Longitudinal evaluation of jaw muscle activity and mandibular kinematics in young patients with Class II malocclusion treated with the Teuscher activator.

OBJECTIVES: A longitudinal study was performed to evaluate the jaw muscle activity and mandibular kinematics after Teuscher activator treatment and at 2 years after orthodontic treatment completion. MATERIAL AND METHODS: Twenty-seven children with Class II division 1 malocclusion were evaluated before treatment (T0; mean: 11.6 years), after functional treatment (T1; mean: 12.8 years), and 2 years after orthodontic treatment (T2; mean: 18 years). Bilateral surface electromyographic activities of the anterior temporalis, posterior temporalis, masseter, and suprahyoid muscle areas were analyzed at rest and during clenching, swallowing, and mastication. Kinematic recordings of the mandibular maximum opening, lateral shift, right and left lateral excursions, and protrusion were evaluated. RESULTS: Compared to T0, the left masseter activity during clenching was decreased at T1 but increased at T2, similar to the other evaluated muscles. The suprahyoid activity during swallowing was increased at T1 but decreased at T2. The masseter activity during mastication was increased at T1 and further increased at T2. The left and right lateral excursions and protrusion did not show significant changes throughout the experiment. CONCLUSIONS: Teuscher activator and subsequent fixed orthodontic treatment improved jaw muscle function; however, a long period was needed to attain complete neuromuscular adaptation.

[Effect of an acute exercise bout on Toll-like receptor 4 and inflammatory mechanisms in rat heart]. / Efecto del ejercicio agudo sobre la expresión del receptor tipo Toll-4 y los mecanismos inflamatorios en corazón de rata.

BACKGROUND: Toll like receptor 4 (TLR-4) is a protein located in the cell membrane with an important function in the immune response of the organism. Its activation decreases heart contractility and activates nuclear transcription factor kappa B (NF-kB ). This in turn, increases the synthesis of different pro-inflammatory cytokines and the inducible enzyme nitric oxide (iNOS), which plays an important role in the inflammatory processes when nitric oxide production is enhanced. AIM: To determine if, after one session of acute exercise, expression of TLR-4 and iNOS, and activation of NF-kB are induced in rat cardiac tissue. MATERIAL AND METHODS: Exercise and control groups of eight male Wistar rats each, were studied. The exercise group was subjected to an acute exercise bout lasting one hour. After the exercise, the heart was excised to measure the expression of iNOS and TLR-4 genes by quantitative polyme-rase chain reaction, NF-kB activation by electrophoretic mobility shift assay (EMSA) and p50 by Western blot. RESULTS: After exercise, there was an increase in TLR-4 and of iNOS mRNA levels (+46.7 and +74.3% respectively). NF-kB activation and the nuclear expression of its p50 subunit also increased significantly (+240 and +306% respectively). CONCLUSIONS: Increased expression of TLR4 following a session of acute exercise may contribute to the activation of the NF-kB signaling route, promoting the synthesis of nitric oxide, which could influence negatively the cardiac response to high intensity physical exercise.

Nitric oxide regulates the repair of injured skeletal muscle.

Skeletal muscle repair can be understood as a balance between fibrosis and regeneration, the result of which may lead to complete recovery or loss of muscle function. To study the involvement of nitric oxide in post-trauma muscle repair, we used an experimental murine model of crush injury muscle. The animals were divided into four groups, (i) control (CO), (ii) sham trauma, (iii) trauma and (iv) trauma+l-NAME. The animals received a single dose of 100mg/kg of the l-NAME, an inhibitor of nitric oxide synthase, 2h after lesion, and the muscle tissue was analyzed in two time-points: 24h and 7 days. Twenty-four hours after injury, the crushed muscle was characterized by an intense inflammatory cell infiltrate and edema demonstrated by histological analysis. These changes were accompanied by increased iNOS, MMP-2 and HGF mRNA transcription and protein expression of the iNOS and MMP-2 in the gastrocnemius muscle. Crushing injury also promoted cell proliferation and increase number satellite cell, responsible for the regeneration of the muscle fiber. Treatment with l-NAME blocking local NO production, greatly attenuated these histological and molecular findings at 24h. On the 7th day the molecular findings of both groups were comparable to the control (sham trauma) group. However, the l-NAME group showed increase deposition of collagen and decrease of SC expression. These findings demonstrate that activation of NO during muscle crush is critical in the early phases of the skeletal muscle repair process and indicate its possible role as a regulator of the balance between fibrosis and muscle regeneration.

The role of nitric oxide during healing of trauma to the skeletal muscle.

INTRODUCTION: The role of NO in muscle injury is not clear. METHODS: We examined the involvement of the NO system in the development of muscle damage in an experimental model of crush injury. The animals were divided into four groups: (1) control (CO), (2) sham trauma, (3) trauma, (4) trauma + L -NAME, in two experimental phases, 24 h and 7 days after injury. RESULTS: Twenty-four hours post-trauma, the crushed muscle was characterized by an intense inflammatory reaction. These changes were accompanied by increased oxidative damage, increased cytokine mRNA transcription, NF-κB binding ability and TGF-ß growth factor expression in the gastrocnemius muscle. Treatment with L: -NAME markedly decreased these histological and molecular abnormalities at 24 h. However, at 7 days post-trauma, increased collagen formation was observed in the L: -NAME group. DISCUSSION: These findings indicate that NO is involved in the balance between fibrosis and healing with regeneration.

Disease-Related Malnutrition and Sarcopenia Predict Worse Outcome in Medical Inpatients: A Cohort Study.

(1) Background: Both sarcopenia and disease-related malnutrition (DRM) are unfortunately underdiagnosed and undertreated in our Western hospitals, which could lead to worse clinical outcomes. Our objectives included to determine the impact of low muscle mass (MM) and strength, and also DRM and sarcopenia, on clinical outcomes (length of stay, death, readmissions at three months, and quality of life). (2) Methodology: Prospective cohort study in medical inpatients. On admission, MM and hand grip strength (HGS) were assessed. The Global Leadership Initiative on Malnutrition (GLIM) criteria were used to diagnose DRM and EWGSOP2 for sarcopenia. Assessment was repeated after one week and at discharge. Quality of life (EuroQoL-5D), length of stay (LoS), readmissions and mortality are reported. (3) Results: Two hundred medical inpatients, median 76.0 years-old and 68% with high comorbidity. 27.5% met GLIM criteria and 33% sarcopenia on admission, increasing to 38.1% and 52.3% on discharge. Both DRM and sarcopenia were associated with worse QoL. 6.5% died and 32% readmission in 3 months. The odds ratio (OR) of mortality for DRM was 4.36 and for sarcopenia 8.16. Readmissions were significantly associated with sarcopenia (OR = 2.25) but not with DRM. A higher HGS, but not MM, was related to better QoL, less readmissions (OR = 0.947) and lower mortality (OR = 0.848) after adjusting for age, sex, and comorbidity. (4) Conclusions: In medical inpatients, mostly polymorbid, both DRM but specially sarcopenia are associated with poorer quality of life, more readmissions, and higher mortality. Low HGS proved to be a stronger predictor of worse outcomes than MM.

Beneficial effects of exercise on gut microbiota functionality and barrier integrity, and gut-liver crosstalk in an in vivo model of early obesity and non-alcoholic fatty liver disease.

Childhood obesity has reached epidemic levels, representing one of the most serious public health concerns associated with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). There is limited clinical experience concerning pediatric NAFLD patients, and thus the therapeutic options are scarce. The aim of this study was to evaluate the benefits of exercise on gut microbiota composition and functionality balance, and consequent effects on early obesity and NAFLD onset in an in vivo model. Juvenile (21-day-old) male Wistar rats fed a control diet or a high-fat diet (HFD) were subjected to a combined aerobic and resistance training protocol. Fecal microbiota was sequenced by an Illumina MiSeq system, and parameters related to metabolic syndrome, fecal metabolome, intestinal barrier integrity, bile acid metabolism and transport, and alteration of the gut-liver axis were measured. Exercise decreased HFD-induced body weight gain, metabolic syndrome and hepatic steatosis, as a result of its lipid metabolism modulatory capacity. Gut microbiota composition and functionality were substantially modified as a consequence of diet, age and exercise intervention. In addition, the training protocol increased Parabacteroides, Bacteroides and Flavobacterium genera, correlating with a beneficial metabolomic profile, whereas Blautia, Dysgonomonas and Porphyromonas showed an opposite pattern. Exercise effectively counteracted HFD-induced microbial imbalance, leading to intestinal barrier preservation, which, in turn, prevented deregulation of the gut-liver axis and improved bile acid homeostasis, determining the clinical outcomes of NAFLD. In conclusion, we provide scientific evidence highlighting the benefits of gut microbiota composition and functionality modulation by physical exercise protocols in the management of early obesity and NAFLD development.

Eccentric training impairs NF-kappaB activation and over-expression of inflammation-related genes induced by acute eccentric exercise in the elderly.

The present study was aimed to investigate in elderly humans changes in NF-kappaB activation and in the expression of the inflammation-related genes inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) induced in peripheral blood mononuclear cells (PBMC) by acute eccentric exercise and by submaximal eccentric training. Eleven subjects, aged 66-75 years, carried out 2 bouts of eccentric exercise separated by 8 weeks of training. Following the first bout, NF-kappaB activation, and protein level of p50/p65 subunits, phospho-IkappaBalpha and phospho-IKKalpha increased, while IkappaBalpha protein level was significantly reduced. This was accompanied by a significant increase in iNOS, COX-2 and IL-6 mRNA protein level and protein content. Changes were significantly attenuated following the second exercise bout. In conclusion, acute eccentric exercise increases NF-kappaB activation and the expression of several inflammation-related genes in PBMC from elderly individuals. Regular eccentric training might be an effective method of preventing undesirable inflammatory responses induced by eccentric exercise.

Diclofenac pretreatment modulates exercise-induced inflammation in skeletal muscle of rats through the TLR4/NF-κB pathway.

Nonsteroidal anti-inflammatory drugs, such as diclofenac, are widely used to treat inflammation and pain in several conditions, including sports injuries. This study analyzes the influence of diclofenac on the toll-like receptor-nuclear factor kappa B (TLR-NF-κB) pathway in skeletal muscle of rats submitted to acute eccentric exercise. Twenty male Wistar rats were divided into 4 groups: control-saline, control-diclofenac, exercise-saline, and exercise-diclofenac. Diclofenac or saline were administered for 7 days prior to an acute eccentric exercise bout. The inflammatory status was evaluated through mRNA levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor alpha (TNF-α), and protein content of COX-2, IL-6, and TNF-α in vastus lateralis muscle. Data obtained showed that a single bout of eccentric exercise significantly increased COX-2 gene expression. Similarly, mRNA expression and protein content of other inflammation-related genes also increased after the acute exercise. However, these effects were attenuated in the exercise + diclofenac group. TLR4, myeloid differentiation primary response gene 88 (MyD88), and p65 were also upregulated after the acute eccentric bout and the effect was blunted by the anti-inflammatory drug. These findings suggest that pretreatment with diclofenac may represent an effective tool to ameliorate the pro-inflammatory status induced by acute exercise in rat skeletal muscle possibly through an attenuation of the TLR4-NF-κB signaling pathway.

Diclofenac pretreatment effects on the toll-like receptor 4/nuclear factor kappa B-mediated inflammatory response to eccentric exercise in rat liver.

UNLABELLED: Acute exercise is a stress stimulus that may cause cell damage through the activation of the toll-like receptor (TLR)4 pathway, resulting in the translocation of nuclear factor kappa B (NF-κB) into the cell nucleus and the upregulation of inflammatory genes. Nonsteroidal anti-inflammatory drugs, such as diclofenac, are often prescribed to counteract exercise-induced inflammation. AIMS: This study analyzed effects of diclofenac pretreatment on the TLR4/NF-κB pathway in rat liver after an acute eccentric exercise. MAIN METHODS: Twenty male Wistar rats were divided in four groups: control-saline, control-diclofenac, exercise-saline and exercise-diclofenac. The rats received saline or diclofenac (10mg/kg) for 7days prior to an eccentric exercise bout. KEY FINDINGS: After exercise there was an increase in TLR4, myeloid differentiation primary response gene 88 (MyD88), TIR domain-containing adaptor inducing interferon (TRIF) and p65 NF-κB subunit protein levels. Exercise also resulted in increased mRNA and protein expression of interleukin (IL)-6, inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α. Proinflammatory effects of exercise were prevented by the administration of diclofenac, which blunted the activation of the TLR4/NF-κB pathway and the inflammatory response in the liver of exercised rats. SIGNIFICANCE: Results from the present study highlight the role of TLR4 as a target for anti-inflammatory interventions.

[Factors predicting detectable viral load in patients with highly active antiretroviral treatment]. / Factores predictores de carga viral detectable en pacientes en tratamiento antirretroviral de gran actividad.

BACKGROUND AND OBJECTIVE: Knowledge of the variables predicting detectable viral load in patients with highly active antiretroviral treatment. PATIENTS AND METHOD: Observational and cross-sectional study in patients with antiretroviral treatment receiving two nucleoside reverse transcriptase inhibitors and one protease inhibitor. Several sociodemographic and clinic variables were registered. Two models were designed in order to assess the adherence: I. combining self-report and pharmacy criteria, and II. including drug plasma levels in adherent patients with the two former criteria and detectable viral load. Logistic regression analysis with variables found to be associated with detectable viral load in the univariate analysis, diagnostic algorithm and ROC statistics were performed in order to select the best model to predict detectable viral load. RESULTS: Among of 136 patients studied, 39 (28.7%) had detectable viral load. Patients less than 35 years old (OR = 2.68), intravenous drug users or heterosexual contacts as the way of HIV infection (OR = 6.42), patients not fully convinced of the capacity of mutation of the HIV by poor adherence (OR = 3.25) and patients considered non-adherent according to the drug plasma levels criteria (OR = 6.91) had more frequently detectable viral load. The best model to predict detectable viral load would include patients considered non-adherent according to the two models used, and moreover, patients where another of the factors of risk were detected; the prevalence of detectable viral load in these was of 10% versus 43%. CONCLUSION: Adherence to HAART is a key factor to predict detectable viral load, specially in young patients, infected by intravenous drug use or heterosexual contacts, and patients not convinced of the importance of the adherence.

[Assessment of adherence to antiretroviral: role of determination of plasma levels of non nucleosides anologues]. / Valoración de la adhesión al tratamiento antirretroviral: papel de la determinación de la concentración plasmática de los fármacos no análogos de nucleósidos.

BACKGROUND AND OBJECTIVE: Our purpose was to assess the contribution of efavirenz and nevirapine plasma concentrations in the assessment of self-reported adherence and punctuality of appointments to take the drugs. PATIENTS AND METHOD: Adherence was assessed using questionnaires and plasma concentrations of efavirenz and nevirapine were determined. Patients received efavirenz or nevirapine in combination with two nucleotides reverse transcriptase inhibitors. RESULTS: Among the 45 enrolled patients, 7 were considered non-adherent according to the questionnaires, 17 regarding pharmacy appointments and 5 according to the plasma levels of efavirenz and nevirapine. 3.3% participants had detectable viral loads. CONCLUSION: Cross-validation between patients'self-reports and pharmacy appointments can improve the measurement of adherence to antiretroviral therapy.

[Benefits of strength training for the prevention and treatment of sarcopenia]. / Beneficios del entrenamiento de fuerza para la prevención y tratamiento de la sarcopenia.

Sarcopenia is a syndrome characterized by a gradual loss and generalized skeletal muscle mass and strength at risk for adverse outcomes such as physical disability, poor quality of life and mortality. It has several contributing factors: the aging process throughout life, influences on development in the early stages of life, eating sub optimal, bed rest or sedentary lifestyle, chronic diseases and certain drug treatments. Sarcopenia represents a deterioration of health status with a high personal cost: mobility disorders, increased risk of falls and fractures, impaired ability to perform everyday activities, disability, loss of independence and increased risk of death. The strength training is currently one of the most effective methods for combating sarcopenia by stimulating hypertrophy and increase strength. The strength training programs in older people themselves are probably one of the most effective preventive measures to delay the onset of sarcopenia. In this literature review different factors related sarcopenia and strength training as a preventive method is analyzed.

La sarcopenia es un síndrome que se caracteriza por una pérdida gradual y generalizada de la masa muscular esquelética y la fuerza, con riesgo de presentar resultados adversos como discapacidad física, calidad de vida deficiente y mortalidad. Existen varios factores que contribuyen: el proceso de envejecimiento a lo largo de la vida, influencias sobre el desarrollo en las etapas iniciales de la vida, una alimentación inadecuada, el reposo en cama o sedentarismo, enfermedades crónicas y determinados tratamientos farmacológicos. La sarcopenia representa un deterioro del estado de salud con un costo personal elevado: trastornos de la movilidad, mayor riesgo de caídas y fracturas, deterioro de la capacidad de realizar actividades cotidianas, discapacidad, perdida de independencia y mayor riesgo de muerte. El entrenamiento de la fuerza es actualmente uno de los métodos más eficaces para combatir la sarcopenia mediante la estimulación de la hipertrofia e incremento de la fuerza. Los programas de entrenamiento de fuerza en personas mayores probablemente constituyen, por sí mismos, una de las medidas preventivas más eficaces para retrasar la aparición de sarcopenia. En la presente revisión bibliográfica se analizarán diferentes factores relacionados con la sarcopenia y el entrenamiento de la fuerza como método preventivo.

Effects of short-term strength training on body composition, muscle strength and functional capacity of elderly: a systematic review and meta-analysis / Efeitos do treinamento de força de curta duração sobre a composição corporal, a força muscular e a capacidade funcional de idosos: revisão sistemática e meta-análise

To examine the effects of short-term strength training (STST) on different manifestations of muscle strength in the lower limbs, functional capacity and body composition of people 65 years old or older. We searched the electronic databases (PubMed, Web of Science and Cochrane) to identify all publications using STST (up to 12 weeks) in people aged 65 or older, published in the last five years, prior to May 2018. Results were analyzed as continuous data using random effects to calculate the standardized mean difference (SMD) and the 95% confidence interval (95%CI). 28 studies with 921 subjects met the inclusion criteria and were analyzed. These works were grouped into three categories for analysis: Muscular Strength, Functional Capacity and Body Composition. In Muscular Strength category, the overall pooled effect estimate was 0.95 (95%CI: 0.63; 1.26), with a significant STST effect (Z= 5.93; p<0.001), over the different strength manifestations analyzed. In Functional Capacity category, the STST decreased the Time Up-and-Go test run time (SMD: -1.01; 95%CI: -1.56; -0.47) and increased the repetitions' number performed in 30-s chair-stand test (SMD: 1.07, 95% CI: 0.79, 1.34). In Body Composition category, the overall pooled effect estimate was 0.13 (95%CI: -0.16; 0.42), without finding a significant effect of STST (Z= 0.87; p= 0.38). STST has a moderate to large effect in improving the different manifestations of muscle strength and functional capacity. However, this type of intervention has no effect on body composition.

Examinar os efeitos do treinamento de força de curta duração (TFCD) em diferentes manifestações de força muscular nos membros inferiores, capacidade funcional e composição corporal de pessoas maiores de 65 anos. Foram pesquisadas bases de dados eletrônicas (PubMed, Web of Science e Cochrane) para identificar todas as publicações utilizando TFCD (até 12 semanas) em pessoas maiores de 65 anos, publicadas nos últimos cinco anos, antes de maio de 2018. Os resultados foram analisados como dados contínuos usando efeitos aleatórios para calcular a diferença padronizada da média (SMD) e o intervalo de confiança de 95% (IC95%). 28 estudos com 921 sujeitos preencheram os critérios de inclusão e foram analisados. Esses trabalhos foram agrupados em três categorias para análise: Força Muscular, Capacidade Funcional e Composição Corporal. Na categoria Força Muscular, a estimativa geral do efeito combinado foi de 0,95 (95% CI: 0,63; 1,26), com um efeito significativo do TFCD (Z = 5,93; p <0,001), sobre as diferentes manifestações de força analisadas. Na categoria Capacidade Funcional, o TFCD diminuiu o tempo de execução do teste Timed Up-and-Go (SMD: -1.01; 95% CI: -1.56; -0.47) e aumentou o número de repetições realizadas no teste de levantar e sentar na cadeira de 30 segundos (SMD: 1,07, IC 95%: 0,79, 1,34). Na categoria de Composição Corporal, a estimativa geral do efeito combinado foi de 0,13 (IC 95%: -0,16; 0,42), sem encontrar efeito significativo do TFCD (Z = 0,87; p = 0,38). O TFCD apresenta efeito moderado a grande na melhora das diferentes manifestações de força muscular e capacidade funcional. No entanto, este tipo de intervenção não tem efeito sobre a composição corporal.

S-nitroso-N-acetylcysteine attenuates liver fibrosis in cirrhotic rats.

This study was aimed to investigate the molecular mechanisms underlying prevention of hepatic fibrosis by S-nitroso-N-acetylcysteine (SNAC), a nitric oxide donor that inhibits lipid peroxidation. Secondary biliary cirrhosis was induced by 4 weeks of common bile duct ligation (CBDL). Both sham-operated and CBDL animals received SNAC (6.0 micromol/kg/day) starting 2 weeks after surgery. SNAC treatment reduced the increase in blood enzyme activities (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), induced by CBDL. Histological changes were attenuated and there was a significant decrease in the area of liver fibrosis and in the activation of stellate cells measured by alpha-smooth muscle actin (alpha-SMA) immunostaining. The increase in TBARS concentration and hydroperoxide-induced chemiluminescence were also reduced by SNAC treatment. SNAC down-regulated expression of collagen 1 alpha, alpha-SMA, tumor necrosis factor-alpha, tumor growth factor-beta, metalloproteinase-2, metalloproteinase inhibitor 1, platelet-derived growth factor (PDGF), and PDGF receptor in CBDL rats. These effects were accompanied by inhibited activation of extracellular signal-regulated kinases, Jun amino-terminal kinases, p38 and Akt. Antifibrotic effects were more efficient than those of the free thiol NAC administered at a dose of 60 mumol/kg. In conclusion, results obtained indicate that SNAC, beyond its antioxidant capacity, exerts antifibrotic effects in rats with secondary biliary cirrhosis by down-regulating increased expression of genes and modulating intracellular signaling pathways that contribute to the accumulation of matrix proteins. Thus, SNAC may be an interesting candidate for the treatment of human fibrosis and cirrhosis.

Efecto del ejercicio agudo sobre la expresión del receptor tipo Toll-4 y los mecanismos inflamatorios en corazón de rata / Effect of an acute exercise bout on Toll-like receptor 4 and inflammatory mechanisms in rat hear

Background: Toll like receptor 4 (TLR-4) is a protein located in the cell membrane with an important function in the immune response of the organism. Its activation decreases heart contractility and activates nuclear transcription factor kappa B (NF-kB ). This in turn, increases the synthesis of different pro-inflammatory cytokines and the inducible enzyme nitric oxide (iNOS), which plays an important role in the inflammatory processes when nitric oxide production is enhanced. Aim: To determine if, after one session of acute exercise, expression of TLR-4 and iNOS, and activation of NF-kB are induced in rat cardiac tissue. Material and Methods: Exercise and control groups of eight male Wistar rats each, were studied. The exercise group was subjected to an acute exercise bout lasting one hour. After the exercise, the heart was excised to measure the expression of iNOS and TLR-4 genes by quantitative polyme-rase chain reaction, NF-kB activation by electrophoretic mobility shift assay (EMSA) and p50 by Western blot. Results: After exercise, there was an increase in TLR-4 and of iNOS mRNA levels (+46.7 and +74.3% respectively). NF-kB activation and the nuclear expression of its p50 subunit also increased significantly (+240 and +306% respectively). Conclusions: Increased expression of TLR4 following a session of acute exercise may contribute to the activation of the NF-kB signaling route, promoting the synthesis of nitric oxide, which could influence negatively the cardiac response to high intensity physical exercise.

Effects of epomediol on ethinyloestradiol-induced changes in glutathione homeostasis in the rat.

Epomediol is a synthetic terpenoid compound that has been reported to reduce ethinyloestradiol-induced cholestasis. The choleretic action of epomediol is related to an increase in both the bile acid-dependent and independent fractions of bile flow, but the role of glutathione metabolism and transport is still unknown. This study was aimed to evaluate if changes in glutathione homeostasis could contribute to the beneficial effects of epomediol in rats with ethinyloestradiol-induced cholestasis. When compared to control animals, ethinyloestradiol treatment resulted in a significant decrease in the liver concentration of reduced (GSH) and oxidized glutathione. Both GSH and oxidized glutathione concentrations returned to normal in animals receiving ethinyloestradiol plus epomediol. Ethinyloestradiol administration induced a significant decrease in plasma and renal GSH and the tripeptide was almost absent from bile. Combined treatment with epomediol plus ethinyloestradiol normalised renal GSH and both biliary and liver cysteine were significantly increased. Liver and kidney gamma-glutamyltranspeptidase activities were higher in rats receiving ethinyloestradiol and still remained elevated in animals with the combined treatment. Liver gamma-glutamylcysteine synthetase activity rose significantly by administration of ethinyloestradiol plus epomediol but the corresponding mRNA levels were not modified. Changes in glutathione homeostasis and higher biliary levels of GSH amino acid constituents could contribute to the beneficial effects of epomediol in rats with ethinyloestradiol-induced cholestasis.