía. El sistema intrauterino de liberación de levonorgestrel puede ser el tratamiento indicado en mujeres jóvenes que prefieren conservar su capacidad reproductiva. La cirugía tradicional es la histerectomía; sin embargo, estamos viendo como técnicas menos agresivas de ablación endometrial pueden ser preferibles. La primera generación de técnicas de ablación endometrial incluye: la resección transcervical del endometrio y la ablación con láser Nd-YAG; constituyendo actualmente el patrón de oro de los tratamientos histeroscópicos de la menorragia. La segunda generación incluye: balones térmicos, radiofrecuencia, microondas, crioablación endometrial, ablación endometrial fotodinámica. Estos métodos intentan ser más sencillos y con menor riesgo que la electrocirugía o la ablación con láser. La ablación endometrial más que reemplazar a la histerectomía, parece haber añadido una alternativa a la técnica quirúrgica (AU)

Influence of aging on Kupffer cell respiratory activity in relation to particle phagocytosis and oxidative stress parameters in mouse liver.

The influence of aging on the respiratory activity of stimulated Kupffer cells was investigated in the isolated perfused mouse liver in relation to colloidal carbon phagocytosis, and the content of glutathione (GSH) and protein carbonyls as parameters related to oxidative stress. Livers from aged (22 months) mice exhibited significant 35% and 65% decreases in the carbon uptake and in the carbon-induced O2 consumption compared to young (3 months) animals, respectively, with a concomitant 46% diminution in the carbon-induced O2 consumption/carbon uptake ratio. Hepatic GSH depletion was observed in aged mice compared to young animals, whereas protein oxidation was enhanced. It is concluded that aging leads to an impairment in the functional capacity of Kupffer cells reflected by a substantial reduction in their respiratory burst activity, lessened endocytic capacity and enhanced oxidative stress, that may contribute to increased susceptibility of the liver to noxious challenges.

Iron-induced changes in nitric oxide and superoxide radical generation in rat liver after lindane or thyroid hormone treatment.

The involvement of cytosolic nitric oxide (NO) and mitochondrial superoxide radical (O2(.-)) production was evaluated as a mechanism triggering liver oxidative stress in lindane (40 mg/kg) or L-3,3',5-triiodothyronine (T3, 0.1 mg/kg for 2 consecutive days) treated animals (male Sprague-Dawley rats) subjected to iron overload (200 mg/kg). Lindane and iron led to 504 and 210% increases in the content of hepatic protein carbonyls as an index of oxidative stress, with a 706% enhancement being produced by their combined administration. T3 did not alter this parameter, whereas iron overload increased the content of protein carbonyls by 116% in hyperthyroid rats. Lindane increased NO generation by 106% without changes in generation of O2(.-), whereas iron enhanced both parameters by 109 and 80% over control values, respectively, with a net 33 and 46% decrease, respectively, being elicited by the combined treatment related to iron overload alone. Hyperthyroidism increased liver NO (69%) and O2(.-) (110%) generation compared to controls, effects that were either synergistically augmented or suppressed by iron overload, respectively. The in vitro addition of iron (1 micromol/mg protein) to liver cytosolic fractions from euthyroid (97%) and hyperthyroid (173%) rats also enhanced NO generation. The effects of iron overload on mitochondrial O2(.-) production by hyperthyroid rats were reproduced by the in vitro addition of 1 micromol iron/mg protein and abolished by the in vivo pretreatment with the iron chelator desferrioxamine (500 mg/kg). It is concluded that liver oxidative stress induced by iron overload is independent of NO and O2(.-) production in lindane-treated rats, whereas in hyperthyroid animals NO generation is a major factor contributing to this redox imbalance.

Effects of iron overload and lindane intoxication in relation to oxidative stress, Kupffer cell function, and liver injury in the rat.

Parameters related to liver oxidative stress, Kupffer cell function, and hepatocellular injury were assessed in control rats and in animals subjected to lindane (40 mg/kg; 24 h) and/or iron (200 mg/kg; 4 h) administration. Independently of lindane treatment, iron overload enhanced the levels of iron in serum and liver. Biliary efflux of glutathione disulfide increased by 140, 160, or 335% by lindane, iron, or their combined administration, respectively, and the hepatic content of protein carbonyls was elevated by 5.84-, 2.95-, and 10-fold. Colloidal carbon uptake by perfused livers was not modified by lindane and/or iron, whereas gadolinium chloride (GdCl(3)) pretreatment diminished uptake by 60-72%. Carbon-induced liver O(2) uptake was not altered by lindane, whereas iron produced a 61% increase and the combined treatment led to a 72% decrease over control values. Pretreatment with GdCl(3) abolished these effects in all groups. Lindane-treated rats showed acidophilic hepatocytes in periportal areas and some hepatic cells with nuclear pyknosis, whereas iron overload led to moderate hyperplasia and hypertrophy of Kupffer cells and moderate inflammatory cell infiltration. Combined lindane-iron treatment led to hepatocytes with pyknotic nuclei, significant acidophilia, and extensive lymphatic and neutrophil infiltration in the portal space. Hepatic myeloperoxidase activity increased by 1.1-, 2.1-, or 6.7-fold by lindane, iron, or their combined administration, respectively. Liver sinusoidal lactate dehydrogenase efflux increased by 2.2-fold (basal conditions) and 9.7-fold (carbon infusion) in the lindane-iron treated rats, effects that were diminished by 35 and 78% by GdCl(3) pretreatment, respectively. These data support the contention that lindane sensitizes the liver to the damaging effects of iron overload by providing an added enhancement to the oxidative stress status in the tissue, and this may contribute to the alteration of the respiratory activity of Kupffer cells and the development of an inflammatory response.

Content of liver and brain ubiquinol-9 and ubiquinol-10 after chronic ethanol intake in rats subjected to two levels of dietary alpha-tocopherol.

To assess the effect of chronic ethanol ingestion in the content of the reduced forms of coenzymes Q9 (ubiquinol-9) and Q10 (ubiquinol-10) as a factor contributing to oxidative stress in liver and brain, male Wistar rats were fed ad libitum a basal diet containing either 10 or 2.5 mg alpha-tocopherol/100 g diet (controls), or the same basal diet plus a 32% ethanol-25% sucrose solution. After three months treatment, ethanol chronically-treated rats showed identical growth rates to the isocalorically pair-fed controls, irrespectively of alpha-tocopherol dietary level. Lowering dietary alpha-tocopherol led to a decreased content of this vitamin in the liver and brain of control rats, without changes in that of ubiquinol-9, and increased levels of hepatic ubiquinol-10 and total glutathione (tGSH), accompanied by a decrease in brain tGSH. At the two levels of dietary alpha-tocopherol, ethanol treatment significantly decreased the content of hepatic alpha-tocopherol and ubiquinols 9 and 10. This effect was significantly greater at 10 mg alpha-tocopherol/100 g diet than at 2.5, whereas those of tGSH were significantly elevated by 43% and 9%, respectively. Chronic ethanol intake did not alter the content of brain alpha-tocopherol and tGSH, whereas those of ubiquinol-9 were significantly lowered by 20% and 14% in rats subjected to 10 and 2.5 mg alpha-tocopherol/100 g diet, respectively. It is concluded that chronic ethanol intake at two levels of dietary alpha-tocopherol induces a depletion of hepatic alpha-tocopherol and ubiquinols 9 and 10, thus contributing to ethanol-induced oxidative stress in the liver tissue. This effect of ethanol is dependent upon the dietary level of alpha-tocopherol, involves a compensatory enhancement in hepatic tGSH availability, and is not observed in the brain tissue, probably due to its limited capacity for ethanol biotransformation and glutathione synthesis.