Creatine and the Liver: Metabolism and Possible Interactions.

The process of creatine synthesis occurs in two steps, catalyzed by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT), which take place mainly in kidney and liver, respectively. This molecule plays an important energy/pH buffer function in tissues, and to guarantee the maintenance of its total body pool, the lost creatine must be replaced from diet or de novo synthesis. Creatine administration is known to decrease the consumption of Sadenosyl methionine and also reduce the homocysteine production in liver, diminishing fat accumulation and resulting in beneficial effects in fatty liver and non-alcoholic liver disease. Different studies have shown that creatine supplementation could supply brain energy, presenting neuroprotective effects against the encephalopathy induced by hyperammonemia in acute liver failure. Creatine is also taken by many athletes for its ergogenic properties. However, little is known about the adverse effects of creatine supplementation, which are barely described in the literature, with reports of mainly hypothetical effects arising from a small number of scientific publications. Antioxidant effects have been found in several studies, although one of the theories regarding the potential for toxicity from creatine supplementation is that it can increase oxidative stress and potentially form carcinogenic compounds.

Understanding nutritional interventions and physical exercise in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in adults and its prevalence is rising around the world. This pathology is characterized by accumulation of liver fat, which exceeds 5% of liver weight in absence of alcohol consumption, viral infection or other hepatic etiology. Since NAFLD has been associated with obesity, insulin resistance, diabetes or alteration of lipid profiles, it is considered as the liver manifestation of metabolic syndrome. Pathogenic mechanisms of NAFLD have not been clearly elucidated, but different events such as lipid accumulation, insulin resistance, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction and inflammation are involved. Modifications in lifestyle constitute the first line for the management of NAFLD. Nutritional interventions include low fat and carbohydrate diet with higher polyunsaturated fatty acids ingestion. Moreover, supplementation with antioxidant and cytoprotective agents could be useful to decrease oxidative stress, inflammation and fibrosis. Physical activity enables to reduce the expression of lipogenic genes, fat accumulation, or insulin resistance and improves cardiorespiratory fitness. Benefits have been found following both aerobic exercise and resistance training, and remain even after exercise cessation. However, more studies are required to analyze the molecular and cellular mechanisms involved in nutritional and physical intervention, and to define the volume of activity required and its association with weight loss. In this paper, we offer an updated overview of the mechanisms implicated in the progression of NAFLD, and analyze the beneficial effects of nutritional interventions and physical exercise in the prevention and treatment of this condition.

On-line surface plasmon resonance biosensing of vascular endothelial growth factor signaling in intact-human hepatoma cell lines.

Surface plasmon resonance (SPR) monitoring of biorecognition events at intracellular levels is a valuable tool for studying the angiogenic response of carcinoma living cells during tumor growth and proliferation. We report here a comparative study of two different strategies to detect human hepatoma cell interactions between transmembrane vascular endothelial growth factor receptor (VEGFR2) and vascular endothelial growth factor (VEGF). To monitor VEGFR2 activation after VEGF stimulation, intact hepatocellular carcinoma HepG2 or Huh7 cells (2 × 10(5) cells per mL) were directly immobilized on the sensor chip. Distinguishable SPR sensorgrams were obtained for each cell line depending on the time required for VEGFR2 activation. SPR signals for VEGF-VEGFR2 binding were inhibited by the VEGFR inhibitor, CBO-P11. The SPR response after VEGF stimulation/inhibition was in good agreement with the results observed by immunoblotting analysis. In a second approach we used intact cell lines as analytes. SPR analysis was done by injecting HepG2 and HuH7 cell suspensions (2-4 × 10(4) cells per mL) onto a sensor surface previously immobilized with VEGF via a thiol self-assembled monolayer (SAM). Specificity and reproducibility were evaluated reusing the same chip surface over more than 60 complete regeneration cycles. Comparison between both methods yielded differences in terms of reliability, making the latter strategy more effective for the analysis of real samples. The investigation of VEGF signaling in intact human hepatoma living cells by SPR monitoring comprises a novel and promising design for the study of tumor angiogenesis via downregulation of VEGF and VEGFR2 pathways. Further investigation on VEGFR activation and vascular function could contribute to establish a robust and meaningful tool for early cancer diagnostics.

FoxO proteins: regulation and molecular targets in liver cancer.

Human forkhead box class O (FoxO) transcription factors, activated in response to a wide range of external stimuli, like growth factors, insulin, nutrient levels and oxidative stress, are able to control several specific geneexpression programs. Besides their clear implication in metabolic processes, they appear to play a relevant role in tumour suppression by upregulation of genes involved in cell cycle arrest or apoptosis. Recent research efforts provide new insights into the molecular modulation of FoxO in liver cancer and disclose potential opportunities for developing new antitumor drugs. Through an intricate regulatory model, achieved via several post-translational modifications, including phosphorylation, acetylation, and ubiquitination, which control their subcellular localization and DNA binding activity, FoxO factors act as tumour suppressors. Low levels of FoxOs are associated with poor prognosis in cancer patients, and seem to confer chemotherapy resistance. Within FoxO members, FoxO3a appears to present anti-tumour properties in hepatocellular carcinoma, inducing the expression of pro-apoptotic genes, or interfering with signaling cascades commonly altered in this disease such as Wnt/ß-catenin, PI3K/AKT/mTOR or MAPKs pathways. Here, we describe the main mechanisms of FoxO proteins regulation, and their cross-link with altered pathways in liver cancer. Moreover, based on the current knowledge of FoxO modulation, emphasis is placed on the development of novel agents which specifically activate FoxO family members and could be useful in the treatment of hepatocarcinoma.

The MnSOD Ala16Val SNP: relevance to human diseases and interaction with environmental factors.

The relevance of reactive oxygen species (ROS) production relies on the dual role shown by these molecules in aerobes. ROS are known to modulate several physiological phenomena, such as immune response and cell growth and differentiation; on the other hand, uncontrolled ROS production may cause important tissue and cell damage, such as deoxyribonucleic acid oxidation, lipid peroxidation, and protein carbonylation. The manganese superoxide dismutase (MnSOD) antioxidant enzyme affords the major defense against ROS within the mitochondria, which is considered the main ROS production locus in aerobes. Structural and/or functional single nucleotide polymorphisms (SNP) within the MnSOD encoding gene may be relevant for ROS detoxification. Specifically, the MnSOD Ala16Val SNP has been shown to alter the enzyme localization and mitochondrial transportation, affecting the redox status balance. Oxidative stress may contribute to the development of type 2 diabetes, cardiovascular diseases, various inflammatory conditions, or cancer. The Ala16Val MnSOD SNP has been associated with these and other chronic diseases; however, inconsistent findings between studies have made difficult drawing definitive conclusions. Environmental factors, such as dietary antioxidant intake and exercise have been shown to affect ROS metabolism through antioxidant enzyme regulation and may contribute to explain inconsistencies in the literature. Nevertheless, whether environmental factors may be associated to the Ala16Val genotypes in human diseases still needs to be clarified.

Inhibition of VEGF expression through blockade of Hif1α and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells.

BACKGROUND: Hepatocellular carcinoma (HCC) growth relies on angiogenesis via vascular endothelial growth factor (VEGF) release. Hypoxia within tumour environment leads to intracellular stabilisation of hypoxia inducible factor 1 alpha (Hif1α) and signal transducer and activator of transcription (STAT3). Melatonin induces apoptosis in HCC, and shows anti-angiogenic features in several tumours. In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate the anti-angiogenic effects of melatonin. METHODS: HepG2 cells were treated with melatonin under normoxic or CoCl2-induced hypoxia. Gene expression was analysed by RT-qPCR and western blot. Melatonin-induced anti-angiogenic activity was confirmed by in vivo human umbilical vein endothelial cells (HUVECs) tube formation assay. Secreted VEGF was measured by ELISA. Immunofluorescence was performed to analyse Hif1α cellular localisation. Physical interaction between Hif1α and its co-activators was analysed by immunoprecipitation and chromatin immunoprecipitation (ChIP). RESULTS: Melatonin at a pharmacological concentration (1 mM) decreases cellular and secreted VEGF levels, and prevents HUVECs tube formation under hypoxia, associated with a reduction in Hif1α protein expression, nuclear localisation, and transcriptional activity. While hypoxia increases phospho-STAT3, Hif1α, and CBP/p300 recruitment as a transcriptional complex within the VEGF promoter, melatonin 1 mM decreases their physical interaction. Melatonin and the selective STAT3 inhibitor Stattic show a synergic effect on Hif1α, STAT3, and VEGF expression. CONCLUSION: Melatonin exerts an anti-angiogenic activity in HepG2 cells by interfering with the transcriptional activation of VEGF, via Hif1α and STAT3. Our results provide evidence to consider this indole as a powerful anti-angiogenic agent for HCC treatment.

Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells.

BACKGROUND: Melatonin induces apoptosis in many different cancer cell lines, including hepatocellular carcinoma cells. However, the responsible pathways have not been clearly elucidated. A member of the forkhead transcription factors' family, FoxO3a, has been implicated in the expression of the proapoptotic protein Bim (a Bcl-2-interacting mediator of cell death). In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate whether melatonin treatment induces Bim through regulation by the transcription factor FoxO3a. METHODS: Cytotoxicity of melatonin was compared in HepG2 hepatoblastoma cells and primary human hepatocytes. Proapoptotic Bim expression was analysed by reverse transcriptase-polymerase chain reaction and western blot. Reporter gene assays and chromatin immunoprecipitation assays were performed to analyse whether FoxO3a transactivates the Bim promoter. Small interfering RNA (siRNA) was used to study the role of FoxO3a in Bim expression. Immunofluorescence was performed to analyse FoxO3a localisation in HepG2 cells. RESULTS: Melatonin treatment induces apoptosis in HepG2 cells, but not in primary human hepatocytes. The proapoptotic effect was mediated by increased expression of the BH3-only protein Bim. During melatonin treatment, we observed increased transcriptional activity of the forkhead-responsive element and could demonstrate that FoxO3a binds to a specific sequence within the Bim promoter. Furthermore, melatonin reduced phosphorylation of FoxO3a at Thr(32) and Ser(253), and induced its increased nuclear localisation. Moreover, silencing experiments with FoxO3a siRNA prevented Bim upregulation. CONCLUSION: This study shows that melatonin can induce apoptosis in HepG2 hepatocarcinoma cells through the upregulation of proapoptotic Bim mediated by nuclear translocation and activation of the transcription factor FoxO3a.

Non-alcoholic steatohepatitis: what can we learn from animal models?

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver function and correlates with central adiposity, obesity, insulin resistance, the metabolic syndrome and type 2 diabetes mellitus. The pathological spectrum of NAFLD ranges from fatty liver to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. Though NAFLD and NASH are becoming a major public health problem, ethical constraints on obtaining human liver tissue limit the interpretability of the data and the ability to delineate cause and effect from complex, interactive disease pathogenic pathways. Animal models of NASH can provide critical information leading to identify potential drug targets and to understand their molecular mechanisms, and are platforms for compound screening in drug development and for the assessment of novel therapeutic strategies. This review is aimed to offer an updated overview of the nutritional, genetic and pharmacologic animal models of NASH. Though the information derived from these models has clear relevance for the comprehension of the molecular basis of human disease, most of them fail to reproduce the full spectrum of liver pathology and the metabolic context that characterizes human NASH. Consequently, it is necessary to establish animal models that can best mimic the actual etiology, progression, and pathogenesis of the disease, and prove effectiveness for examining and selecting compounds with potential therapeutic benefit in NASH.

Effects of 7-weeks competitive training period on physiological and mental condition of top level judoists.

AIM: We examined hormonal and haematological parameters and the profile of mood states (POMS) in top level judoists undertaking a 7-week competitive training period in a real contest. METHODS: Participants were 10 top level judoists belonging to the Spanish National Team. Training load was calculated by multiplying the training session intensity by the duration of the training session. The judoists competed in two official events on weeks 3 and 6 of the study. RESULTS: Urinary catecholamines increased at the end of the competitive period. Serum cortisol increased during the weeks in which judoists competed, confirming the existence of and anticipatory cortisol response to exercise; although we failed to find serum testosterone increases. Because of leukocyte values did not change, except monocytes, we speculate that the intensity of training was not sufficiently high to evoke injury to muscle tissue. Anger, tension, and fatigue increased according with training load, suggesting that the training exercise led participants into a negative psychological state. CONCLUSION: Findings indicate that during competitive periods, judoists suffer hormonal and mood changes according to training load and competitive events. Results support the usefulness of monitoring biological and psychological markers during season in order to adjust training loads and periods of recovery.

Biological and psychological monitoring of training status during an entire season in top kayakers.

AIM: The aim of this study was to analyze changes in selected biological and psychological variables in a group of top level kayakers along a 42-week training season. METHODS: Eight top junior sprint kayakers (age=16.8±2.1) (5 men and 3 women) with international competitive experience participated in the research. During the 42-wk season the subjects were tested in three occasions: (T1) in the second week of the general training period, (T2) at the beginning of the specific training period, (T3) at the beginning of the competitive training period. Firstly, subjects were asked to complete the Recovery-Stress Questionnaire for Athletes (RESTQ-Sport) and the Profile of Mood States (POMS) questionnaires, and Borg´s rate of perceived exertion scale (RPE). Immediately after, blood samples were collected and white blood cells, creatine kinase (CK), C-reactive protein (CRP), myeloperoxidase protein levels (MPO) and glutathione status were determined. ANOVA with repeated measures was used to determine the differences between tests. RESULTS: From the hematological and biochemical measures only total leukocytes changed significantly, increasing at T3 when compared to T1. There were no differences along the entire season in both RESTQ-Sport and POMS scores or indices. Concerning performance, the group improved their maximal strength (+17.4% in bench-press 1RM) and their specific-distance time (+9.8%). The main finding of the present study was that training was well-balanced between stress and recovery because while specific performance increased, signs of overtraining were not found. CONCLUSION: Training monitoring in athletes should be performed in a multilevel approach using measurements of performance as well as biological or psychological parameters.

Hepatitis C virus, oxidative stress and steatosis: current status and perspectives.

Reactive oxygen and nitrogen species (ROS/RNS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment. When the production of ROS/RNS overrides the antioxidant capability of the target cells, oxidative damage may occur as a consequence of the interaction with DNA, protein, and lipids. Hepatitis C virus (HCV) is a major cause of viral hepatitis. Although the molecular mechanisms of HCV pathogenesis remain unclear, oxidative stress is emerging as a key step and a major initiator in the development and the progression of liver damage, and the evaluation of oxidative stress may be useful for a better understanding of the pathogenesis of hepatitis C. Liver steatosis is one of the most important histopathological features in patients with chronic hepatitis C. Both viral and host factors contribute to the development of steatosis, and putative defects caused by ROS/RNS may be involved through abnormalities in lipid metabolism. This review is aimed to offer an updated overview of the relationship between oxidative stress and HCV infection, focusing on the significance of ROS/RNS in the pathogenesis of liver disease. The potential role played by oxidative stress in the pathogenic mechanisms of HCV-related steatosis is also discussed.

Signs of overload after an intensified training.

This study investigated effects of a 9-week intensified aerobic training and 3-weeks of recovery on signs of overload in 9 healthy active young males. Blood and saliva samples were collected and psychological questionnaires were administered during baseline (T1), intermediate load (T2), maximal load (T3), and recovery (T4) periods. Maximal oxygen uptake increased and blood lactate concentration decreased in T3, while running time in a 3 000 m track field test was significantly shorter. No significant changes were found in hematocrit, haemoglobin concentration, white blood cell count, lactate dehydrogenase, transaminases, interleukin-6, tumour necrosis factor-α, myeloperoxidase and markers of oxidative stress in plasma, or salivary cortisol and testosterone. Increases in different negative affect scales and in the total mood disturbance score of the Profile of Mood States were observed during T3. Scores in the stress scales of the Recovery-Stress Questionnaire for Athletes and in the State Anxiety Scale of the State-Trait Anxiety Inventory also showed significant increases during T3. The lack of effects in biomarkers together with the changes observed in psychological assessment indicates that an intensified training can produce psychological disturbances prone to early overreaching development. Additionally, it seems that psychological parameters are sensitive markers to detect stress produced by load increases.

Evaluation of the potential protective effects of ad libitum black grape juice against liver oxidative damage in whole-body acute X-irradiated rats.

AIMS: The aim of this study was to evaluate the potential protective effects of ad libitum black grape (Vitis labrusca) juice against liver oxidative damage in whole-body acute X-irradiated rats. MAIN METHODS: Animals were fed ad libitum and drank voluntarily black grape juice or placebo (isocaloric glucose and fructose solution) for 6 days before and 15 days following a 6 Gy X-irradiation from a 200 kV machine. KEY FINDINGS: Irradiated animals receiving placebo showed a significant increase in the concentration of thiobarbituric acid-reactive substances (TBARS), a marker of lipid peroxidation, as well as a significant decrease in both Cu/Zn superoxide dismutase (Cu/ZnSOD) and glutathione peroxidase (GPx) activity and reduced glutathione concentration (GSH). Black grape juice supplementation resulted in a reversal of lipid peroxidation, Cu/ZnSOD activity, and GSH concentration, towards values not significantly differing from those in non-irradiated, placebo-supplemented rats. Poly(ADP-ribose) polymerase (PARP-1) and Cu/ZnSOD changes in protein expression were observed for irradiated rats. No change in p53 expression or DNA fragmentation was found. SIGNIFICANCE: Ad libitum black grape juice intake is able to restore the liver primary antioxidant system against adverse effects due to whole-body acute X-irradiation in rats after 15 days post-irradiation. The results support using antioxidant supplements as a preventive tool against radiation-induced harm.

Physical activity and energy expenditure measurements using accelerometers in older adults.

The purpose of this review is to address methodological issues related to accelerometer-based assessments of physical activity (PA) in older individuals. Special interest is also put on recently updated technology. No definitive evidence exists currently to indicate which are the more valid and reliable accelerometer models for use with older people. When it comes to selecting an accelerometer, issues of affordability, product reliability, monitor size, technical support, and comparability with other studies may be equally as important as the relative validity and reliability of an instrument. The accelerometer should be attached as close as possible to the body's center of mass, and in the case of elders using walking aids, it should be placed on the same body side. Variability due to positioning can be reduced with careful training and supervision. Typically, the sampling period is between 3 and 7 days and it is not yet clear if variability exists between weekdays and weekend in the elderly. It is possible that aging effects on physical and cognitive health may limit the ability of an older adult to be compliant with an accelerometer protocol; in this line many methods have been suggested for increasing compliance to protocols for research studies. Accelerometers can provide reliable information on mobility and objective measurement of PA. These activity monitors have significant advantages when compared with other quantitative methods for measurement of energy expenditure. Accelerometers are currently used mainly in a research setting; however, with recent advances, incorporation into clinical and fitness practice is possible and increasing.

Physical activity and energy expenditure measurements using accelerometers in older adults / Utilización de los acelerómetros para la medida de la actividad física y el gasto energético en personas mayores

The purpose of this review is to address methodological issues related to accelerometer-based assessments of physical activity (PA) in older individuals. Special interest is also put on recently updated technology. No definitive evidence exists currently to indicate which are the more valid and reliable accelerometer models for use with older people. When it comes to selecting an accelerometer, issues of affordability, product reliability, monitor size, technical support, and comparability with other studies may be equally as important as the relative validity and reliability of an instrument. The accelerometer should be attached as close as possible to the body's center of mass, and in the case of elders using walking aids, it should be placed on the same body side. Variability due to positioning can be reduced with careful training and supervision. Typically, the sampling period is between 3 and 7 days and it is not yet clear if variability exists between weekdays and weekend in the elderly. It is possible that aging effects on physical and cognitive health may limit the ability of an older adult to be compliant with an accelerometer protocol; in this line many methods have been suggested for increasing compliance to protocols for research studies. Accelerometers can provide reliable information on mobility and objective measurement of PA. These activity monitors have significant advantages when compared with other quantitative methods for measurement of energy expenditure. Accelerometers are currently used mainly in a research setting; however, with recent advances, incorporation into clinical and fitness practice is possible and increasing (AU)

El objetivo de esta revisión se centra en cuestiones metodológicas relacionadas con la medición de la actividad física mediante acelerómetros en personas mayores. Se pone un especial énfasis en la tecnología más reciente. Actualmente no existen pruebas definitivas que indiquen que un modelo es más válido y fiable que otro para su utilización con los ancianos. Al seleccionar un acelerómetro, la comodidad, la fiabilidad del producto, el tamaño, el apoyo técnico y la comparación con otros estudios pueden ser tan importantes como la validez y la fiabilidad del instrumento. Los acelerómetros deben colocarse lo más cerca posible del centro de masas del cuerpo y en el caso de que los ancianos utilicen ayudas técnicas para caminar se deben situar en el mismo lado del cuerpo. La variabilidad debida a la colocación puede reducirse con un cuidadoso entrenamiento y supervisión. Normalmente el periodo de registro es entre 3 y 7 días y todavía no está claro si existe suficiente variabilidad entre días de la semana y de fin de semana en ancianos. Es posible que los efectos del envejecimiento sobre la salud física y cognitiva puedan limitar la capacidad de un anciano de adaptarse al protocolo de utilización de un acelerómetro; en esta línea se han sugerido métodos para incrementar el cumplimiento de los protocolos en estudios de investigación. Los acelerómetros pueden aportar información fiable sobre la movilidad y medidas objetivas de actividad física. Estos monitores presentan ventajas significativas cuando se comparan con otros métodos cuantitativos utilizados en la actualidad para la medida de la actividad física habitual. Actualmente los acelerómetros se utilizan principalmente en investigación; sin embargo, con la incorporación de avances recientes, su empleo es posible y se está incrementando en clínica y para la mejora de la forma física (AU)

Whole-body vibration training increases muscle strength and mass in older women: a randomized-controlled trial.

To determine whether 10 weeks of whole-body vibration (WBV) training has a significant effect on strength, muscle mass, muscle power, and mobility in older women, 26 subjects were randomly assigned to a WBV training group (n=13; mean age 79 years) and a control (CON) group (n=13; mean age 76 years). Maximal voluntary isometric contraction (MVIC) increased 38.8% in the WBV group, without changes in the CON group. Electromyographic activity of the vastus medialis (VM), the vastus lateralis, and the biceps femoris (BF) did not change in either group. Thigh muscle cross-sectional area increased significantly after training in VM (8.7%) and BF (15.5%). Muscle power at 20%, 40%, and 60% MVIC decreased from pre-test to post-test in the CON group; however, WBV training prevented the decrease in the WBV group. Consequently, mobility, measured by the Timed Up and Go test, increased significantly after training (9.0%) only in the WBV group. Ten weeks of lower limb WBV training in older women produces a significant increase in muscle strength induced by thigh muscle hypertrophy, with no change in muscle power. The adaptations to WBV found in the present study may be of use in counteracting the loss of muscle strength and mobility associated with age-induced sarcopenia.

Potential of flavonoids as anti-inflammatory agents: modulation of pro-inflammatory gene expression and signal transduction pathways.

Flavonoids are a large class of naturally occurring compounds widely present in fruits, vegetables, and beverages derived from plants. Reports have suggested that these compounds might be useful for the prevention of a number of diseases, partly due to their anti-inflammatory properties. It has been demonstrated that flavonoids are able to inhibit expression of isoforms of inducible nitric oxide synthase, ciclooxygenase and lipooxygenase, which are responsible for the production of a great amount of nitric oxide, prostanoids and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines or adhesion molecules. Modulation of the cascade of molecular events leading to the over-expression of those mediators include inhibition of transcription factors such as nuclear factor kappa B, activator protein 1, signal transducers and activators of transcription, CCAAT/enhancer binding protein and others. Effects on the binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen activated protein kinases. Although the numerous studies published with in vitro approaches allow identifying molecular mechanisms of flavonoid effects, the limited bioavailability of these molecules makes necessary validation in humans. Whatever the case, the data available make clear the potential utility of dietary flavonoids or new flavonoid-based agents for the possible treatment of inflammatory diseases. The present review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by flavonoids and the effects on cell signaling pathways responsible for their anti-inflammatory activity.

Effects of resistance training in multiple sclerosis.

This study examined the effects of an eight-week progressive resistance training on different strength manifestations, muscle mass and functionality in multiple sclerosis patients. Thirteen volunteered patients (average age 43 years; range 35-51) with a confirmed diagnosis by a neurologist and mild to moderate disability participated twice a week in an eight-week progressive resistance training program after an eight-week control period without training. Intensity ranged from 40-70% of their maximal voluntary contraction. Outcome assessments included magnetic resonance image of the right and left thighs, strength manifestations (maximal voluntary contraction, muscular endurance and power), and functionality by the Up and Go test. All outcome assessments remained unaltered during the eight-week control period. After the eight-week strength training period, isometric strength (+16%, p<0.01), muscular endurance (+84%; p<0.001), maximal power (+51%, p<0.001), muscular hypertrophy from slice 6/27 to slice 11/27 of both thighs (p<0.05), and functionality (p<0.001) improved significantly. Moderate resistance training programs can improve muscle function without injuries and can be a promising therapy to delay the functional deterioration in multiple sclerosis patients.

Apoptotic signaling pathways as a target for the treatment of liver diseases.

Dysregulation of apoptosis is a major contributor to the initiation and aggravation of liver injury. Agents that modulate apoptosis may be of therapeutic benefit in a number of liver diseases, and research related to cell type-specific activation or inhibition of apoptotic signaling pathways will provide new strategies for treatment.

Monitoring the effects of training load changes on stress and recovery in swimmers.

This study was designed to investigate if monitoring of stress and recovery may be useful to detect overreaching in its early stages and may be used to evaluate effects of changes in training load. Nine swimmers were applied the Recovery-Stress Questionnaire for Athletes (RESTQ-Sport) in four different occasions (M1, M2, M3, M4) along a 6-week training period prior to a competition. During the basal training period (M1), recovery scales scored higher than stress scales, being the scales General well-being, Social recovery and Being in shape those reaching higher scores. Following the measure corresponding to the second training period (M2), in which training volume reached a maximum, there were significant increases in two stress scales (Injury and Emotional exhaustion), and decreases in three recovery scales (Success, Physical recovery, and Self-efficacy). Values increased again and did not significantly differ from those corresponding to the first measure during measures M3 and M4, in which there was a decrease in training volume and training time. Only a recovery scale score (Success) increased significantly from period M2 to period M4. When the recovery-stress (total recovery - total stress) state was calculated, it was found that there was a significant decreases in M2, and values progressively increased in measures M3 and M4, with no significant difference from M1. Results obtained indicate that the RESTQ-Sport is able to show significant changes concurrently with training loads. Regular monitoring of stress and recovery by these measures may help to detect overreaching in its early stages.