Mariana Migliorini Parisi

Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging

Abstract Background: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls. Methods: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-α, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Results: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers. Conclusions: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.

Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease

Objective: Bipolar disorder (BD) has been associated with increased rates of age-related diseases, such as type II diabetes, metabolic syndrome, osteoporosis, and cardiovascular disorders. Several biological findings have been associated with age-related disorders, including increased oxidative stress, inflammation, and telomere shortening. The objective of this study was to compare telomere length among participants with BD at early and late stages and age- and gender-matched healthy controls. Methods: Twenty-six euthymic subjects with BD and 34 healthy controls were recruited. Genomic DNA was extracted from peripheral blood and mean telomere length was measured using real-time quantitative polymerase chain reaction. Results: Telomere length was significantly shorter in both the early and late subgroups of BD subjects when compared to the respective controls (p = 0.002 and p = 0.005, respectively). The sample size prevented additional subgroup analyses, including potential effects of medication, smoking status, and lifestyle. Conclusion: This study is concordant with previous evidence of telomere shortening in BD, in both early and late stages of the disorder, and supports the notion of accelerated aging in BD.

Quinolinic acid neurotoxicity: Differential roles of astrocytes and microglia via FGF-2-mediated signaling in redox-linked cytoskeletal changes.

QUIN is a glutamate agonist playing a role in the misregulation of the cytoskeleton, which is associated with neurodegeneration in rats. In this study, we focused on microglial activation, FGF2/Erk signaling, gap junctions (GJs), inflammatory parameters and redox imbalance acting on cytoskeletal dynamics of the in QUIN-treated neural cells of rat striatum. FGF-2/Erk signaling was not altered in QUIN-treated primary astrocytes or neurons, however cytoskeleton was disrupted. In co-cultured astrocytes and neurons, QUIN-activated FGF2/Erk signaling prevented the cytoskeleton from remodeling. In mixed cultures (astrocyte, neuron, microglia), QUIN-induced FGF-2 increased level failed to activate Erk and promoted cytoskeletal destabilization. The effects of QUIN in mixed cultures involved redox imbalance upstream of Erk activation. Decreased connexin 43 (Cx43) immunocontent and functional GJs, was also coincident with disruption of the cytoskeleton in primary astrocytes and mixed cultures. We postulate that in interacting astrocytes and neurons the cytoskeleton is preserved against the insult of QUIN by activation of FGF-2/Erk signaling and proper cell-cell interaction through GJs. In mixed cultures, the FGF-2/Erk signaling is blocked by the redox imbalance associated with microglial activation and disturbed cell communication, disrupting the cytoskeleton. Thus, QUIN signal activates differential mechanisms that could stabilize or destabilize the cytoskeleton of striatal astrocytes and neurons in culture, and glial cells play a pivotal role in these responses preserving or disrupting a combination of signaling pathways and cell-cell interactions. Taken together, our findings shed light into the complex role of the active interaction of astrocytes, neurons and microglia in the neurotoxicity of QUIN.

Natural Products with Antiplatelet Action

BACKGROUND Complex hemostatic mechanisms are involved in the pathophysiology of various diseases, including cardiovascular diseases. Among them, dysregulation of platelet activity is linked to the progression of atherosclerosis and mainly involves platelet aggregation and a decrease in blood flow in the vascular endothelium. The major platelet activation pathways mediated by agonists involve the arachidonic acid pathway, adenosine diphosphate pathway, serotonin pathway, nitric oxide pathway, and action of free radicals on molecules involved in platelet aggregation. These mechanisms have been widely studied and discussed because they are inhibited by the use of medicinal plants in complementary and alternative medicine, thus reducing platelet aggregation. RESULTS Of the main plants discussed in this review, which have antiplatelet activity, some include saffron, garlic, green tea, St. Johns wort, ginger, ginkgo biloba, ginseng, and guavirova. These herbal medicines have phytochemical components, which are directly related to the antiplatelet activity of the plant, such as flavonoids, curcumins, catechins, terpenoids, polyphenols, and saponins. While the majority of the medicinal plants mentioned here were native to the Asian continents, some are distributed worldwide, and found to a smaller extent throughout the American continent, European continent, Mediterranean, African continent, and the Middle East. CONCLUSION This review showed that several plants and/or compounds exhibit anti-platelet activity, and are therefore potential research targets for developing drugs to treat diseases related to aggregation disorders.

γ‐oryzanol reduces caveolin‐1 and PCGEM1 expression, markers of aggressiveness in prostate cancer cell lines

Prostate cancer is a leading cause of death among men due to the limited number of treatment strategies available for advanced disease. γ‐oryzanol is a component of rice bran, rich in phytosterols, known for its antioxidant, anti‐carcinogenic and endocrinological effects. It is known that γ‐oryzanol may affect prostate cancer cells through the down regulation of the antioxidant genes and that phytosterols have anti‐proliferative and apoptotic effects. There are evidences showing that some of the components of γ‐oryzanol can modulate genes involved in the development and progression of prostate cancer, as caveolin‐1 (Cav‐1) and prostate specific androgen‐regulated gene (PCGEM1).

Intracerebroventricular D-galactose administration impairs memory and alters activity and expression of acetylcholinesterase in the rat.

Tissue accumulation of galactose is a hallmark in classical galactosemia. Cognitive deficit is a symptom of this disease which is poorly understood. The aim of this study was to investigate the effects of intracerebroventricular administration of galactose on memory (inhibitory avoidance and novel object recognition tasks) of adult rats. We also investigated the effects of galactose on acetylcholinesterase (AChE) activity, immunocontent and gene expression in hippocampus and cerebral cortex. Wistar rats received a single injection of galactose (4 mM) or saline (control). For behavioral parameters, galactose was injected 1 h or 24 h previously to the testing. For biochemical assessment, animals were decapitated 1 h, 3 h or 24 h after galactose or saline injection; hippocampus and cerebral cortex were dissected. Results showed that galactose impairs the memory formation process in aversive memory (inhibitory avoidance task) and recognition memory (novel object recognition task) in rats. The activity of AChE was increased, whereas the gene expression of this enzyme was decreased in hippocampus, but not in cerebral cortex. These findings suggest that these changes in AChE may, at least in part, to lead to memory impairment caused by galactose. Taken together, our results can help understand the etiopathology of classical galactosemia.

Biomarkers of Subclinical Atherosclerosis and Natural Products as Complementary Alternative Medicine

Cardiovascular diseases (CVD) are considered the leading cause of morbidity and mortality from chronic diseases in the world. In addition, about 20% of first and recurrent acute myocardial infarctions (MI) are silent. In this context, subclinical atherosclerosis culminates in evident CVD, through the evolution of early risk factors such as hypercholesterolemia, hypertriglyceridemia and others. The main problem in CVD is related to the long-time between the start of the subclinical atherosclerosis and the manifestation of the disease. The identification of subjects at risk of such events is obviously substantial, since identification leads to implementation and compliance with effective preventive measures that reduce such risk. In this sense, this review demonstrates biomarkers as an alternative to early detection of subclinical atherosclerosis. One of the proposed biomarkers is the Ischemia-modified albumin (IMA), being considered a promising biochemical biomarker for atherosclerotic conditions. Another marker that is gaining strength and is associated with the IMA are the advanced oxidation protein products (AOPP), its measurement provides information on the level of exposure to potentially harmful changes to proteins and metabolic control. And last but not least we have nitric oxide as an early marker mainly related to endothelial dysfunction. In this review also is evidenced the use of the Campomanesia xanthocarpa, a plant native to southern region from Brazil extensively used as complementary and alternative medicine, and natural products to reduce protein oxidation and improve the availability of nitric oxide and consequently vascular function, reducing the risk for development of CVD.

Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder

Objective Evidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages. Methods Eighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR. Results Macrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1β (6.40±3.47 and 9.04±5.84 vs. 0.23±0.11; p<0.05) and tumor necrosis factor-α (2.23±0.91 and 2.03±0.45 vs. 0.62±0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29±0.20 vs. 1.86±1.61; p=0.006) and CXCL10 expression (0.36±0.15 and 0.86±0.24 vs. 1.83±0.88; p<0.000 and p=0.04) compared to the euthymia group. Conclusion Our results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD.

Analyzing leukocyte telomere length in bipolar disorder: Authors’ reply

Our original study adds important information to the evidence base for bipolar disorder (BD) pathology. We show, for the first time, that shorter leukocyte telomere length (LTL) is already present in individuals with the early stages of BD and is comparable to LTL from individuals in the late stages of the disease. This result is at least surprising. We might speculate that, in BD, LTL would be proportional to disease duration. A recent study from our group in patients with schizophrenia (SZ) showed that duration of illness, but not age itself, is related to many markers of aging; these results are consistent with the hypothesis of accelerated aging induced by a pathological state. Still, SZ is associated with a higher burden of disease. In our recent study, the similar LTL among early-stage and late-stage BD patients could indeed have many other explanations. First, although hypertension, dyslipidemia, and diabetes mellitus are risk factors for telomere erosion and senescence, and were present in our cohort of BD patients, we chose not to report these data, because we have no information regarding comorbidity duration and its differential impact. Telomeres are naturally shortened during cell division and this process can be accelerated under oxidative, inflammatory or glucocorticoid stress, all of which are present in patients with BD. Importantly, augmented peripheral cell apoptosis, which may be a consequence of augmented turn-over secondary to chronic stress, has been reported in BD. Thus, during chronic stress, cells with shorter telomeres might have already been eliminated, selecting for medium to large telomeres. Second, quantification of telomere length by quantitative PCR (qPCR) provides a measure of the mean LTL present in a given cell population. A major limitation of this technique is its sensitivity, as qPCR does not detect short telomeres. Because short but not average LTL determines pathological phenotypes and drives cell fate, our results must be interpreted with caution. In addition, LTL is a mosaic trait, and reflects the replicative history of the analyzed tissue. Granulocytes have longer telomeres than any other leukocyte subset and are present in higher numbers in BD patients. LTL from patients with late-stage BD could be enriched in the granulocyte population, leading to overestimation and misinterpretation of the real impact of LTL. Finally, we could also argue that similar LTL could be a consequence of pharmacotherapy. Lithium therapy is associated with neuroprotective properties. This effect could explain why euthymic patients in late-stage BD under longer lithium therapy might have similar LTL to early-stage BD patients. Two recently published reports from our group address telomere shortening and familial traits in BD and SZ. Our findings show a significant negative trend for shorter LTL among patients with BD when compared to their healthy siblings, and similar and shorter LTL among patients with SZ and their unaffected siblings. More importantly, in both studies, LTL was shorter in unaffected siblings than in healthy nonrelated controls (HCs). Because HCs and unaffected siblings of BD patients had significant differences in LTL, we might speculate that telomere shortening is not influenced by medication and is indeed a neurobiological change with a clear genetic background. Furthermore, we might consider that genetic background in unaffected siblings could be seen as a susceptibility or vulnerability trait, and that resilience mechanisms may inhibit the appearance of pathological BD. In this study, we indeed failed to address important confounders, such as comorbidities, physical activity, smoking, and lifestyle factors. We also did not include data regarding familial history of major psychiatric disorders, nor did we quantify LTL in participants’ parents. Both of our studies had cross-sectional designs, thus precluding inference of any causal associations. Prospective epidemiological studies with adequately calculated sample sizes should be designed and conducted in newly diagnosed, therapy-naive BD patients to evaluate specific mechanisms potentially associated with lithium neuroprotection in telomere homeostasis.

Immunosenescence induced by plasma from individuals with obesity caused cell signaling dysfunction and inflammation

To evaluate the consequences of plasma from individuals with obesity on parameters associated with immunosenescence in unrelated healthy peripheral blood mononuclear cells (PBMC).