Non-thyroidal illness syndrome in chronic diseases: role of irisin as modulator of antioxidants.

OBJECTIVE: Non-thyroidal-illness syndrome (NTIS) refers to condition found in chronic diseases that is an adaptive mechanism. However, oxidative stress is related to NTIS in a vicious circle, due to deiodinases alteration and negative effects of low T3 on antioxidant levels or activity. Muscle is one of the main targets of thyroid hormones and it can secrete a myokine named irisin, which is able to induce the browning of white adipose tissue, energy expenditure and protect against insulin resistance. Inconclusive data have been reported about irisin role in chronic diseases. Moreover, no correlation with antioxidants has been investigated. Therefore, we performed a case-control study with the primary endpoint to evaluate irisin levels in two models of NTIS, such as chronic heart failure (CHF) and chronic kidney disease (CKD) during haemodialytic treatment. The secondary endpoint was the correlation with total antioxidant capacity (TAC) to establish a possible role of irisin in the modulation of antioxidant systems. PATIENTS AND METHODS: Three groups of subjects were enrolled. Group A included CHF patients (n=18; aged 70.22 ± 2.78 ys; BMI ± 27.75 ± 1.28 kg/m2); Group B included CKD patients (n=29; aged 67.03 ± 2.64; BMI 24.53 ± 1.01); finally, 11 normal subjects (Group C) have been enrolled as controls. Irisin has been evaluated by ELISA method and Total Antioxidant Capacity (TAC) by spectrophotometric method. RESULTS: Irisin was significantly higher in Group B vs. A and C groups (Mean ± SEM: 20.18 ± 0.61 ng/ml vs. 2.77 ± 0.77 and 13.06 ± 0.56, respectively; p<0.05); a significant correlation between irisin and TAC was observed in group B. CONCLUSIONS: These preliminary data suggest a possible role of irisin in the modulation of antioxidants in two chronic syndromes with low T3 (i.e., CHF and CKD) with differential pattern in these two models studied. Further insights are needed to confirm this pilot study, which could be the basis for a longitudinal investigation, to assess a prognostic role of irisin with possible therapeutic implications.

Evaluation of Kisspeptin levels in prepubertal obese and overweight children: sexual dimorphism and modulation of antioxidant levels.

OBJECTIVE: Kisspeptin, neuropeptide involved in puberty beginning and regulation of pituitary-gonadal axis, has been shown to stimulate antioxidant defenses in murine models. Its levels are greater in females than males and also in obese prepubertal girls. Therefore, our aim was to evaluate sex-related differences in prepubertal obese patients and the relationships of Kisspeptin with metabolic/hormonal parameters. PATIENTS AND METHODS: We studied Kisspeptin concentrations in 54 children (22 males and 32 females, Tanner stage 1), 5-12 ys, classified according to Cole's criteria into 17 overweight and 37 obese; 25 normal-weight children, aged 6-12 years, were studied as controls. We evaluated metabolic (glucose and insulin levels after oral glucose load, total- LDL- HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters. Moreover, total antioxidant capacity (TAC) was evaluated by spectrophotometric method, using the system H202-metmyoglobin-ABTS. Kisspeptin levels were measured by RIA. RESULTS: We did not find significant differences between obese and normal-weight children, but obese males presented significantly lower levels than females. Kisspeptin did not correlate with BMI, HOMA-IR, Insulin peak levels and TAC; a significant correlation was found between Kisspeptin and fT3 (r2=0.25; p=0.003) in the obese group; leptin levels, significantly greater in obese vs. overweight and control children, significantly correlated with TAC (r2=0.39; p=0.03). CONCLUSIONS: These data suggest that both hormones could modulate antioxidants, Kisspeptin indirectly via influence on thyroid hormones, and Leptin by a direct effect. This mechanism seems to be sex-related, not attributable to peripheral steroid levels. Further studies can clarify the complex interrelationship between central and peripheral Kisspeptin secretion and oxidative stress in children obesity.

Oxidative stress as a possible mechanism underlying multi-hormonal deficiency in chronic heart failure.

OBJECTIVE: Chronic Heart Failure (CHF) is associated with multi-hormonal derangement depicting a prevalence of catabolic vs. anabolic axes. Moreover, thyroid adaption is characterized by the reduced conversion of thyroxine to the active hormone triiodothyronine. On the other hand, hormones modulate synthesis and utilization of antioxidant systems. Therefore, hormonal failure can cause unbalance between reactive radical species and the defenses, resulting in oxidative stress (OS). OS is well described in CHF, but the relationship with the hormonal picture is not entirely known. In the present review, we firstly analyze the mechanisms of ROS production in the heart, discussing animal and human studies, and focusing on new discovered protective mechanisms such as sirtuins and fibroblast growth factor 21 (FGF21). The second section is dedicated to the role of main anabolic axes influencing antioxidant systems. Finally, we present some data supporting the hypothesis that OS could be the link between hormonal derangement and clinical outcome of CHF.

Thyroid Function and its Implications in Oxidative Stress Influencing the Pathogenesis of Osteoporosis in Adults with Down Syndrome: A Cohort Study.

People with Down syndrome (DS) show lower bone mass density (BMD) and a higher prevalence of hypothyroidism compared to general population. Furthermore, DS is a well-known high oxidative stress (OS) condition because genes involved in OS map on chromosome 21. Thyroid function too is involved in OS. Since both thyroid function and OS lead to lower BMD and osteoporotic fractures, we have explored correlations among BMD, thyroid hormones, and parameters of OS in DS adults. A total of 105 DS patients (48 males; 21-71 years; mean BMI 28.88±7.12 kg/m(2)) were enrolled in a cohort study, 48 of them undergoing thyroid replacement therapy. We evaluated thyroid function, BMD, and total antioxidant capacity (TAC) in blood plasma. TAC was assayed by H2O2-metmyoglobin system, as source of radicals, and by the chromogenous ABTS, with a latency time (LAG) in the appearance of its cation ABTS+proportional to antioxidant concentration. BMD was evaluated with DEXA, using WHO criteria to classify osteoporosis. Low BMD was found in 83.78% of patients. TSH and LAG did not correlate with BMD. Nevertheless, LAG significantly correlates to Z-scores estimated at the lumbar spine (r(2)=0.558; p=0.03) in hypothyroid patients. Our data show that low TAC could be more associated with reduced BMD rather than TSH itself in DS patients and that the OS could have a role in the pathogenesis of osteoporosis regarding the hypothyroid subgroup.

Frailty of Obese Children: Evaluation of Plasma Antioxidant Capacity in Pediatric Obesity.

Background: Obese children are subject to the same chronic oxidative and inflammatory stress, responsible for the onset of all the complications typical of adult age, such as insulin resistance, type 2 diabetes, dyslipidemia and cardiovascular disease. Objectives: Since few studies are reported in prepubertal obese children, we investigated the relationship between oxidative stress, body composition and metabolic pattern in childhood obesity in comparison with adult obese patients. Methods: We enrolled 25 prepubertal children (12 males and 13 females) aged 5-12 years with a mean value of standard deviation of BMI (SDS-BMI)±SEM of 1.96±0.09. We performed oral glucose tolerance test, hormonal and metabolic evaluation, bioimpedentiometry, evaluation of total antioxidant capacity using spectroscopical method using a radical cation, 2,2I- azinobis(3-ethylbenzothiazoline-6 sulphonate) (ABTS), as indicator of radical formation, with a latency time (LAG) proportional to antioxidant in the sample. Results: LAG values significantly correlate with % fat mass, waist circumference and waist/hip ratio. However mean LAG values were significantly lower than in obese adults. Conclusions: We suggest that children are more susceptible to oxidative stress than adults, possibly to incomplete development of antioxidant system. Prognostic and therapeutical implications need to be further investigated.

Comparison of plasma antioxidant levels in middle-aged and old male with idiopatic osteoporosis: preliminary data.

OBJECTIVES: With the purpose of evaluating the role of oxidative stress (OS) in male idiopatic osteoporosis, we have evaluated plasma total antioxidant capacity (TAC) in patients classified according to age (< 65 or ≥ 65 yrs), with normal hormone values and in age-matched healthy control subjects. PATIENTS AND METHODS: TAC was evaluated with a colorimetric method, using the system metamyoglobin-H2O2 and the chromogen ABTS; the latency time (LAG, sec) in the appearance of ABTS radical species is proportional to antioxidant content of the system. RESULTS: We found slightly increased LAG values in middle-aged patients, compared with age-matched controls, probably expression of a compensatory mechanism to OS; on the contrary aged patients showed significantly lower LAG values in comparison with age-matched controls, suggesting a defective compensatory mechanism and, therefore, a risk for oxidative damage. CONCLUSIONS: OS could be a possible mechanism underlying male osteoporosis, both in middle-aged and aged patients, but compensatory mechanisms seem to be defective in the last group.

Increased expression of Aquaporin 4 in the rat hippocampus and cortex during trimethyltin-induced neurodegeneration.

Trimethyltin chloride (TMT) is a neurotoxicant producing neuronal degeneration and reactive astrogliosis in the mammalian central nervous system, especially the hippocampus. A previous magnetic resonance imaging investigation in TMT-treated rats evidenced dilation of lateral ventricles, also suggesting alterations in blood-brain barrier permeability and brain edema. Aquaporin 4 (AQP4), a glial water channel protein expressed mainly in the nervous system, is considered a specific marker of vascular permeability and thought to play an important role in brain edema (conditions). We studied AQP4 expression in the hippocampus and cerebral cortex of TMT-treated rats in order to explore the molecular mechanisms involved in brain edema occurring in these experimental conditions. Real-time PCR and western blotting data showed significant up-regulation of both AQP4 mRNA and protein levels starting 14 days after TMT treatment in the hippocampus and cortex. Parallel immunofluorescence studies indicated intense astrogliosis and AQP4 immunoreactivity diffusely pronounced in the hippocampal and cortex areas starting 14 days after TMT intoxication. In order to study the effects of TMT on vascular integrity, double-label immunofluorescence experiments for rat immunoglobulin G (IgG) and rat endothelial cell antigen-1 (RECA-1) or neuronal nuclei (NeuN) (endothelial and neuronal markers respectively) were performed. The results indicated, at 21 and 35 days after treatment, the presence of rat IgG in paravasal parenchyma and in some neuronal cells of the hippocampus and cortex. The extravasated IgG staining was temporally correlated with over-expression of neuronal vascular endothelial growth factor (VEGF) and the active phosphorylated form of its neuronal receptor (VEGFR-2P), suggesting that these factors may cooperate in mediating vascular leakage.

Coenzyme Q10 supplementation in infertile men with low-grade varicocele: an open, uncontrolled pilot study.

Many conditions associated with male infertility are inducers of oxidative stress, including varicocele. Antioxidants, such as coenzyme Q10, may be useful in this case. To evaluate the antioxidant capacity of seminal plasma of infertile men with varicocele before and after an oral supplementation with coenzyme Q10 , 38 patients were recruited from a pilot clinical trial. A standard semen analysis was also performed at baseline and 3 months after an oral supplementation with exogenous coenzyme Q10 100 mg per die. Seminal plasma antioxidant capacity was measured using a spectroscopic method. Coenzyme Q10 therapy improved semen parameters and antioxidant status. This study highlights the importance of oxidative stress in the pathogenesis of male infertility, namely in varicocele, and strengthens the possibility of the usefulness of the antioxidant therapy.

Estrogens as antioxidant modulators in human fertility.

Among treatments proposed for idiopathic male infertility, antiestrogens, like tamoxifen, play a possible role. On the other hand, oxidative stress is a mechanism well recognized for deleterious effects on spermatozoa function. After reviewing the literature on the effects of estrogens in modulation of antioxidant systems, in both sexes, and in different in vivo and in vitro models, we suggest, also on the basis of personal data, that a tamoxifen treatment could be active via an increase in seminal antioxidants.

Relationship between plasma antioxidants and thyroid hormones in chronic obstructive pulmonary disease.

BACKGROUND: A low-T3 syndrome is observed in chronic diseases, but its treatment is still debated. Chronic obstructive pulmonary disease (COPD) has not been conclusively studied under this aspect. COPD is a complex condition, which cannot be considered a lung-related disorder, but rather a systemic disease also associated to increased oxidative stress. We evaluated thyroid hormones and antioxidant systems, the lipophilic Coenzyme Q10 (CoQ10) and total antioxidant capacity (TAC) in COPD patients to reveal the presence of a low-T3 syndrome in COPD and investigate the correlation between thyroid hormones, lung function parameters and antioxidants. METHODS: We studied: 32 COPD patients and 45 controls, evaluating thyrotropin (TSH), free-triiodotyronine (fT3), free-tetraiodotyronine (fT4), CoQ10 (also corrected for cholesterol) and TAC. CoQ10 was assayed by HPLC; TAC by the metmyoglobin-ABTS method and expressed as latency time (LAG) in radical species appearance. RESULTS: We found significantly lower LAG values, fT3 and fT4 levels and significantly higher TSH in COPD patients vs. controls. LAG values significantly correlated with fT3 concentration. 12 out of 32 patients exhibited fT3 levels lower than normal range. So we divided COPD patients in 2 groups on the basis of the fT3 concentration (normal fT3 COPD and low fT3 COPD). We observed lower LAG values in normal fT3-COPD, compared to healthy subjects, with a further significant reduction in low fT3-COPD patients. Moreover higher TSH concentration was present in normal fT3-COPD, compared to healthy subjects, with a further significant increase in low fT3-COPD patients. CoQ10/cholesterol ratio was higher in low fT3-COPD vs. normal fT3-COPD, with a nearly significant difference. CONCLUSIONS: These data seem to indicate an increased oxidative stress in low fT3-COPD and a role of fT3 in modulating antioxidant systems. However low fT3 levels are joined to metabolic indexes of true hypothyroidism, suggesting that elevated CoQ10 expresses a reduced tissue utilization. These data might suggest the need of thyroid replacement therapy in such a condition.

Lycopene and cardiovascular diseases: an update.

Cardiovascular disease (CVD) is the leading cause of death in Western societies and accounts for up to a third of all deaths worldwide. In comparison to the Northern European or other Western countries, the Mediterranean area has lower rates of mortality from cardiovascular diseases and cancer, and this is attributed, at least in part, to the so-called Mediterranean diet, which is rich in plantderived bioactive phytochemicals. Identification of the active constituents of the Mediterranean diet is therefore crucial to the formulation of appropriate dietary guidelines. Lycopene is a natural carotenoid found in tomato, an essential component of the Mediterranean diet, which, although belonging to the carotenoid family, does not have pro-vitamin A activity but many other biochemical functions as an antioxidant scavenger, hypolipaemic agent, inhibitor of pro-inflammatory and pro-thrombotic factors, thus potentially of benefit in CVD. In particular, the review intends to conduct a systematic analysis of the literature (epidemiological studies and interventional trials) in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians. Several reports have appeared in support of the role of lycopene in the prevention of CVD, mostly based on epidemiological studies showing a dose-response relationship between lycopene and CVD. A less clear and more complex picture emerges from the interventional trials, where several works have reported conflicting results. Although many aspects of lycopene in vivo metabolism, functions and clinical indications remain to be clarified, supplementation of low doses of lycopene has been already suggested as a preventive measure for contrasting and ameliorating many aspects of CVD.

Hormones and antioxidant systems: role of pituitary and pituitary-dependent axes.

Oxidative stress, a condition defined as unbalancing between production of free radicals and antioxidant defenses, is an important pathogenetic mechanism in different diseases. Despite the abundant literature, many aspects of hormone role in regulating antioxidant synthesis and activity still remain obscure. Therefore, we reviewed experimental data, in vivo and in vitro, about the effects of the different pituitary- dependent axes on antioxidant levels, trying to give a broad view from hormones which also have antioxidant properties to the classic antioxidants, from the lipophilic antioxidant Coenzyme Q10, strictly related to thyroid function, to total antioxidant capacity, a measure of non-protein non-enzymatic antioxidants in serum and other biological fluids. Taken together, these data underline the importance of oxidative stress in various pituitary-dependent disorders, suggesting a possible clinical usefulness of antioxidant molecules.

Evaluation of antioxidant systems in pituitary-adrenal axis diseases.

The role of adrenal steroids in antioxidant regulation is not known. Previously, we demonstrated some Coenzyme Q(10) (CoQ(10)) alterations in pituitary diseases, which can induce complex pictures due to alterations of different endocrine axes. Therefore we determined CoQ(10) and Total Antioxidant Capacity (TAC) in pituitary-dependent adrenal diseases: 6 subjects with ACTH-dependent adrenal hyperplasia (AH); 19 with secondary isolated hypoadrenalism (IH), 19 with associated hypothyroidism (multiple pituitary deficiencies, MPH). CoQ(10) was assayed by HPLC; TAC by the system metmyoglobin-H(2)O(2), which, interacting with the chromogenous 2,2(I)-azinobis-(3-ethylbenzothiazoline-6-sulphonate), generates a spectroscopically revealed radical compound after a latency time (Lag) proportional to the antioxidant content. CoQ(10) levels were significantly lower in IH than AH and MPH, with a similar trend when adjusted for cholesterol. Also TAC was lower in IH than in AH and MPH, suggesting that adrenal hormones can influence antioxidants. However, since thyroid hormones modulate CoQ(10) levels and metabolism, when thyroid deficiency coexists it seems to play a prevalent influence.

New developments in anthracycline-induced cardiotoxicity.

Anthracyclines are among the most effective anticancer drugs ever developed. Unfortunately, their clinical use is severely limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure, usually refractory to conventional therapy. The pathophysiology of anthracycline-induced cardiomyopathy remains controversial and incompletely understood. The current thinking is that anthracyclines are toxic per se but gain further cardiotoxicity after one-electron reduction with ROS overproduction or two-electron reduction with conversion to C-13 alcohol metabolites. ROS overproduction can probably be held responsible for anthracycline acute cardiotoxicity, but not for all the aspects of progressive cardiomyopathy. Intramyocardial formation of secondary alcohol metabolites might play a key role in promoting the progression of cardiotoxicity toward end-stage cardiomyopathy and congestive heart failure. In this review we also discuss recent developments in: a) the molecular mechanisms underlying anthracycline-induced cardiotoxicity; b) the role of cytosolic NADPH-dependent reductases in anthracycline metabolism; c) the influence of genetic polymorphisms on cardiotoxicity outcome; d) the perspectives on the most promising strategies for limiting or preventing anthracycline-induced cardiotoxicity, focusing on controversial aspects and on recent data regarding analogues of the natural compounds, tumor-targeted formulations and cardioprotective agents.

Triterpenoids and ellagic acid derivatives from in vitro cultures of Camptotheca acuminata Decaisne.

The metabolic profile of secondary products in calli and cell suspension cultures of Camptotheca acuminata Decaisne was investigated and compared to that of the leaves and roots taken from the plant. Neither in vitro system produced the anticancer quinoline alkaloid camptothecin (CPT); they accumulated discrete quantities of polyhydroxylated triterpenoids, different from those found in the plant organs, and ellagic acid derivatives. Nine ellagic acid derivatives (1a-1d and 2a-2e) and eight triterpenoid acids (3a-3e and 4a-4c) were isolated and characterised. All the identified triterpenes were related to ursane- or oleanane-type skeletons and their concentrations rose to 4.5% in suspended cells.

Accumulation of essential oils in relation to root differentiation in Angelica archangelica L.

The accumulation of essential oils in Angelica archangelica subsp. archangelica roots at different developmental stages was investigated through histochemical and chemical analyses. Roots less than 1 mm in diameter showed a primary diarch structure and two primary secretory ducts in the pericycle. These ducts were ephemeral and probably became dysfunctional early on. Oil accumulation was observed only in the secondary secretory ducts formed by cambium activity and located in the secondary phloem. Gas chromatographic analyses revealed that only taproots exceeding 5 mm in diameter contained a high concentration of alpha- and beta-phellandrene, which appreciably influence the oil's aroma.

Effect in vitro of gamma interferon and interleukin-10 on generation of oxidizing species by human granulocytes.

We examined the effect of interleukin-10 (IL-10), gamma interferon (IFN-gamma), phorbol ester (PDB), opsonized zymosan (OZ) and aminophylline (a cAMP phosphodiesterase inhibitor) on the reducing power and oxidizing species generation by human neutrophils, using MTT dye reduction and luminol-dependent chemiluminescence assays, respectively. Gamma interferon (IFN-gamma), phorbol ester (PDB) and opsonized zymosan (OZ) were activators while interleukin-10 (IL-10) and aminophylline were inhibitors. A strong parallelism was observed between oxidizing species generation and cellular reducing power in both activation and inhibition experiments. Our results also demonstrate for the first time the effect of IL-10 on free radical generation by neutrophils. The consequence of these activating and inhibiting effects on the inflammatory process are discussed.