light phase (the period during which rats sleep most) the PD group showed a significant reduction... more light phase (the period during which rats sleep most) the PD group showed a significant reduction in sleep efficiency and total non-REM sleep time as well as an increase in the number of arousal events compared with control animals. In the dark period, the PD group also had lower sleep efficiency (day 7 to 28). REM sleep was only affected toward the end of the experimental period (day 21-28). Conclusion: Our results suggest that PD resulted in marked sleep disruption, especially in non-REM sleep, likely due to the development of orofacial pain.
light phase (the period during which rats sleep most) the PD group showed a significant reduction... more light phase (the period during which rats sleep most) the PD group showed a significant reduction in sleep efficiency and total non-REM sleep time as well as an increase in the number of arousal events compared with control animals. In the dark period, the PD group also had lower sleep efficiency (day 7 to 28). REM sleep was only affected toward the end of the experimental period (day 21-28). Conclusion: Our results suggest that PD resulted in marked sleep disruption, especially in non-REM sleep, likely due to the development of orofacial pain.
In the present study, we addressed the role of intercellular adhesion molecule type 1 (ICAM-1/CD5... more In the present study, we addressed the role of intercellular adhesion molecule type 1 (ICAM-1/CD54) in neutrophil migration to inflammatory site and whether the inhibitory effect of nitric oxide (NO) upon the neutrophil rolling, adhesion and migration involves down-modulation of ICAM-1 expression through a cyclic GMP (cGMP) dependent mechanism. It was observed that neutrophil migration induced by intraperitoneal administration of endotoxin (LPS), carrageenan (Cg) or N-formyl peptide (fMLP) in ICAM-1 deficient (ICAM-1-/-) is similar to that observed in wild type (WT) mice. The treatment of mice with NO synthase (NOS) inhibitors, NG-nitro-l-arginine, aminoguanidine or with a soluble guanylate cyclase (sGC) inhibitor, ODQ enhanced LPS- or Cg-induced neutrophil migration, rolling and adhesion on venular endothelium. These parameters induced by LPS were also enhanced by 1400 W, a specific iNOS inhibitor, treatment. On the other hand, the treatment of the mice with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, reduced these parameters induced by LPS or Cg by a mechanism sensitive to ODQ pretreatment. The NOS inhibitors did not enhance LPS-, Cg- or fMLP-induced migration and adhesion in ICAM-1-/- mice. Moreover, genetic (iNOS-/- mice) or pharmacological inhibition of NOS or of sGC enhanced LPS-induced ICAM-1 expression on mesenteric microcirculation vessels of WT mice. By contrast, SNAP reduced the ICAM-1 expression by a mechanism dependent on cGMP. In conclusion, the results suggest that although during inflammation, ICAM-1 does not contribute to neutrophil migration, it is necessary for the down-modulatory effect of inflammation-released NO on the adhesion and transmigration of neutrophils. Moreover, these NO effects are mediated via cGMP.
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumul... more Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid-β (Aβ) peptide in brain regions that are important for memory and cognition. The buildup of Aβ aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Aβ-induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 μm of Aβ25–35 in the absence or in the presence of melatonin (25, 50, or 100 μm). In addition, the authors have investigated the involvement of GSK-3β, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Aβ-induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Aβ25–35. In addition, melatonin significantly reduced the activation of GSK-3β, the phosphorylation of tau protein, the glial activation and the Aβ-induced increase of TNF-α and IL-6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Aβ-induced phosphorylation of tau protein, and preventing GSK-3β activation and neuroinflammation.
Sepsis results from an overwhelming response to infection and is a major contributor to death in ... more Sepsis results from an overwhelming response to infection and is a major contributor to death in intensive care units worldwide. In recent years, we and others have shown that neutrophil functionality is impaired in sepsis. This correlates with sepsis severity and contributes to aggravation of sepsis by precluding bacterial clearance. Nitric oxide (NO) is a major contributor to the impairment of neutrophil function in sepsis. However, attempts to inhibit NO synthesis in sepsis resulted in increased death despite restoring neutrophil migration. This could be in part attributed to a reduction of the NO-dependent microbicidal activity of neutrophils. In sepsis, the beneficial effects resulting from the inhibition of soluble guanylyl cyclase (sGC), a downstream target of NO, have long been appreciated but poorly understood. However, the effects of sGC inhibition on neutrophil function in sepsis have never been addressed. In the present study, we show that TLR activation in human neutrophils leads to decreased chemotaxis, which correlated with chemotactic receptor internalization and increased G protein-coupled receptor kinase 2 expression, in a process involving the NO-sGC-protein kinase G axis. We also demonstrate that inhibition of sGC activity increased survival in a murine model of sepsis, which was paralleled by restored neutrophil migratory function and increased bacterial clearance. Finally, the beneficial effect of sGC inhibition could also be demonstrated in mice treated after the onset of sepsis. Our results suggest that the beneficial effects of sGC inhibition in sepsis could be at least in part attributed to a recovery of neutrophil functionality.
light phase (the period during which rats sleep most) the PD group showed a significant reduction... more light phase (the period during which rats sleep most) the PD group showed a significant reduction in sleep efficiency and total non-REM sleep time as well as an increase in the number of arousal events compared with control animals. In the dark period, the PD group also had lower sleep efficiency (day 7 to 28). REM sleep was only affected toward the end of the experimental period (day 21-28). Conclusion: Our results suggest that PD resulted in marked sleep disruption, especially in non-REM sleep, likely due to the development of orofacial pain.
light phase (the period during which rats sleep most) the PD group showed a significant reduction... more light phase (the period during which rats sleep most) the PD group showed a significant reduction in sleep efficiency and total non-REM sleep time as well as an increase in the number of arousal events compared with control animals. In the dark period, the PD group also had lower sleep efficiency (day 7 to 28). REM sleep was only affected toward the end of the experimental period (day 21-28). Conclusion: Our results suggest that PD resulted in marked sleep disruption, especially in non-REM sleep, likely due to the development of orofacial pain.
In the present study, we addressed the role of intercellular adhesion molecule type 1 (ICAM-1/CD5... more In the present study, we addressed the role of intercellular adhesion molecule type 1 (ICAM-1/CD54) in neutrophil migration to inflammatory site and whether the inhibitory effect of nitric oxide (NO) upon the neutrophil rolling, adhesion and migration involves down-modulation of ICAM-1 expression through a cyclic GMP (cGMP) dependent mechanism. It was observed that neutrophil migration induced by intraperitoneal administration of endotoxin (LPS), carrageenan (Cg) or N-formyl peptide (fMLP) in ICAM-1 deficient (ICAM-1-/-) is similar to that observed in wild type (WT) mice. The treatment of mice with NO synthase (NOS) inhibitors, NG-nitro-l-arginine, aminoguanidine or with a soluble guanylate cyclase (sGC) inhibitor, ODQ enhanced LPS- or Cg-induced neutrophil migration, rolling and adhesion on venular endothelium. These parameters induced by LPS were also enhanced by 1400 W, a specific iNOS inhibitor, treatment. On the other hand, the treatment of the mice with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, reduced these parameters induced by LPS or Cg by a mechanism sensitive to ODQ pretreatment. The NOS inhibitors did not enhance LPS-, Cg- or fMLP-induced migration and adhesion in ICAM-1-/- mice. Moreover, genetic (iNOS-/- mice) or pharmacological inhibition of NOS or of sGC enhanced LPS-induced ICAM-1 expression on mesenteric microcirculation vessels of WT mice. By contrast, SNAP reduced the ICAM-1 expression by a mechanism dependent on cGMP. In conclusion, the results suggest that although during inflammation, ICAM-1 does not contribute to neutrophil migration, it is necessary for the down-modulatory effect of inflammation-released NO on the adhesion and transmigration of neutrophils. Moreover, these NO effects are mediated via cGMP.
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumul... more Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid-β (Aβ) peptide in brain regions that are important for memory and cognition. The buildup of Aβ aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Aβ-induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 μm of Aβ25–35 in the absence or in the presence of melatonin (25, 50, or 100 μm). In addition, the authors have investigated the involvement of GSK-3β, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Aβ-induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Aβ25–35. In addition, melatonin significantly reduced the activation of GSK-3β, the phosphorylation of tau protein, the glial activation and the Aβ-induced increase of TNF-α and IL-6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Aβ-induced phosphorylation of tau protein, and preventing GSK-3β activation and neuroinflammation.
Sepsis results from an overwhelming response to infection and is a major contributor to death in ... more Sepsis results from an overwhelming response to infection and is a major contributor to death in intensive care units worldwide. In recent years, we and others have shown that neutrophil functionality is impaired in sepsis. This correlates with sepsis severity and contributes to aggravation of sepsis by precluding bacterial clearance. Nitric oxide (NO) is a major contributor to the impairment of neutrophil function in sepsis. However, attempts to inhibit NO synthesis in sepsis resulted in increased death despite restoring neutrophil migration. This could be in part attributed to a reduction of the NO-dependent microbicidal activity of neutrophils. In sepsis, the beneficial effects resulting from the inhibition of soluble guanylyl cyclase (sGC), a downstream target of NO, have long been appreciated but poorly understood. However, the effects of sGC inhibition on neutrophil function in sepsis have never been addressed. In the present study, we show that TLR activation in human neutrophils leads to decreased chemotaxis, which correlated with chemotactic receptor internalization and increased G protein-coupled receptor kinase 2 expression, in a process involving the NO-sGC-protein kinase G axis. We also demonstrate that inhibition of sGC activity increased survival in a murine model of sepsis, which was paralleled by restored neutrophil migratory function and increased bacterial clearance. Finally, the beneficial effect of sGC inhibition could also be demonstrated in mice treated after the onset of sepsis. Our results suggest that the beneficial effects of sGC inhibition in sepsis could be at least in part attributed to a recovery of neutrophil functionality.
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Papers by Andressa Paula