Antioxidant effect of immediate- versus sustained-release melatonin in type 2 diabetes mellitus and healthy controls.

Oxidative damage has been suggested as the primary cause of aging and age-associated diseases including type 2-dependent diabetes mellitus (T2DM) and therefore there is a growing interest in exploring therapeutic potential of antioxidant agents including melatonin. In the present study, we analyzed red blood cell antioxidants and lipid peroxidation after 5 mg/daily immediate-release melatonin treatment of elderly T2DM patients and healthy elderly subjects in comparison with 2 mg/daily sustained-release melatonin treatment of elderly T2DM patients and healthy elderly subjects, to determine the antioxidant effect of different doses and formulations of melatonin in these groups. Our study revealed that there was no significant difference in antioxidant status of red blood cells measured by glutathione concentration and activities of GPx-1, CAT, GR, SOD-1 and MDA levels, after supplementation with 2 mg-sustained release melatonin or with 5 mg-immediate release melatonin, either in T2DM or in healthy elderly subjects. These results suggest that both preparations may exert similar therapeutic effect related to melatonin's action on antioxidant defense system.

The links between chronic obstructive pulmonary disease and comorbid depressive symptoms: role of IL-2 and IFN-γ.

Depression is highly prevalent in COPD patients, and both diseases are believed to be associated with inflammation. The aim of this study was to elucidate the role of the immune system alterations in pathogenesis of depression in COPD patients. Blood was collected from patients diagnosed with chronic obstructive pulmonary disease and comorbid depressive symptoms [COPD + DS, (N = 13)], from individuals with either COPD (N = 16) or recurrent depressive disorder (rDD) alone (N = 15), and from healthy controls (N = 19). Surface phenotype expression of T regulatory and T effector cells was analyzed with a flow cytometry, and IL-2, IL-6, IL-8, IFN-γ, IL-17, and neopterin were detected with ELISA. We demonstrated that COPD, depression, and COPD with comorbid depression are associated with increased IL-6 levels when compared with healthy controls 42.2 ± 1.87, 40.9 ± 2.12, 41.7 ± 1.31, and 33.2 ± 1.23 pg/ml, respectively (p < 0.05). A significant increase in neopterin levels was observed both in rDD and COPD patients when compared with controls (15.69 ± 0.095, 13.98 ± 0.887 vs. 9.22 ± 0.466 nmol/l, p < 0.001 and p < 0.05, respectively). Concentrations of IFN-γ were significantly increased in COPD + DS patients when compared with controls (24.3 ± 1.49 and 17.8 ± 0.70 pg/ml, respectively, p < 0.05). IL-2 levels were highest in COPD + DS (3.20 ± 0.389 pg/ml) and differed significantly when this group was compared with controls (2.20 ± 0.184 pg/ml), p ≤ 0.05). In this study, we demonstrated for the first time that depressive symptoms in COPD patients may be related to inflammatory state as confirmed by increased levels of IL-6 both in COPD and depression and also in COPD with comorbid depressive symptoms, despite the fact that the patients were treated with anti-inflammatory drugs and/or antidepressants. We also identified IFN-γ and IL-2 as putative inflammatory agents associated with depressive symptoms in COPD patients. Prospective studies will need to confirm whether measuring IL-2 and IFN-γ can identify COPD patients at risk of depression. These findings suggest that T helper cell 1-derived cellular immune activation may play significant role in developing depressive symptoms in COPD patients.

Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder.

Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD.

[Lactic acid bacteria and health: are probiotics safe for human?]. / Bakterie kwasu mlekowego i zdrowie: czy probiotyki sa bezpieczne dla czlowieka?

The effect of Lactobacillus and Bifidobacterium on human health has been examined for many years. Numerous in vivo and in vitro studies have confirmed the beneficial activity of some exogenous lactic acid bacteria in the treatment and prevention of rotaviral infection, antibiotic-associated diarrhea, inflammatory bowel disease and other gastrointestinal disorders. Probiotics support the action of the intestinal microflora and exhibit a favorable modulatory effect on the host's immune system. However, it should be remembered that relatively harmless lactobacilli can occasionally induce opportunistic infections. Due to reaching almost 20x10(12) probiotic doses per year which contain live cultures of bacteria, it is essential to monitor the safety aspect of their administration. In recent years, infections caused by Lactobacillus and Bifidobacterium made up 0.05% to 0.4% of cases of endocarditis and bacteremia. In most cases, the infections were caused by endogenous microflora of the host or bacterial strains colonizing the host's oral cavity. According to a review of cases of infections caused by bacteria of the genus Lactobacillus from 2005 (collected by J.P. Cannot'a), 1.7% of infections have been linked directly with intensive dairy probiotic consumption by patients. Additionally, due to the lack of a precise description of most individuals' eating habits, the possible effect of probiotics on infection development definitively should not be ruled out. The present paper describes cases of diseases caused by lactic acid bacteria, a potential mechanism for the adverse action of bacteria, and the possible hazard connected with probiotic supplementation for seriously ill and hospitalized patients.

Lipopolysaccharide increases degradation of central monoamines: an in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice.

Peripheral administration of lipopolysaccharide (LPS) in rodents induces anhedonia, i.e. the inability to experience pleasure. Recently, we reported that serotonin transporter (SERT) function is required for LPS-induced anhedonia. Less is known about the effect of LPS on the biological activity of dopamine transporters (DAT) and norepinephrine transporters (NET). Therefore, in vivo microdialysis was performed in the nucleus accumbens and medial prefrontal cortex of C57BL6/J mice exposed to saline or LPS (133 µg/kg i.p.). To investigate the possible involvement of different monoamine transporters, the triple reuptake inhibitor DOV 216,303 or saline was i.p. injected 30 min before the saline/LPS injection. The dose of LPS, shown to decrease responding for brain stimulation reward in mice, significantly increased extracellular levels of monoamine metabolites (5-HIAA, DOPAC and HVA) in the nucleus accumbens and medial prefrontal cortex. Remarkably, DOV 216,303 abolished LPS-induced DOPAC and HVA formation in the nucleus accumbens, suggesting that LPS increases DAT activity in this brain area. DOV 216,303 also inhibited LPS-induced DOPAC and HVA formation in the medial prefrontal cortex. Since DAT density is very low in this brain structure, reuptake of DA predominantly takes place via NET, suggesting that LPS increases DAT and NET activity in the medial prefrontal cortex. Furthermore, DOV 216,303 pretreatment prevented LPS-induced 5-HIAA formation only in the medial prefrontal cortex, indicating that LPS increases prefrontal SERT activity. In conclusion, the present findings suggest that peripheral LPS increases DAT activity in the nucleus accumbens and increases NET and SERT activity in the medial prefrontal cortex of mice.

Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression.

As there is strong evidence for inflammation and oxidative stress in depression, the aim of this study was to elucidate the relationship between oxidative imbalance and cellular immune response and to ask whether these processes are linked with iron metabolism in depressed patients. Blood was collected from patients diagnosed with recurrent depressive disorder (n=15) and from healthy controls (n=19). Whole-blood reduced glutathione (GSH), erythrocyte superoxide dismutase (SOD-1), glutathione peroxidase (GPx-1), glutathione reductase, malondialdehyde (MDA), and methemoglobin (MetHb) and plasma H2O2 were assayed spectrophotometrically. The serum heme oxygenase 1 (HO-1), cytokine, neopterin, and iron statuses were measured by ELISA. DNA damage was analyzed by comet assay. Serum concentrations of ferritin and soluble transferrin receptor were assayed by ELISA. MetHb saturation was analyzed spectrophotometrically in red blood cell hemolysate. The erythron variables were measured using a hematological analyzer. We observed a significant decrease in GPx-1 and SOD-1 activities and decreased levels of HO-1 and GSH in depressed patients compared to controls. Conversely, compared with controls, we found increased concentrations of MDA and H2O2 and more DNA damage in depressed patients. Furthermore, the levels of the proinflammatory cytokine interleukin-6 and of neopterin were increased in depressed patients along with decreased hemoglobin and hematocrit. A strong association between antioxidant defense, cytokine levels, and iron homeostasis was also revealed. These findings show that depression is associated with increased oxidative stress, inflammation, and restrictions on the available iron supply for red blood cell production. Furthermore, decreased antioxidant defense correlates with an increased cellular inflammatory response, whereas both concur with erythron and iron status, the latter explained by significant canonical correlations with the set of free radical scavenging enzymes and proinflammatory enzymes. The strong links between immune function, oxidative stress, and iron homeostasis suggest the presence of a self-sustaining multipathway mechanism that may progressively worsen, i.e., throughout accumulation of oxidative damage, producing the functional and structural consequences associated with depression. Hence, identifying viable therapeutic strategies to tackle oxidative stress and accompanying physiological disturbances, including inflammation and anemia, of chronic disease provides more opportunities for the treatment and, ultimately, prevention of depression.

Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100ß-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 µM) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFß-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFß-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.

Neuroimmune endocrine effects of antidepressants.

Antidepressant pharmacotherapy is to date the most often used treatment for depression, but the exact mechanism of action underlying its therapeutic effect is still unclear. Many theories have been put forward to account for depression, as well as antidepressant activity, but none of them is exhaustive. Neuroimmune endocrine impairment is found in depressed patients; high levels of circulating corticosteroids along with hyperactivation of the immune system, high levels of proinflammatory cytokines, low levels of melatonin in plasma and urine, and disentrainment of circadian rhythms have been demonstrated. Moreover, antidepressant treatment seems to correct or at least to interfere with these alterations. In this review, we summarize the complex neuroimmune endocrine and chronobiological alterations found in patients with depression and how these systems interact with each other. We also explain how antidepressant therapy can modify these systems, along with some possible mechanisms of action shown in animal and human models.

Age-related changes in an antioxidant defense system in elderly patients with essential hypertension compared with healthy controls.

BACKGROUND AND AIMS: Oxidative stress has been reported to increase with aging. Oxidative stress is also associated with hypertension, and antioxidant treatment has been shown to enhance antioxidant defense system. We therefore aimed to analyze the relationship between aging and some markers of oxidative stress in elderly patients with essential hypertension compared with healthy controls. MATERIAL AND METHODS: Blood was collected from 18 patients with essential hypertension and 21 age- and sex-matched healthy controls aged over 65. Patients were on their usual medications while participating in the study. Oxidative stress parameters were investigated by measuring the concentration of glutathione (GSH) in whole blood and activities of glutathione peroxidase (GPx-1), glutathione reductase (GR), catalase (CAT), and Cu-Zn superoxide dismutase (CuZn SOD, SOD-1) in erythrocytes. GSH, GPx-1, GR, CAT, and CuZn SOD correlations with age were expressed as Pearson product-moment correlation coefficient r. Independent-samples T test was used to compare mean values of parameters between groups. RESULTS: (1) Among all parameters analyzed herein, the activity of SOD-1 showed the most explicit decrease in relation to age, both in healthy controls and hypertensive subjects with r values of -0.54 (P = 0.05) and -0.68 (P < 0.01), respectively. (2) Age-related changes in parameters of oxidative stress did not differ significantly between groups. (3) Mean activity of SOD-1 was significantly higher (P < 0.05) in elderly hypertensives (2341.7 ± 213.71 U/g Hb) when compared with healthy controls (2199.7 ± 213.66 U/g Hb). (4) Mean GSH level was significantly higher (P < 0.01) in patients (3.1 ± 0.29 mmol/l) than in controls (2.8 ± 0.37 mmol/l). (5) Increased level of GSH in hypertension was followed by significantly (P < 0.01) higher activity of GR in this group when compared with controls (83.4 ± 15.25 and 64.1 ± 9.40 U/g Hb, respectively). CONCLUSIONS: (1) The antioxidant barrier changes in elderly subjects with senescence. (2) CuZn SOD activity is negatively correlated with age and this association is not altered by factors that modulate the enzyme activity, such as hypertension and antihypertensive treatment. (3) Significantly higher concentration of GSH and significantly higher GR activity in patients may suggest a significant role of GSH metabolism in the pathogenesis of hypertension, as well as its contribution to the effect of antihypertensive treatment.

Metabolomics in urogenital cancer.

Although in recent decades the development of many drugs against cancer has been witnessed, the morbidity and mortality for the most prevalent urogenital cancer have not been significantly reduced. A key task in cancer medicine is to detect the disease as early as possible. In order to achieve this, many new technologies have been developed for cancer biomarker discovery. Monitoring fluctuations of certain metabolite levels in body fluids, such as urine, has become an important way to detect early stages in carcinogenesis. Moreover metabolomic approaches are likely to be used to screen for potential diagnostic and prognostic biomarkers of urogenital cancer. In future work, these potential biomarkers should be further validated with a large enough patient cohort to achieve earlier diagnosis not only of urogenital cancer, but also other malignancies. Moreover, the improvement of patient prognosis will be another aim of such investigations. This novel metabolomic approach has the potential to provide more information about the pathophysiological status of an organism and distinguish precancerous and cancerous stages.

[Melatonin and oxidative stress in elderly patients with type 2 diabetes]. / Melatonina a stres oksydacyjny u chorych na cukrzyce typu 2 w wieku podeszlym.

Type 2 diabetes is a metabolic disease, which frequency increases substantially with age. Oxidative stress as a result of production and deactivation of free radicals unbalance, may play an important role in a complex pathogenesis of disease. Free radicals are by-products of metabolism, which in regard to their chemical structure, readily react with DNA, lipids, proteins and carbohydrates and cause changes in their structure and function. Antioxidant enzyme system and small molecule antioxidants protect organism against harmful effect of free radicals. In accordance to free radical theory of aging, antioxidant enzymes and molecules activity decrease with age. At the same time, quantity of disadvantageous changes caused by reactive oxygen species (RFT) increase. Disturbance in the prooxidant-antioxidant balance causes organism senescence and development of age-related diseases including diabetes mellitus. Hyperglycemia is an additional factor which can escalate systemic oxidative stress in diabetes mellitus. Elevated concentration of glucose increases generation of reactive oxygen species and accumulation of oxidative modified macromolecules as a result of accelerated activation of a few independent molecular pathways such as autooxidation of monosacharides, non-enzymatic glycosylation, activation of protein kinase C, phospholipase A2 and polyol pathway. Moreover aging is associated with decrease of melatonin concentration, which leads to physiological dysfunctions including depressed antioxidant defense mechanisms. Antioxidant properties of melatonin, which protects macromolecules, especially DNA, from harmful effects of RFT, are particularly important in aspect of free radical theory of aging.