RESUMO
The therapeutic potential of ultramicronized palmitoylethanolamide (um-PEA) was investigated in young (6-month-old) and adult (12-month-old) 3 × Tg-AD mice, which received um-PEA for 3 months via a subcutaneous delivery system. Mitochondrial bioenergetics, ATP homeostasis, and magnetic resonance imaging/magnetic resonance spectroscopy were evaluated in the frontal cortex (FC) and hippocampus (HIPP) at the end of um-PEA treatment. Glutamate release was investigated by in vivo microdialysis in the ventral HIPP (vHIPP). We demonstrated that chronic um-PEA treatment ameliorates the decrease in the complex-I respiration rate and the FoF1-ATPase (complex V) activity, as well as ATP content depletion in the cortical mitochondria. Otherwise, the impairment in mitochondrial bioenergetics and the release of glutamate after depolarization was not ameliorated by um-PEA treatment in the HIPP of both young and adult 3 × Tg-AD mice. Moreover, progressive age- and pathology-related changes were observed in the cortical and hippocampal metabolism that closely mimic the alterations observed in the human AD brain; these metabolic alterations were not affected by chronic um-PEA treatment. These findings confirm that the HIPP is the most affected area by AD-like pathology and demonstrate that um-PEA counteracts mitochondrial dysfunctions and helps rescue brain energy metabolism in the FC, but not in the HIPP.
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BACKGROUND: The emission of lead (Pb) occurring during the extraction, processing and industrial applications of this element remains a significant environmental risk factor. The absorbability of lead in humans is strongly associated with the general health status of exposed individuals. Existing mineral deficiencies are considered being a predisposition to an increased Pb uptake. Both, iron deficiency and lead poisoning are the major causative factors responsible for the prevalence of anemia within the vulnerable population, especially in children. Although some of the intervention programs of counteracting lead poisoning by iron supplementation proved to be effective in the Pb-exposed population, the exact mechanisms of this interaction still require further studies. The objective of the presented study was to examine the association of iron level on oxidative stress measures and its effects on the severity of lead toxicity in the exposed population. METHODS: The analyzed population consisted of 270 male workers from the lead-zinc smelter. The studied population was divided into two sub-groups based on the serum iron concentration: low iron level group (L-Fe; Fe < median value) and high iron level group (H-Fe; Fe > median value). Measured traits comprised of blood lead (PbB), serum Fe and zinc protoporphyrin (ZPP) levels as well as a blood count and oxidative stress markers. RESULTS: No significant correlation between serum iron concentration and PbB in the tested cohort was found. On the contrary, the analysis of ZPP levels (long-term marker related to a hematologic toxic effect of Pb) within the subgroups differing in serum Fe level shown that ZPP was 12.3 % lower (p = 0.043) in subjects classified within the H-Fe group. A positive correlation of serum Fe and total antioxidant capacity (TAC) was found (R = 0.1999). The conducted 3-D PCA analysis showed that individuals classified within the H-Fe group were characterized by the co-occurrence of higher Fe levels, lower ZPP, and higher TAC value. CONCLUSION: These results support the existing evidence providing that maintaining the optimal status of Fe may play a significant role in preventing the lead poisoning and alleviating harmful effects of Pb on the oxidative balance in humans.
Assuntos
Deficiências de Ferro , Intoxicação por Chumbo , Chumbo/metabolismo , Estresse Oxidativo , Antioxidantes , Biomarcadores , Criança , Humanos , Ferro , MasculinoRESUMO
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease globally, and represents a health care burden as treatment options are very scarce. The reason behind the NAFLD progression to non-alcoholic steatohepatitis (NASH) is not completely understood. Recently, the deficiency of micronutrients (e.g., vitamins, minerals, and other elements) has been suggested as crucial in NAFLD progression, such that recent studies reported the potential hepatic antioxidant properties of micronutrients supplementation. However, very little is known. Here we have explored the potential beneficial effects of dietary supplementation with FLINAX, a novel mixture of nutraceuticals (i.e., vitamin E, vitamin D3, olive dry-extract, cinnamon dry-extract and fish oil) in a NAFLD model characterized by oxidative stress and mitochondrial function impairment. Steatosis was firstly induced in Wistar rats by feeding with a high-fat/high-cholesterol diet for 4 weeks, and following this the rats were divided into two groups. One group (n = 8) was treated for 2 weeks with a normal chow-diet, while a second group (n = 8) was fed with a chow-diet supplemented with 2% FLINAX. Along with the entire experiment (6 weeks), a third group of rats was fed with a chow-diet only as control. Statistical analysis was performed with Student's T test or one-way ANOVA followed by post-hoc Bonferroni test when appropriate. Steatosis, oxidative stress and mitochondrial respiratory chain (RC) complexes activity were analyzed in liver tissues. The dietary supplementation with FLINAX significantly improved hepatic steatosis and lipid accumulation compared to untreated rats. The mRNA and protein levels analysis showed that CPT1A and CPT2 were up-regulated by FLINAX, suggesting the enhancement of fatty acids oxidation (FAO). Important lipoperoxidation markers (i.e., HNE- and MDA-protein adducts) and the quantity of total mitochondrial oxidized proteins were significantly lower in FLINAX-treated rats. Intriguingly, FLINAX restored the mitochondrial function, stimulating the activity of mitochondrial RC complexes (i.e., I, II, III and ATP-synthase) and counteracting the peroxide production from pyruvate/malate (complex I) and succinate (complex II). Therefore, the supplementation with FLINAX reprogrammed the cellular energy homeostasis by restoring the efficiency of mitochondrial function, with a consequent improvement in steatosis.
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Suplementos Nutricionais , Fígado Gorduroso/tratamento farmacológico , Doenças Mitocondriais/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Transporte de Elétrons/efeitos dos fármacos , Transporte de Elétrons/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
Iron deficiency (ID) is the most frequent nutritional deficiency in the whole population worldwide, and the second most common cause of anemia in the elderly. The prevalence of anemia is expecting to rise shortly, because of an ageing population. Even though WHO criteria define anemia as a hemoglobin serum concentration <12 g/dL in women and <13 g/dL in men, several authors propose different and specific cut-off values for the elderly. Anemia in aged subjects impacts health and quality of life, and it is associated with several negative outcomes, such as longer time of hospitalization and a higher risk of disability. Furthermore, it is an independent risk factor of increased morbidity and mortality. Even though iron deficiency anemia is a common disorder in older adults, it should be not considered as a normal ageing consequence, but a sign of underlying dysfunction. Relating to the molecular mechanism in Iron Deficiency Anemia (IDA), hepcidin has a key role in iron homeostasis. It downregulates the iron exporter ferroportin, inhibiting both iron absorption and release. IDA is frequently dependent on blood loss, especially caused by gastrointestinal lesions. Thus, a diagnostic algorithm for IDA should include invasive investigation such as endoscopic procedures. The treatment choice is influenced by the severity of anemia, underlying conditions, comorbidities, and the clinical state of the patient. Correction of anemia and iron supplementation should be associated with the treatment of the causal disease.
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Anemia Ferropriva/etiologia , Anemia Ferropriva/terapia , Ferro/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Algoritmos , Pessoas com Deficiência , Feminino , Hemoglobinas/análise , Hepcidinas/fisiologia , Humanos , Infusões Parenterais , Ferro/farmacocinética , Deficiências de Ferro , Masculino , Ciências da Nutrição , Prevalência , Qualidade de Vida , Fatores de RiscoRESUMO
The current study evaluated levels of macro-/trace elements, select cytokines, and sperm quality, in the semen of men with abnormal spermograms. The study population of men with abnormal spermograms was divided into three groups, i.e., oligospermic, asthenozoospermic, and oligoasthenozoospermic. The control group was fertile men with normal semen parameters. Analyses showed that in comparison with that in the semen of the fertile men, levels of calcium, magnesium, and selenium were significantly lower in men with all three groups. Semen levels of zinc were significantly lower in men with asthenospermia as compared with that in control. GGT (gamma-glutamyltranspeptidase) activity in semen was significantly higher in men in any of the three states as compared with that seen in control semen. In contrast, semen ALT (alanine aminotransferase) activity was reduced in men with any of these abnormalities compared with that in the controls. Semen cholesterol levels were significantly lower in men with asthenospermia as compared with control semen. Of all the measured cytokines, only IL-5 levels were reduced in the semen of the men with any of the conditions as compared with control semen. The semen of infertile males is characterized by reduced levels of calcium, magnesium, and trace metals such as zinc and selenium. The study also indicated that measures of cholesterol and of GGT/ALT activities could serve as supplementary parameters indicative of semen quality. Further investigations are needed to clarify the role of the measured parameters in sperm physiology.
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Infertilidade Masculina , Oligoelementos , Citocinas , Humanos , Masculino , Sêmen , Análise do Sêmen , Motilidade dos Espermatozoides , EspermatozoidesRESUMO
OBJECTIVE: Older patients are frequently subjected to prolonged hospitalization and extended bed rest, with a negative effect on physical activity and caloric intake. This results in a consistent loss of muscle mass and function, which is associated with functional decline and high mortality. The aim of this study was to investigate the effect of 1 wk of oral amino acid (AA) supplementation in older patients subjected to low mobility during hospitalization. METHODS: Hospitalized older patients (69-87) were included in the control group (nâ¯=â¯50) or were administered 25 g of AA mixture (nâ¯=â¯44) twice daily throughout 7 d of low mobility. We collected data related to length of stay as primary outcome measure. In-hospital mortality, 90-d postdischarge mortality, 90-d postdischarge rehospitalization, and falls also were considered. Moreover, variations of anthropometric measures, body composition and muscle architecture/strength, circulating interleukins, and oxidative stress markers between the beginning and the end of the supplementation period were analyzed as secondary outcomes. RESULTS: Similar values were reported between the two groups regarding age (76.6 ± 6.8 versus 79 ± 7.2 y old), body weight (61.5 ± 14.3 versus 62.1 ± 16.1 kg), and body mass index (28.7 ± 4.15 versus 28.1 ± 3.62 kg/m2). Although no difference in terms of in-hospital, 90-d postdischarge, or overall mortality rate was observed between the two groups, a reduction in length of stay, 90-d postdischarge hospitalization, and falls was observed in the AA supplementation group rather than in controls. Furthermore, the AA mixture limited muscle architecture/strength impairment and circulating oxidative stress, which occurred during hospitalization-related bed rest. The latter data was associated with increased circulating levels of anti-inflammatory cytokines interleukin-4 and -10. CONCLUSIONS: These results suggest that the AA mixture limits several alterations associated with low mobility in older hospitalized patients, such as length of stay, 90-d postdischarge hospitalization, and falls, preventing the loss of muscle function, as well as the increase of circulating interleukins and oxidative stress markers.
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Aminoácidos/administração & dosagem , Repouso em Cama/efeitos adversos , Suplementos Nutricionais , Sarcopenia/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Composição Corporal/efeitos dos fármacos , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Ingestão de Energia , Feminino , Avaliação Geriátrica , Mortalidade Hospitalar , Unidades Hospitalares , Humanos , Medicina Interna , Tempo de Internação , Masculino , Limitação da Mobilidade , Força Muscular/efeitos dos fármacos , Projetos Piloto , Resultado do TratamentoRESUMO
Lipid accumulation is the hallmark of Non-alcoholic Fatty Liver Disease (NAFLD) and has been suggested to play a role in promoting fatty liver inflammation. Previous findings indicate that during oxidative stress conditions excess cholesterol autoxidizes to oxysterols. To date, the role of oxysterols and their potential interaction with fatty acids accumulation in NASH pathogenesis remains little investigated. We used the nutritional model of high fatty acids (HFA), high cholesterol (HCh) or high fat and high cholesterol (HFA+FCh) diets and explored by a lipidomic approach, the blood and liver distribution of fatty acids and oxysterols in response to dietary manipulation. We observed that HFA or HCh diets induced fatty liver without inflammation, which was otherwise observed only after supplementation of HFA+HCh. Very interestingly, the combination model was associated with a specific oxysterol fingerprint. The present work provides a complete analysis of the change in lipids and oxysterols profile induced by different lipid dietary model and their association with histological alteration of the liver. This study allows the generation of interesting hypotheses on the role of interaction of lipid and cholesterol metabolites in the liver injury during NAFLD development and progression. Moreover, the changes in the concentration and quality of oxysterols induced by a combination diet suggest a novel potential pathogenic mechanism in the progression from simple steatosis to steatohepatitis.
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Colesterol/metabolismo , Dieta , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Colesterol/sangue , Dieta Hiperlipídica , Ácidos Graxos/sangue , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Oxirredução , Estresse Oxidativo , Oxisteróis/metabolismo , RatosRESUMO
PURPOSE: Here we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload. The therapeutic effect of deferoxamine is used to illustrate the application of disease modelling as a means to characterising treatment response in individual patients. METHODS: Serum ferritin, demographic characteristics and individual treatment data from clinical routine practice on 27 patients affected by ß-thalassaemia major were used for the purposes of this analysis. The time course of serum ferritin was described by a hierarchical nonlinear mixed effects model, in which compliance was parameterised as a covariate factor. Modelling and simulation procedures were implemented in NONMEM (7.2.0). RESULTS: A turnover model best described serum ferritin changes over time, with the effect of blood transfusions introduced on the ferritin conversion rate and the effect of deferoxamine on the elimination parameter (Kout) in a proportional manner. The results of the simulations showed that poor quality of execution is preferable over drug holidays; and that independently of the compliance pattern, the therapeutic intervention is not effective if >60% of the doses are missed. CONCLUSIONS: Modelling of ferritin response enables characterisation of the dynamics of iron overload due to chronic transfusion. The approach can be used to support decision making in clinical practice, including personalisation of the dose for existing and novel chelating agents.
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Terapia por Quelação/métodos , Desferroxamina/uso terapêutico , Ferritinas/sangue , Sobrecarga de Ferro/tratamento farmacológico , Sideróforos/uso terapêutico , Talassemia beta/terapia , Adolescente , Adulto , Criança , Simulação por Computador , Desferroxamina/sangue , Desferroxamina/farmacologia , Relação Dose-Resposta a Droga , Transfusão de Eritrócitos/efeitos adversos , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etiologia , Modelos Biológicos , Sideróforos/sangue , Sideróforos/farmacologia , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/complicaçõesRESUMO
The accumulation of toxic hydrophobic bile acids in hepatocytes, observed during chronic cholestasis, induces substantial modification in the redox state and in mitochondrial functions. Recent reports have suggested a significant role of impaired lipid metabolism in the progression of chronic cholestasis. In this work we report that changes observed in the expression of the lipogenic enzymes acetyl-CoA carboxylase and fatty acid synthase were associated with a decrease in the activity of citrate carrier (CIC), a protein of the inner mitochondrial membrane closely related to hepatic lipogenesis. We also verified that the impairment of citrate transport was dependent on modification of the phospholipid composition of the mitochondrial membrane and on cardiolipin oxidation. Silybin, an extract of silymarin with antioxidant and anti-inflammatory properties, prevented mitochondrial reactive oxygen species (ROS) production, cardiolipin oxidation, and CIC failure in cirrhotic livers but did not affect the expression of lipogenic enzymes. Moreover, supplementation of silybin was also associated with mitochondrial biogenesis. In conclusion, we demonstrate that chronic cholestasis induces cardiolipin oxidation that in turn impairs mitochondrial function and further promotes ROS production. The capacity of silybin to limit mitochondrial failure is part of its hepatoprotective property.